Ideal Cardiovascular Health
Introduction
Section titled “Introduction”Ideal cardiovascular health (CVH) represents an optimal state of cardiovascular well-being, characterized by the absence of major cardiovascular risk factors and the presence of healthy lifestyle behaviors. This state is defined by specific clinical and behavioral metrics that are associated with a significantly reduced risk of cardiovascular disease (CVD) morbidity and mortality.[1] Achieving and maintaining ideal CVH is a crucial public health goal, as it has been linked to greater longevity, lower rates of chronic diseases, improved quality of life, and reduced healthcare costs in older age.[1] Despite its profound benefits, the prevalence of ideal CVH remains low in the general population, highlighting the importance of understanding its underlying determinants.[1]
Biological Basis of Ideal Cardiovascular Health
Section titled “Biological Basis of Ideal Cardiovascular Health”While lifestyle modifications are known to be critical for attaining ideal CVH, genetic factors also play a role in influencing an individual’s predisposition to maintain this healthy state. Research into the genetic architecture of ideal CVH aims to identify specific gene variants associated with its components. Early genome-wide association studies (GWAS) identified a single nucleotide polymorphism (SNP) such asrs445925 in the APOC1/APOE gene region, significantly associated with clinical ideal CV health. This association was largely driven by its influence on lipid levels.[1] Further comprehensive genetic analyses have since expanded this understanding, identifying multiple genetic loci associated with an ideal health score. These loci often include genes previously linked to cardiometabolic diseases and their risk factors, with alleles associated with better ideal CVH typically being the protective variants for these conditions.[2] The heritability of ideal health scores suggests a measurable genetic contribution to maintaining this protective health status.[2]
Clinical Relevance
Section titled “Clinical Relevance”The clinical relevance of ideal CVH is substantial, extending beyond the mere absence of disease to encompass long-term health and well-being. Individuals who achieve or maintain ideal CVH into middle age exhibit markedly lower risks for developing cardiovascular diseases, other chronic conditions, and experience lower mortality rates.[1]Genetically defined ideal CVH has been robustly associated with a reduced likelihood of various adverse cardiovascular outcomes, including coronary artery disease, heart failure, and ischemic stroke.[2]Furthermore, these genetic predispositions are linked to lower odds of developing key cardiovascular risk factors such as hyperlipidemia, hypertension, type 2 diabetes, and obesity.[2]These findings underscore that both modifiable lifestyle factors and underlying genetic influences contribute to a protective health profile that mitigates the risk of future disease.
Public Health Importance
Section titled “Public Health Importance”Understanding the factors that contribute to ideal CVH, including its genetic underpinnings, is a vital public health objective. Given the significant burden of cardiovascular disease globally, identifying mechanisms that allow individuals to achieve and maintain optimal health can inform targeted prevention strategies. Organizations like the American Heart Association have set ambitious goals to improve the cardiovascular health of populations, recognizing the profound impact of ideal CVH on individual and societal well-being.[1] The consistent protective associations observed between genetic factors and ideal CVH across diverse populations provide scientific support for current public health recommendations focused on promoting healthy lifestyles.[2]By elucidating the interplay between genetics, behaviors, and environment, research into ideal CVH contributes to efforts aimed at reducing disease burden and enhancing overall population health.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The initial meta-analysis of genome-wide association studies (GWAS) for ideal cardiovascular health, involving 11,708 participants, faced limitations in statistical power, particularly given the low prevalence of the ideal cardiovascular health phenotype, which ranged from 7.6% to 19.2% across cohorts.[1]This restricted sample size likely limited the ability to detect common genetic variants with small to moderate effects, resulting in the identification of only one genome-wide significant single nucleotide polymorphism (rs445925 ) for clinical ideal cardiovascular health and none for the clinical plus behavioral phenotype.[1]Furthermore, the imputation quality for this identified SNP was low (~0.3), which can diminish confidence in the precise effect size and replicability of the finding.[1] While subsequent larger studies, such as one involving over 142,000 discovery participants and a replication cohort, identified 17 associated loci.[2]the overall genetic architecture of ideal cardiovascular health remains complex. The initial findings highlight the challenge of identifying robust genetic signals for composite, low-prevalence phenotypes without extremely large sample sizes. These statistical constraints imply that numerous other genetic variants contributing to ideal cardiovascular health may still be undiscovered, and the reported effect sizes for initially identified variants might be inflated in smaller studies, necessitating further validation in independent, well-powered cohorts.
Generalizability and Phenotypic Measurement Challenges
Section titled “Generalizability and Phenotypic Measurement Challenges”A significant limitation concerns the generalizability of findings, as the initial meta-analysis was exclusively conducted in cohorts of individuals of Caucasian descent, predominantly aged around 50 years.[1]This demographic specificity means that the identified genetic associations may not be directly applicable to or representative of racial and ethnic minority populations or different age groups, where genetic backgrounds, environmental exposures, and lifestyle factors can vary substantially.[1] Although larger multi-ethnic studies have since included African American and Hispanic participants, they still noted a lack of genome-wide significance in these groups, likely due to insufficient sample sizes compared to European American cohorts, underscoring persistent gaps in diverse population representation.[2]Phenotypic definition and measurement issues also pose challenges to interpreting genetic associations with ideal cardiovascular health. The composite nature of ideal cardiovascular health, comprising several dichotomous factors like ideal cholesterol, blood pressure, BMI, and non-smoking status.[1] means that genetic effects could be driven by a single component rather than a holistic predisposition, as observed when conditioning on LDL levels attenuated the association of rs445925 .[1] Moreover, practical limitations in data collection, such as the inability to confirm fasting status for a substantial portion of participants in some studies.[2]introduce potential measurement error for components like plasma glucose, which could dilute or obscure true genetic signals and impact the accuracy of the ideal health phenotype assessment.
Complexity of Genetic Architecture and Environmental Influences
Section titled “Complexity of Genetic Architecture and Environmental Influences”The current understanding of the genetic architecture of ideal cardiovascular health remains incomplete, with identified variants explaining only a fraction of its heritability. Despite the identification of some genetic loci, the concept of “missing heritability” likely applies, indicating that many genetic determinants, including rare variants or complex gene-gene interactions, are yet to be discovered.[1] This suggests that the observed genetic associations represent only a partial picture, and a more comprehensive understanding requires exploring a broader spectrum of genetic variation and their cumulative effects.
Furthermore, ideal cardiovascular health is profoundly influenced by a complex interplay of genetic predispositions and environmental factors, including lifestyle, diet, and socioeconomic status, which are often not fully captured or adjusted for in genetic studies. While some analyses adjust for basic covariates like age, sex, and ancestry.[1], [2]the intricate gene-environment interactions that shape cardiovascular health are challenging to model comprehensively. The observed genetic associations may therefore be confounded or modified by unmeasured environmental variables, making it difficult to disentangle purely genetic effects from those influenced by broader contextual factors and highlighting the need for future research to integrate detailed environmental and lifestyle data.
Variants
Section titled “Variants”Genetic variants play a significant role in influencing an individual’s predisposition to achieving and maintaining ideal cardiovascular health, impacting both clinical metrics and lifestyle behaviors. These genetic markers often affect fundamental biological pathways, from lipid metabolism to glucose regulation and inflammatory responses. Understanding their associations provides insights into the intricate interplay between genetics and cardiovascular well-being.
The APOE/APOC1 gene cluster, located on chromosome 19, is central to lipid metabolism and transport. APOEprovides instructions for apolipoprotein E, a key component of lipoproteins vital for clearing fats from the bloodstream. Thers7412 variant, a significant marker of the APOEε2 allele, is strongly associated with both Clinical ideal cardiovascular health and Clinical+Behavioral ideal cardiovascular health.[1] Another variant in this critical region, rs1065853 , influences lipid levels and overall cardiovascular risk, contributing to the ability to maintain ideal cholesterol profiles, and this region has broad implications for heart disease, longevity, and metabolic syndrome.[1] The PCSK9gene, encoding proprotein convertase subtilisin/kexin type 9, critically regulates low-density lipoprotein (LDL) receptor levels, with thers11591147 variant being associated with multiple cardiovascular risk factors and outcomes, directly affecting ideal cholesterol levels.[2] Similarly, the LDLRgene, or low-density lipoprotein receptor, is essential for removing LDL cholesterol from the blood, and genetic variations in theSMARCA4 - LDLR region, such as rs114846969 , can affect the efficiency of this receptor, directly impacting an individual’s cholesterol profile and their capacity to achieve ideal cardiovascular health.
Several other variants are implicated in broader metabolic and lifestyle factors crucial for cardiovascular health. TheFTOgene, known as “fat mass and obesity-associated,” is a significant player in energy homeostasis and adipogenesis. Thers1421085 variant in FTOis strongly linked to body mass index (BMI) and obesity, which are critical behavioral components of ideal cardiovascular health, and variants in this gene are associated with obesity-related traits.[1] The TCF7L2gene is a key regulator in glucose metabolism and is strongly associated with type 2 diabetes risk. Variants likers7903146 can influence pancreatic beta-cell function and insulin secretion, directly impacting blood glucose levels, a core clinical component of ideal cardiovascular health, and were associated with multiple cardiovascular risk factors and outcomes.[2] Moreover, the CELSR2 gene, located in a region often associated with PSRC1 and SORT1, has variants, including rs12740374 , that influence lipid metabolism, particularly LDL cholesterol levels, significantly determining ideal cholesterol, a key clinical metric for cardiovascular health.[2]Beyond core metabolic regulators, other genetic factors contribute to ideal cardiovascular health through diverse mechanisms. TheABCG8 gene, part of a cluster involved in sterol transport, encodes a protein critical for cholesterol excretion. Variations like rs6544717 can affect cholesterol absorption and efflux, influencing ideal cholesterol levels.[1] Furthermore, ABCG8is associated with smoking initiation, highlighting its relevance to behavioral ideal cardiovascular health.[2] The NFAT5 gene, also known as TONEBP, plays a role in osmoregulation and immune responses. While its direct link to ideal cardiovascular health is complex, its influence on cellular stress responses and inflammation could indirectly affect blood pressure regulation and overall vascular health, contributing to maintaining ideal clinical parameters. ThePLCG1-AS1 gene is an antisense RNA, suggesting a regulatory role over the PLCG1 gene, which is involved in intracellular signaling. Although rs6029552 ’s specific mechanism in cardiovascular health is still being elucidated, such regulatory elements can subtly influence processes like endothelial function, inflammation, and cellular growth, which are all underlying factors for achieving and maintaining ideal cardiovascular health.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs1421085 | FTO | body mass index obesity energy intake pulse pressure measurement lean body mass |
| rs7903146 | TCF7L2 | insulin measurement clinical laboratory measurement, glucose measurement body mass index type 2 diabetes mellitus type 2 diabetes mellitus, metabolic syndrome |
| rs1065853 | APOE - APOC1 | low density lipoprotein cholesterol measurement total cholesterol measurement free cholesterol measurement, low density lipoprotein cholesterol measurement protein measurement mitochondrial DNA measurement |
| rs114846969 | SMARCA4 - LDLR | lipoprotein-associated phospholipase A(2) measurement depressive symptom measurement, low density lipoprotein cholesterol measurement social deprivation, low density lipoprotein cholesterol measurement low density lipoprotein cholesterol measurement, physical activity Sphingomyelin (d18:1/20:0, d16:1/22:0) measurement |
| rs11591147 | PCSK9 | low density lipoprotein cholesterol measurement coronary artery disease osteoarthritis, knee response to statin, LDL cholesterol change measurement low density lipoprotein cholesterol measurement, alcohol consumption quality |
| rs244417 | NFAT5 | clinical and behavioural ideal cardiovascular health |
| rs12740374 | CELSR2 | low density lipoprotein cholesterol measurement lipoprotein-associated phospholipase A(2) measurement coronary artery disease body height total cholesterol measurement |
| rs7412 | APOE | low density lipoprotein cholesterol measurement clinical and behavioural ideal cardiovascular health total cholesterol measurement reticulocyte count lipid measurement |
| rs6544717 | ABCG8 | clinical and behavioural ideal cardiovascular health |
| rs6029552 | PLCG1-AS1 | total cholesterol measurement non-high density lipoprotein cholesterol measurement clinical and behavioural ideal cardiovascular health |
Conceptualization and Core Definitions
Section titled “Conceptualization and Core Definitions”Ideal cardiovascular health (ICH) represents a state characterized by optimal levels across multiple cardiovascular risk factors, serving as a robust indicator for a significantly reduced risk of cardiovascular disease (CVD) morbidity and mortality.[1] Historically, research often focused on individual risk factors, but there has been an evolving emphasis on defining and studying a holistic healthy phenotype comprising several well-defined health factors.[1] This conceptual framework is primarily rooted in the American Heart Association (AHA) 2020 goals and further elaborated by the AHA’s Life’s Simple 7 (LS7) factors.[1]The presence of multiple ideal cardiovascular health factors is strongly associated with lower all-cause mortality, reduced CVD mortality, and increased longevity.[2]
Operational Definitions and Measurement Criteria
Section titled “Operational Definitions and Measurement Criteria”The operational definition of ideal cardiovascular health involves precise diagnostic and measurement criteria for its constituent factors. For instance, “Clinical ideal CV health” is defined by the simultaneous presence of untreated serum cholesterol levels below 200 mg/dl (<5.16 mmol/l), untreated blood pressure under 120/80 mm Hg, and the absence of diabetes, indicated by fasting glucose below 126 mg/dL or casual glucose below 201 mg/dL without anti-diabetic medication use.[1]The more comprehensive “Clinical+Behavioral ideal CV health” extends these criteria to include not being a current smoker and maintaining a body mass index (BMI) below 25 kg/m2.[1]Measurement approaches involve self-reported data for lifestyle factors such as smoking and medication use, while physical examinations are conducted by trained personnel to determine height, weight, and calculate BMI.[1]Clinical components are often derived from electronic health records, with adaptations such as the potential use of non-fasting plasma glucose values when fasting status cannot be confirmed.[2]
Classification Systems and Terminology
Section titled “Classification Systems and Terminology”The classification of ideal cardiovascular health employs both categorical and dimensional approaches to assess an individual’s status. Initially, dichotomous phenotypes such as “Clinical ideal CV health” and “Clinical+Behavioral ideal CV health” categorize individuals based on meeting specific thresholds for a set of defined health factors.[1] Building upon the LS7 framework, individual components are further classified into three severity gradations: poor (0 points), intermediate (1 point), and ideal (2 points).[2]These component scores are then aggregated to calculate an “Ideal Health Score (IHS),” which typically ranges from 0 to 12, reflecting a more dimensional assessment of overall cardiovascular health.[2] A “Binary Ideal Health (BIH)” variable is derived from the IHS, often defined as achieving an overall score of 9 or greater, providing a simplified categorical representation of high ideal health status.[2] Separate clinical and behavioral IHS scores, each ranging from 0 to 6, allow for a more nuanced evaluation of an individual’s health profile.[2]
Genetic Predisposition to Ideal Cardiovascular Health
Section titled “Genetic Predisposition to Ideal Cardiovascular Health”Genetic factors play a significant role in an individual’s propensity for achieving and maintaining ideal cardiovascular health. Genome-wide association studies (GWAS) have identified specific genetic variants associated with this trait. For instance, a single nucleotide polymorphism (SNP)rs445925 located in the APOC1/APOEregion on chromosome 19 has been significantly associated with clinical ideal cardiovascular health.[1]This association appears to be largely driven by the SNP’s impact on lipid levels, particularly lower LDL. A beneficial genetic background, such as one predisposing to lower LDL and potentially lower triglycerides, can significantly contribute to maintaining ideal cardiovascular health, as low lipid levels may reduce the likelihood of developing other risk factors like hypertension and diabetes.[1]Beyond single variants, the cumulative effect of multiple genetic factors, often termed polygenic risk, contributes to ideal cardiovascular health. Alleles found to be associated with better ideal cardiovascular health are typically protective alleles for various cardiovascular diseases and their related risk factors, supporting the broad role of genetic variation in these pathways.[2]Genetic determinants of ideal cardiovascular health can be linked to one or more of the individual health factors that collectively define the phenotype, such as ideal cholesterol, blood pressure, or a non-diabetic state.[1]A Polygenic Risk Score for Ideal Cardiovascular Health (PRSIHS) has been shown to be associated with lower odds of a wide spectrum of cardiovascular outcomes and cardiometabolic diseases, further underscoring the importance of inherited genetic predispositions.[2]
Lifestyle and Behavioral Determinants
Section titled “Lifestyle and Behavioral Determinants”Lifestyle and behavioral choices are crucial modifiable factors in attaining and sustaining ideal cardiovascular health. The definition of ideal cardiovascular health explicitly incorporates behavioral metrics, such as not being a current smoker and maintaining a Body Mass Index (BMI) below 25 kg/m².[1] These behavioral components, alongside clinical factors like untreated cholesterol levels below 200 mg/dl, untreated blood pressure below 120/80 mmHg, and absence of diabetes, are fundamental to the ideal state.[1]Ideal levels of these risk factors are largely achievable through consistent lifestyle modifications.
Specific behaviors, including physical activity levels and patterns of tobacco and alcohol use, have been recognized as key determinants. Studies have investigated genetic interactions related to physical activity and adiposity, as well as genetic etiologies of tobacco and alcohol use, highlighting the profound impact of these daily choices on cardiovascular well-being.[2]The consistent adherence to healthy lifestyle practices, such as maintaining an ideal BMI and refraining from smoking, directly contributes to both the behavioral and clinical components of ideal cardiovascular health.
Interplay of Genes and Environment
Section titled “Interplay of Genes and Environment”The achievement of ideal cardiovascular health is not solely dictated by genetics or environment but rather emerges from their complex interplay. Genetic predispositions can interact with environmental and behavioral factors, influencing an individual’s likelihood of reaching or maintaining ideal health metrics. For example, while lifestyle modifications are acknowledged as having a significant impact, genetic backgrounds that predispose individuals to lower LDL cholesterol levels can make it easier for them to achieve and maintain ideal cardiovascular health, even with similar lifestyle efforts.[1] This suggests that certain individuals may have a “beneficial genetic background” that enhances the effectiveness of healthy behaviors.
Understanding how genetic, behavioral, and environmental factors combine is vital for identifying precise strategies to modify risk factors and potentially develop new therapeutic targets. Studies have explored gene-environment interactions in areas such as adiposity and the genetic etiology of tobacco and alcohol use, demonstrating how an individual’s genetic makeup can influence their susceptibility to environmental triggers or their response to lifestyle interventions.[2]This interaction means that while lifestyle factors play an important role, their ultimate effect on ideal cardiovascular health can be modulated by an individual’s unique genetic profile.
Age and Comorbidity Influences
Section titled “Age and Comorbidity Influences”Age is an important demographic factor influencing the prevalence of ideal cardiovascular health, which is a relatively low prevalence phenotype, particularly as individuals age. Research on ideal cardiovascular health has often focused on middle-aged participants, such as those aged 50 ± 5 years, where the prevalence of ideal health metrics can vary across cohorts.[1]The decline in the likelihood of maintaining ideal health with advancing age suggests that age-related physiological changes contribute to the challenges of sustaining optimal cardiovascular parameters.
The presence or absence of comorbidities significantly impacts an individual’s status regarding ideal cardiovascular health. Ideal clinical cardiovascular health is defined by the absence of diabetes and having untreated cholesterol and blood pressure levels within ideal ranges, implying that existing conditions requiring medication to control these factors would preclude an individual from meeting the ideal criteria.[1]Furthermore, genetically defined ideal cardiovascular health has been associated with a lower risk of a broad spectrum of cardiovascular diseases and related cardiometabolic conditions, including congestive heart failure, peripheral vascular disease, cerebrovascular disease, atrial fibrillation, hyperlipidemia, hypercholesterolemia, type 2 diabetes, and hypertension.[2]The absence of these comorbidities, therefore, is a direct contributor to the attainment of ideal cardiovascular health.
Biological Background of Ideal Cardiovascular Health
Section titled “Biological Background of Ideal Cardiovascular Health”Ideal cardiovascular health represents a state where major cardiovascular risk factors are maintained at optimal levels, significantly reducing the risk of cardiovascular disease (CVD) morbidity and mortality.[1] This optimal state is influenced by a complex interplay of genetic, molecular, cellular, and environmental factors, reflecting robust homeostatic mechanisms and the absence of significant pathophysiological disruptions.[1], [2]Understanding the biological underpinnings of ideal cardiovascular health can inform strategies to enhance prevention and promote long-term well-being.
Genetic Regulation of Metabolic Health
Section titled “Genetic Regulation of Metabolic Health”The maintenance of ideal cardiovascular health is partly influenced by an individual’s genetic makeup, particularly genes involved in metabolic regulation. A notable example is a single nucleotide polymorphism (rs445925 ) located in the APOC1/APOEregion, which has been associated with ideal clinical cardiovascular health.[1], [2] The APOEgene encodes apolipoprotein E, a critical protein involved in the metabolism and transport of lipids, including cholesterol and triglycerides, by binding to lipid particles and receptors to facilitate cellular uptake.[1] Similarly, the APOC1gene codes for apolipoprotein C-I, which also plays a role in lipid metabolism, primarily by inhibiting the uptake of triglyceride-rich lipoproteins by the liver.[1] Variations in this genetic region can significantly impact lipid levels, with rs445925 specifically linked to protective cholesterol levels and lower cardiovascular risk, as well as influencing long-term LDL cholesterol levels.[1]The association of this SNP with ideal cardiovascular health is largely driven by its effect on LDL cholesterol, highlighting the direct link between genetic predispositions in lipid metabolism and the achievement of ideal health metrics.[1]Furthermore, genetic variants associated with ideal cardiovascular health often correspond to protective alleles for a broad spectrum of cardiometabolic diseases and their risk factors, underscoring the role of favorable genetic backgrounds in maintaining optimal health.[2]
Molecular Pathways and Homeostatic Control
Section titled “Molecular Pathways and Homeostatic Control”Achieving ideal cardiovascular health relies on the precise functioning of various molecular and cellular pathways that maintain critical physiological parameters. Central to this is lipid metabolism, where complex signaling pathways regulate the synthesis, transport, and catabolism of cholesterol and triglycerides. Maintaining untreated serum cholesterol levels below 200 mg/dl, particularly low LDL cholesterol, reflects efficient hepatic processing and cellular uptake of lipids, preventing their accumulation in arterial walls.[1]Similarly, glucose homeostasis is crucial, involving intricate insulin signaling pathways that control blood glucose uptake by cells and regulate glucose production by the liver, ensuring fasting glucose levels remain below 126 mg/dL without medication.[1]Beyond lipids and glucose, the regulation of blood pressure involves sophisticated molecular networks controlling vascular tone, fluid balance, and cardiac output. Ideal blood pressure (below 120/80 mm Hg) indicates a healthy endothelium, balanced renin-angiotensin-aldosterone system activity, and appropriate kidney function.[1]The absence of current smoking and a body mass index (BMI) below 25 kg/m2 further contribute to this ideal state by minimizing inflammatory and oxidative stress pathways and optimizing energy metabolism, respectively.[1]These coordinated molecular and cellular functions prevent the systemic disruptions that lead to cardiovascular disease.
Integrated Organ Function and Systemic Well-being
Section titled “Integrated Organ Function and Systemic Well-being”Ideal cardiovascular health is a reflection of the harmonious functioning and interaction of multiple tissues and organs throughout the body. The cardiovascular system itself, comprising the heart and blood vessels, operates optimally with ideal blood pressure, indicating healthy arterial elasticity and efficient cardiac pumping without undue strain.[1]The liver plays a central role in maintaining ideal cholesterol levels, processing fats and regulating lipoprotein synthesis and clearance.[1]The pancreas is critical for glucose homeostasis, with its beta cells producing adequate insulin to regulate blood sugar, preventing the onset of diabetes.[1]Furthermore, adipose tissue, when maintained at an ideal BMI, contributes to systemic metabolic health by avoiding chronic low-grade inflammation and insulin resistance associated with obesity.[1]The kidneys are vital for blood pressure regulation and fluid balance, while the brain influences behavioral factors like smoking and physical activity, which in turn impact cardiovascular health.[1]This integrated optimal function across metabolic, endocrine, and circulatory systems results in profound systemic consequences, including markedly lower risks for cardiovascular diseases, other chronic conditions, and overall mortality, leading to an improved quality of life.[1], [2]
Preventing Pathophysiological States
Section titled “Preventing Pathophysiological States”The state of ideal cardiovascular health signifies a successful prevention of the pathophysiological processes that lead to disease development. Rather than reacting to disease mechanisms, ideal health is characterized by the absence of homeostatic disruptions that typically precede clinical conditions. This includes effective mechanisms that prevent the development of atherosclerosis, a disease characterized by plaque buildup in arteries, by maintaining healthy lipid profiles and low inflammation.[1]Similarly, the avoidance of chronic hyperglycemia and insulin resistance prevents the cellular damage and vascular complications associated with diabetes.[1]In individuals with ideal cardiovascular health, the body’s intrinsic regulatory networks are robust enough to maintain physiological balance, minimizing the need for compensatory responses that often become pathological over time. For instance, sustained ideal blood pressure prevents the chronic stress on the vascular endothelium that can lead to hypertension-related organ damage.[1] The absence of behavioral risk factors like smoking further reduces oxidative stress and inflammation, protecting cellular integrity and function.[1]This proactive prevention of disease mechanisms and maintenance of stable homeostasis contributes to a significantly reduced lifetime risk for cardiovascular disease.[1], [2]
Genetic and Metabolic Regulation of Lipid Homeostasis
Section titled “Genetic and Metabolic Regulation of Lipid Homeostasis”Ideal cardiovascular health is significantly influenced by the precise regulation of lipid metabolism, a complex interplay of metabolic pathways and genetic determinants. A key genetic locus influencing this is theAPOC1/APOEregion, where a common single nucleotide polymorphism (SNP)rs445925 has been consistently associated with clinical ideal cardiovascular health, primarily driven by its impact on cholesterol levels.[1] The APOEgene encodes apolipoprotein E, a crucial component of very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and chylomicrons, playing a vital role in the catabolism and transport of triglycerides and cholesterol.[1] Variations in this region, such as rs445925 , can alter APOE’s binding affinity to lipoprotein receptors, thereby influencing the clearance of lipid particles from the bloodstream and ultimately impacting circulating LDL cholesterol levels, which are a critical metric for ideal cardiovascular health.[1] This genetic influence extends to the intricate metabolic pathways that govern energy metabolism and biosynthesis. The APOEvariants affect the flux of lipids through the metabolic cascade, from hepatic synthesis to peripheral tissue uptake and reverse cholesterol transport. The protective alleles associated with ideal cardiovascular health have been linked to lower long-term LDL levels and reduced risk of coronary heart disease, indicating a favorable regulation of lipid processing and reduced accumulation of atherogenic particles.[1]This highlights how specific genetic predispositions regulate fundamental metabolic processes, contributing to the maintenance of ideal cholesterol levels, a core component of cardiovascular well-being.
Integrated Pathways for Vascular and Glucose Control
Section titled “Integrated Pathways for Vascular and Glucose Control”Beyond lipid metabolism, ideal cardiovascular health necessitates the robust and coordinated regulation of vascular function and glucose homeostasis, which involves intricate signaling pathways and metabolic regulation. While specific genetic loci for ideal blood pressure and glucose are not as detailed as those for lipids in some studies, the overall ideal cardiovascular health phenotype encompasses ideal untreated blood pressure and non-diabetic status.[1]Maintaining ideal blood pressure involves complex signaling cascades within endothelial cells and vascular smooth muscle, regulating vasoconstriction and vasodilation through receptor activation and intracellular second messenger systems. These pathways are under hierarchical regulation, with systemic factors like the renin-angiotensin-aldosterone system interacting with local endothelial nitric oxide signaling to maintain vascular tone.
Similarly, ideal blood glucose levels reflect efficient metabolic regulation, where insulin signaling pathways are highly functional, promoting glucose uptake and utilization in tissues, and suppressing hepatic glucose production. This involves precise flux control within metabolic pathways like glycolysis and gluconeogenesis, as well as the biosynthesis and catabolism of glycogen. Pathway crosstalk between insulin signaling and inflammatory pathways is critical, as chronic low-grade inflammation can impair insulin sensitivity. The emergent property of ideal cardiovascular health arises from the successful integration and harmonious functioning of these diverse systems, where genetic predispositions and regulatory mechanisms collectively ensure stable blood pressure and glucose metabolism, protecting against dysregulation that leads to hypertension and type 2 diabetes.
Systems-Level Integration of Cardiometabolic Networks
Section titled “Systems-Level Integration of Cardiometabolic Networks”Ideal cardiovascular health represents a complex emergent property arising from the systems-level integration of multiple physiological and behavioral factors, rather than isolated pathway functions. This involves extensive pathway crosstalk and network interactions among genetic, clinical, and behavioral determinants. For instance, a polygenic risk score for ideal cardiovascular health (PRSIHS) has been shown to be associated with lower odds of a broad spectrum of cardiovascular outcomes and related cardiometabolic diseases, including heart failure, peripheral vascular disease, cerebrovascular disease, and atrial fibrillation.[2]This indicates that a favorable genetic architecture influences interconnected networks that collectively maintain cardiovascular integrity.
Furthermore, the PRSIHS is associated with lower odds of multiple cardiovascular risk factors, such as hyperlipidemia, hypercholesterolemia, type 2 diabetes, and hypertension.[2]This demonstrates a hierarchical regulation where genetic influences on individual components converge to create a protective network against a range of cardiometabolic dysregulations. The consistency of protective genetic associations across various health factors underscores the interconnectedness of these pathways, suggesting that beneficial genetic variations may exert pleiotropic effects or act synergistically across different systems to promote overall cardiovascular well-being.
Behavioral Modulators and Disease Protection
Section titled “Behavioral Modulators and Disease Protection”The achievement and maintenance of ideal cardiovascular health are profoundly influenced by behavioral factors, which act as crucial modulators of underlying genetic and molecular pathways, offering significant protection against disease. Ideal cardiovascular health includes factors such as body mass index (BMI), smoking status, diet quality, and physical activity.[2]While genetic predispositions may influence the propensity for certain risk factors, lifestyle modifications can significantly alter the trajectory of these pathways. For example, maintaining an ideal BMI through diet and physical activity can mitigate genetic risks for obesity and related cardiometabolic disorders.[3]Behavioral interventions can directly impact metabolic pathways, influencing energy balance, glucose metabolism, and lipid profiles, often through mechanisms like allosteric control of enzymes or gene regulation via epigenetic modifications. For instance, cessation of smoking can reverse pathway dysregulation associated with nicotine dependence and improve vascular health.[4]The presence of multiple ideal cardiovascular health factors is strongly associated with lower all-cause mortality, lower cardiovascular disease mortality, and greater longevity, highlighting how concerted behavioral efforts, alongside favorable genetic backgrounds, provide robust disease-relevant mechanisms for protection against cardiovascular events.[5]
Prevalence and Epidemiological Landscape of Ideal Cardiovascular Health
Section titled “Prevalence and Epidemiological Landscape of Ideal Cardiovascular Health”Ideal cardiovascular health, defined by specific clinical and behavioral metrics established by the American Heart Association (AHA), is a critical indicator of long-term health and a predictor of reduced cardiovascular disease (CVD) morbidity and mortality. Population studies reveal that the prevalence of achieving ideal cardiovascular health remains low across diverse groups. A meta-analysis of four genome-wide association studies (GWAS) involving 11,708 white participants aged 50 ± 5 years from the CHARGE consortium cohorts reported a prevalence of 19.2% for clinical ideal cardiovascular health (untreated cholesterol < 200 mg/dl, untreated blood pressure <120/<80 mm Hg, and not diabetic), with a range from 10% to 29% across cohorts.[1]When behavioral factors (not being a current smoker and BMI < 25 kg/m2) were added to define clinical and behavioral ideal cardiovascular health, the prevalence dropped significantly to 7.6%, ranging from 5% to 13% among these cohorts.[1]These findings highlight the considerable challenge in achieving and maintaining comprehensive ideal cardiovascular health across the middle-aged population.
Further large-scale epidemiological investigations, such as the VA Million Veteran Program (MVP), underscore the limited attainment of ideal cardiovascular health, with only 4.2% of its discovery GWAS cohort (n=142,404) achieving combined clinical and behavioral ideal cardiovascular health. This study, which included a mean age of 65.8 years and was predominantly male (92.7%), also revealed specific areas of concern within the population. While plasma glucose was the factor for which the greatest proportion of participants achieved ideal levels (37.8%), a significant majority (74%) were categorized as having poor physical activity levels.[2]Such prevalence patterns suggest that while some clinical factors might be better managed, behavioral components like physical activity remain significant public health challenges impacting overall cardiovascular well-being.
Insights from Large-Scale Cohort and Biobank Studies
Section titled “Insights from Large-Scale Cohort and Biobank Studies”Large-scale cohort studies and biobank initiatives have been instrumental in unraveling the genetic and epidemiological underpinnings of ideal cardiovascular health, employing robust methodologies to assess population-level associations. The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) consortium, for instance, conducted a meta-analysis of four GWAS including the Multi-Ethnic Study of Atherosclerosis (MESA), Coronary Artery Risk in Young Adults (CARDIA) Study, Framingham Heart Study (FHS) Original and Offspring Cohorts, and Atherosclerosis Risk in Communities (ARIC) Study.[1] This meta-analysis of 11,708 white participants identified a significant association of rs445925 in the APOC1/APOEregion with clinical ideal cardiovascular health, indicating a genetic component influencing the combined presence of healthy cholesterol, blood pressure, and non-diabetic status.[1] The study utilized logistic regression analyses adjusted for demographic factors and genetic principal components, demonstrating the power of meta-analysis to detect genetic variants associated with complex health phenotypes.
More recently, the VA Million Veteran Program (MVP) conducted a genome-wide and phenome-wide analysis on an even larger and more diverse cohort, comprising 142,404 participants in the discovery GWAS and 45,766 in the replication cohort.[2] This study calculated an Ideal Health Score (IHS) based on three clinical and three behavioral factors and performed a multi-population GWAS, identifying variants at 17 loci associated with IHS.[2]Furthermore, the MVP utilized Mendelian Randomization to establish a protective causal association of ideal cardiovascular health with lower odds of coronary artery disease (CAD), ischemic stroke (IS), and heart failure (HF).[2]A phenome-wide association study (PheWAS) in 456,026 participants revealed that an increased polygenic risk score for IHS was associated with a lower odds ratio for numerous clinically apparent CVDs, including ischemic heart disease and atherosclerosis, and with lower risk of all-cause, CAD, CVD, and atherosclerotic CVD mortality in Cox regression survival analysis.[2]These findings underscore the profound and protective long-term implications of achieving ideal cardiovascular health across a lifespan.
Cross-Population Variability and Genetic Architecture
Section titled “Cross-Population Variability and Genetic Architecture”Population studies reveal significant cross-population variability in the attainment of ideal cardiovascular health and its underlying genetic architecture, highlighting the importance of diverse cohorts in genetic research. The VA Million Veteran Program (MVP) stands out as the largest study to date to investigate the genetic basis of ideal cardiovascular health, specifically incorporating a substantial number of participants from populations typically underrepresented in genetic research, including individuals of African American (AFR) and Hispanic (HIS) descent, alongside European American (EUR) participants.[2] The discovery GWAS cohort in MVP included 83.7% EUR, 11.6% AFR, and 4.7% HIS individuals, demonstrating a commitment to broader representativeness.[2]Differences in ideal cardiovascular health prevalence were also observed across demographic groups within the MVP, with a greater proportion of women achieving ideal cardiovascular health compared to men, and Hispanic women notably showing the highest proportion of individuals in the ideal cardiovascular health category (14.6%).[2] While the heritability of the Ideal Health Score (IHS) was estimated at 0.125 for EUR participants, the proportion of variance explained by the polygenic risk score for IHS was 0.6% for AFR and 0.8% for HIS, suggesting potential differences in the genetic contribution or the need for more population-specific genetic studies.[2] The multi-population meta-analysis in MVP successfully identified 17 loci associated with IHS, with PheWAS analyses showing protective associations for various CVD outcomes across these diverse populations, although some specific phecodes and their associations varied by ancestry.[2]These findings emphasize the necessity of including diverse populations to capture a comprehensive understanding of the genetic and epidemiological factors influencing ideal cardiovascular health and to ensure the generalizability of prevention strategies.
Frequently Asked Questions About Clinical And Behavioural Ideal Cardiovascular Health
Section titled “Frequently Asked Questions About Clinical And Behavioural Ideal Cardiovascular Health”These questions address the most important and specific aspects of clinical and behavioural ideal cardiovascular health based on current genetic research.
1. Why is it easier for some people to stay heart-healthy than me?
Section titled “1. Why is it easier for some people to stay heart-healthy than me?”Yes, some people naturally have a genetic predisposition to maintain ideal cardiovascular health. Research shows a measurable genetic contribution to achieving and maintaining this healthy state, meaning your genes can make it easier or harder to stay healthy. These genetic factors influence your body’s ability to keep key health metrics in an optimal range.
2. My family has heart issues; will I definitely get them too?
Section titled “2. My family has heart issues; will I definitely get them too?”While a family history of heart issues suggests a genetic predisposition, it doesn’t mean you’re destined for them. Your lifestyle choices, like diet and exercise, play a critical role. Both your underlying genetic influences and modifiable behaviors work together to shape your cardiovascular health, giving you power to mitigate risks.
3. Could a DNA test tell me my personal heart disease risk?
Section titled “3. Could a DNA test tell me my personal heart disease risk?”Yes, a DNA test can identify specific genetic markers associated with ideal cardiovascular health or an increased likelihood of adverse outcomes like heart disease. For example, variants in theAPOC1/APOE gene region are linked to lipid levels, a key component of heart health. However, these tests show predispositions, not certainties, and the full genetic picture is still complex.
4. Can I really prevent heart problems even if they run in my family?
Section titled “4. Can I really prevent heart problems even if they run in my family?”Absolutely, you can significantly reduce your risk! Even with a genetic predisposition to heart problems, modifiable lifestyle factors are extremely powerful. A protective health profile emerges from the combination of your genetic influences and healthy behaviors, actively mitigating future disease risk. Consistency in healthy habits is key.
5. Does my ethnic background change my heart health chances?
Section titled “5. Does my ethnic background change my heart health chances?”Yes, your ethnic background can influence the genetic factors relevant to your heart health. Initial studies on ideal cardiovascular health were mainly in people of Caucasian descent, and identified genetic associations may not fully apply to other groups. Larger studies have shown that more research is needed to understand genetic influences across diverse populations, like African American and Hispanic individuals, due to differences in genetic backgrounds and environmental exposures.
6. Why does eating healthy not always lower my cholesterol levels?
Section titled “6. Why does eating healthy not always lower my cholesterol levels?”Sometimes, your genes can influence how your body processes lipids, regardless of a healthy diet. For instance, a specific genetic variant,rs445925 , located in the APOC1/APOE gene region, is known to significantly affect lipid levels. This means that for some people, genetic factors can make it harder to achieve ideal cholesterol, even with diligent healthy eating.
7. Is focusing on just one health factor enough for my heart’s well-being?
Section titled “7. Is focusing on just one health factor enough for my heart’s well-being?”No, ideal cardiovascular health is a composite state involving several factors, not just one. It includes healthy cholesterol, blood pressure, BMI, and non-smoking status, among others. While genetics might influence a single component, a holistic approach to all these factors is crucial for overall well-being and reducing your long-term disease risk.
8. Why do some people just naturally have better heart numbers?
Section titled “8. Why do some people just naturally have better heart numbers?”Some individuals are indeed born with a genetic predisposition that makes it easier for them to maintain ideal cardiovascular health. There’s a measurable genetic contribution to these protective health statuses. These genetic factors can give some people a natural advantage in keeping their heart numbers in a healthy range, even without extraordinary effort.
9. Why do some people get high blood pressure even when they eat well?
Section titled “9. Why do some people get high blood pressure even when they eat well?”Even with a healthy diet and regular exercise, some people have a genetic predisposition to developing conditions like high blood pressure. Genetic research has identified multiple loci associated with an increased likelihood of developing key cardiovascular risk factors, including hypertension. This means that while lifestyle is crucial, underlying genetic influences can still play a role in your blood pressure regulation.
10. If my genes matter, why do doctors emphasize lifestyle changes so much?
Section titled “10. If my genes matter, why do doctors emphasize lifestyle changes so much?”Doctors emphasize lifestyle changes because they are powerful, modifiable factors that you can control. While genetics do influence your predisposition to heart health, lifestyle choices like diet and exercise directly contribute to a protective health profile. The goal is to maximize the benefits of healthy behaviors to mitigate any genetic risks and promote overall well-being.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Allen, N. B., et al. “Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies.”Am Heart J. 2016. PMID: 27179730.
[2] Huang, R. D. L., et al. “Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.”PLoS One, vol. 17, no. 5, 2022, e0267900.
[3] Graff, M, et al. “Genome-wide physical activity interactions in adiposity—A meta-analysis of 200,452 adults.”PLoS Genet, vol. 13, no. 4, 2017, p. e1006528.
[4] Bierut, LJ, et al. “Novel genes identified in a high-density genome wide association study for nicotine dependence.” Hum Mol Genet, vol. 16, no. 19, 2007, pp. 24–36.
[5] Guo, L, Zhang, S. “Association between ideal cardiovascular health metrics and risk of cardiovascular events or mortality: A meta-analysis of prospective studies.”Clin Cardiol, vol. 40, no. 12, 2017, pp. 1339–46.