Heart disease remains a leading cause of mortality worldwide, with both genetic and environmental factors playing pivotal roles in its development. Understanding the genetic components and predispositions of cardiovascular diseases have become increasingly important in recent years, offering insights into individual risk profiles and potential preventive strategies. This article describes in details the role of genetic testing for cardiovascular diseases, exploring inherited heart conditions, the role of genes in hypertension, and possible DNA testing for cardiovascular risks.
Introduction
Cardiovascular diseases (CVDs) encompass a range of disorders affecting the heart and blood vessels, including coronary artery disease, heart failure, arrhythmias, heart valve disease and hypertension. Traditionally, factors such as poor diet, lack of exercise and smoking have been recognised as major contributors to heart disease. However, genetic predisposition also plays a crucial role, influencing an individual’s susceptibility to these conditions.
With advancements in genomic medicine, there is a growing emphasis on understanding how genetic variations contribute to heart disease and possible complications. This knowledge not only aids in identifying individuals at higher risk but also paves the way for personalized prevention and treatment strategies.
Inherited Heart Conditions
Certain heart conditions are directly linked to genetic mutations passed down through families. These inherited heart conditions can manifest at any age and may lead to severe health outcomes if not identified and managed appropriately.
Familial Hypercholesterolemia (FH)
Familial hypercholesterolaemia (FH) is a common inherited condition caused by a genetic mutation that affects the way your liver processes cholesterol. This mutation reduces your liver’s ability to remove excess low-density lipoprotein (LDL) cholesterol — often referred to as ‘bad’ cholesterol — from your bloodstream. As a result, LDL cholesterol can build up to dangerously high levels, significantly increasing your risk of developing heart and circulatory diseases at an early age if left untreated.
FH is one of the most prevalent inherited conditions, affecting approximately 1 in 250 people. In the UK alone, it’s estimated that around 270,000 individuals have FH, although many remain undiagnosed and unaware of their condition. Early detection and treatment are crucial to reducing the long-term health risks associated with high cholesterol.
Because FH is inherited in an autosomal dominant pattern, there is a 50% (1 in 2) chance of passing it on to your children if you have the condition. Similarly, if one of your parents has FH, there is a 50% chance that you may have inherited it. Identifying FH early through genetic testing and family screening can help prevent the development of serious heart-related complications.
(https://www.bhf.org.uk/informationsupport/conditions/familial-hypercholesterolaemia)
Genetic Basis of Familial Hypercholesterolemia
FH is primarily an autosomal dominant disorder caused by mutations in genes integral to LDL-C metabolism. FH is primarily caused by mutations in specific genes responsible for regulating cholesterol levels, including APOB, LDL-R, and PCSK9. These mutations are inherited in an autosomal dominant pattern, meaning that a person only needs to inherit one faulty copy of the gene from either parent to develop the condition. However, in rare cases where FH is caused by a mutation in the LDL-RAP1 gene (low-density lipoprotein receptor adapter protein 1), the condition follows an autosomal recessive inheritance pattern, requiring two faulty copies of the gene (one from each parent) for the condition to manifest.
FH can also be classified based on genotype, resulting in either the heterozygous or homozygous form of the condition. Individuals with heterozygous FH (inheriting one faulty gene) typically exhibit elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, generally ranging between 8 to 15 mmol/L. In contrast, individuals with homozygous FH (inheriting two faulty copies of the gene) experience significantly higher LDL-C concentrations, often between 12 to 30 mmol/L, leading to a more severe and early-onset form of the disease. Early detection and treatment are critical in both forms to prevent the development of premature cardiovascular disease.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC9692978/)
Genetic testing for Familial Hypercholesterolemia
The first step in finding out whether you have familial hypercholesterolaemia (FH) is to have a cholesterol test. A healthcare professional will also ask about your family’s medical history, specifically whether there have been cases of high cholesterol, heart disease, or early heart attacks among your relatives. This information is important, as FH is an inherited condition that runs in families.
If your cholesterol levels are found to be unusually high, or if your doctor notices any of the physical signs commonly associated with FH, they may refer you to a specialist for further assessment. This assessment is likely to include genetic testing to confirm whether you carry a faulty gene that causes FH. The specialist will also discuss the importance of checking your family members for FH, as early diagnosis is crucial in preventing heart-related complications.
Genetic testing is a straightforward procedure designed to identify changes in your DNA that may cause inherited conditions like FH. The test is typically done using either:
- A blood sample, or
- A mouth swab, where a sample is taken from the inside of your cheek.
If you are diagnosed with FH, it’s important that your close family members — including your parents, siblings, and children — are tested as well. Since FH is inherited in an autosomal dominant pattern, there is a 50% (1 in 2) chance that a child of an affected parent will also have the condition. Early identification can ensure they receive treatment to lower their cholesterol and reduce their risk of developing heart disease.
Likewise, if a family member is diagnosed with FH, you should get tested as soon as possible. Early diagnosis and intervention can make a significant difference, allowing you to take steps to manage your cholesterol through medication, lifestyle changes, and ongoing medical care. Detecting FH early helps protect your long-term heart health and prevent serious cardiovascular problems.
(https://www.bhf.org.uk/informationsupport/conditions/familial-hypercholesterolaemia)
Clinical Presentation and Diagnosis
FH is often asymptomatic until cardiovascular complications arise. Clinical indicators include tendon xanthomas, arcus corneae, and a family history of premature coronary artery disease. Diagnostic criteria, such as the Dutch Lipid Clinic Network or Simon Broome criteria, incorporate these clinical features alongside lipid profiles and genetic testing to ascertain the likelihood of FH. Simon Broome criteria are total cholesterol of 7.5 mmol/L or greater and an LDL cholesterol of 4.9 mmol/L or greater with triglyceride levels below 5 mmol/L.
Current Treatment Modalities
The management of FH aims to reduce LDL-C levels to mitigate the risk of cardiovascular events. Treatment strategies encompass a combination of lifestyle modifications, pharmacotherapy, and, in severe cases, invasive procedures:
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Lifestyle Modifications:
- Dietary Changes: Adopting a heart-healthy diet low in saturated fats and cholesterol can aid in lowering LDL-C levels.
- Physical Activity: Regular exercise contributes to improved lipid profiles and overall cardiovascular health.
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Pharmacotherapy:
- Statins: These HMG-CoA reductase inhibitors are the cornerstone of FH treatment, effectively lowering LDL-C levels.
- Ezetimibe: Often used in combination with statins, ezetimibe inhibits intestinal cholesterol absorption, providing an additional reduction in LDL-C levels.
- Bempedoic acid: Relatively new medication, which can be used in patients, who cannot tolerate statins.
- PCSK9 Inhibitors: Monoclonal antibodies such as alirocumab and evolocumab target PCSK9, enhancing LDL receptor recycling and reducing LDL-C levels. These agents are particularly beneficial for patients who do not achieve target LDL-C levels with statins and ezetimibe alone.
Cardiomyopathies
Cardiomyopathies are diseases of the heart muscle that can lead to heart failure and abnormal heart beats (arrhythmias). Dilated cardiomyopathy (DCM) and Hypertrophic cardiomyopathy (HCM) are described below.
Dilated cardiomyopathy (DCM).
Dilated cardiomyopathy (DCM) is a heart disease associated with a dilation and impaired contraction of the left or both ventricles, leading to systolic dysfunction and, often, heart failure. While various factors such as infections, toxins, and metabolic conditions can cause DCM, a proportion of cases have a genetic basis. Understanding the genetic predisposition to DCM is important for early diagnosis, personalised treatment, and familial screening. This pump dysfunction cannot be attributed to other heart conditions such as hypertension, significant valvular disease, or coronary artery disease. DCM is a relatively common condition, affecting an estimated 1 in 250 people in the general population. Despite significant advancements in heart failure management over recent decades, mortality rates associated with DCM remain high, and it remains one of the leading indications for heart transplantation worldwide.
The primary causes of mortality in DCM patients include progressive heart failure (pump failure) and sudden cardiac death (SCD) resulting from life-threatening arrhythmias. However, recent research has revealed that many individuals with DCM exhibit subtle structural cardiac abnormalities and arrhythmogenic phenotypes long before the onset of overt heart failure symptoms. This has presented new diagnostic and management challenges, as these subtle abnormalities may mimic other cardiac conditions, making accurate diagnosis difficult. Additionally, some DCM patients are at a significantly higher risk of developing malignant arrhythmias such as high-grade atrioventricular block, ventricular tachycardia, or ventricular fibrillation, while others demonstrate a poorer response to standard heart failure therapies with limited reverse remodelling of the heart.
Identifying patients at increased risk of arrhythmic events or disease progression is essential for tailoring appropriate treatment strategies, improving clinical outcomes, and reducing mortality. As a result, there is a growing emphasis on early and accurate diagnosis of DCM, coupled with risk stratification to identify individuals who may benefit from advanced therapies such as implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT), or heart transplantation. Developing more refined approaches to predict disease progression and response to therapy is critical in improving long-term survival rates and quality of life in patients with DCM.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC10044994/)
Genetic Predisposition to Dilated Cardiomyopathy
DCM is a highly heterogeneous condition with a wide range of underlying causes, including both genetic and acquired factors. Research shows that a positive family history is present in approximately 30–50% of DCM cases, and a definitive genetic mutation can be identified in around 40% of patients. In familial cases of DCM, the most commonly implicated genetic abnormalities involve sarcomeric proteins, neuromuscular disorders, and mitochondrial dysfunctions. These inherited forms of DCM often follow an autosomal dominant pattern, although some cases may result from autosomal recessive, X-linked, or mitochondrial inheritance.
As already mentioned, in addition to genetic factors, non-genetic causes of DCM are also significant and include a broad range of external triggers such as viral or non-viral infections, autoimmune diseases, toxic exposures (such as alcohol, chemotherapy, or recreational drugs), infiltrative diseases, nutritional deficiencies, and endocrine disorders. Other common contributing factors include pregnancy-associated cardiomyopathy, sustained arrhythmias, diabetes, and myocarditis, all of which can lead to the development or progression of DCM. These acquired conditions may either directly cause DCM or act as disease modifiers, significantly influencing disease progression and clinical outcomes.
Recent research has placed increasing focus on the complex interaction between genetic predisposition and environmental or acquired triggers, as it has become clear that external factors can heavily influence the phenotypic expression of a genetic mutation. This gene-environment interaction has led to the concept of two-hit or multi-hit mechanisms, where a genetic mutation may remain dormant until triggered or exacerbated by environmental stressors such as viral infections, cardiotoxic drugs, or metabolic stress. This insight highlights the importance of a comprehensive clinical evaluation that considers both genetic and non-genetic factors to improve diagnostic accuracy and optimize treatment strategies.
Understanding the interplay between genetic mutations and environmental triggers may also pave the way for personalized medicine approaches in DCM, allowing for targeted therapies based on a patient’s genetic profile and individual risk factors. This approach could improve early diagnosis, enhance risk stratification, and ultimately lead to better patient outcomes.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC10044994/)
Clinical Implications of Genetic Findings
The 2022 European Heart Rhythm Association (EHRA) consensus guidelines recommend that genetic testing for dilated cardiomyopathy (DCM) should prioritize genes with definitive evidence of pathogenicity. Additionally, the initial gene panel may also include genes with moderate evidence of pathogenicity.
Genes with definitive pathogenic evidence include: BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN, and DSP.
Genes with moderate evidence of pathogenicity include: ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, and VCL.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC10044994/)
The identification of genetic mutations associated with DCM has several clinical implications:
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Early Diagnosis and Familial Screening:
Recognizing a genetic predisposition allows for early diagnosis and monitoring of at-risk family members. Genetic counselling can help with decisions regarding lifestyle modifications and medical interventions to prevent or delay disease onset, which may be very beneficial in a long term.
-
Personalized Treatment Strategies:
Understanding the specific genetic mutations can potentially help with tailored treatment approaches.
In summary, dilated cardiomyopathy encompasses a spectrum of genetic mutations affecting various structural and functional components of cardiac muscle. Advancements in genetic research have elucidated the roles of genes such as TTN, LMNA, MYH7, MYBPC3, and DSC2 in the pathogenesis of DCM. These findings underscore the importance of genetic screening and personalized medicine in the management of DCM, offering the potential for early treatment and intervention.
Hypertrophic Cardiomyopathy (HCM).
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by the thickening of the heart muscle, particularly the left ventricle, leading to impaired cardiac function and possible abnormal heart beats.
About 1 in 500 of the UK population is affected by HCM.
(https://www.bhf.org.uk/informationsupport/conditions/hypertrophic-cardiomyopathy)
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart muscle disorder caused by mutations in genes encoding sarcomere or sarcomere-associated proteins, which are essential for the heart’s contractile function. This genetic abnormality leads to structural changes in the heart, most notably increased left ventricular wall thickness (hypertrophy). The resulting pathophysiological consequences may include dynamic left ventricular outflow tract obstruction, diastolic dysfunction, myocardial ischemia, arrhythmias, autonomic dysfunction, and mitral regurgitation.
Approximately 60% of individuals with HCM have a detectable genetic mutation affecting sarcomere or related proteins, underscoring the importance of obtaining a detailed family history to assess genetic risk and guide management. In addition to genetic evaluation, a comprehensive clinical history and physical examination are crucial for identifying individuals at high risk for malignant heart beats. The structural and functional abnormalities seen in HCM can manifest as fatigue, dyspnea, chest pain, palpitations, or syncope.
Advances in early diagnosis and management have significantly improved survival outcomes in patients with HCM. Treatment strategies may include pharmacologic therapy, implantable cardioverter-defibrillator (ICD) placement, or surgical interventions such as septal myectomy when indicated. Prompt identification and personalized management are essential for reducing morbidity and mortality associated with this condition.
(https://www.ncbi.nlm.nih.gov/books/NBK430788/)
Symptoms of HCM
Many individuals with hypertrophic cardiomyopathy (HCM) experience no symptoms or remain stable throughout their lives. However, some may develop symptoms, which can vary in severity. The most common symptoms of HCM include:
- Shortness of breath
- Dizzy spells or fainting
- Palpitations (a rapid, pounding, or irregular heartbeat)
- Chest pains
- Tiredness (feeling easily tired or weak)
- Swelling in the legs, feet, ankles, or abdomen
In some cases, symptoms may worsen with age, often due to the progressive stiffening of the heart muscle, which makes it harder for the heart to pump blood effectively. The location and extent of heart muscle thickening or stiffening largely determine the type and severity of symptoms a person may experience.
(https://www.bhf.org.uk/informationsupport/conditions/hypertrophic-cardiomyopathy)
Genetic Basis of HCM
Familial HCM occurs in approximately 60% of cases as an autosomal dominant Mendelian-inherited disorder. However, incomplete penetrance and variable expression can lead to unpredictable clinical presentations, even among family members. In individuals with HCM and a confirmed pathogenic sarcomeric gene variant, the two most commonly affected genes are β-myosin heavy chain 7 (MYH7) and myosin-binding protein C3 (MYBPC3), collectively accounting for around 75% of genetically positive cases. Less frequently, mutations in thin filament proteins such as troponin T, troponin I, myosin light chains, and actin (genes: TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC1) are identified, representing 1% to 5% of cases. To date, over 1500 genetic variants associated with HCM have been discovered, most of which are unique to each family. However, no clear correlation has been established between specific gene mutations and clinical prognosis.
A significant proportion of HCM cases, up to 40% in some studies, occur without any identifiable genetic mutation or family history—referred to as non-familial HCM. This suggests the existence of alternative, yet undiscovered, pathophysiological mechanisms contributing to disease development. Recent evidence also implicates abnormal myocardial calcium kinetics in promoting inappropriate myocardial hypertrophy and diastolic dysfunction, particularly in patients without clear genetic mutations. Further research is needed to fully understand these alternative mechanisms and their role in HCM pathology.
(https://www.ncbi.nlm.nih.gov/books/NBK430788/)
Clinical Implications and Future Directions
Understanding the genetic basis of HCM has significant clinical implications. It enables personalized medicine approaches, where management strategies are tailored based on the specific genetic mutation and associated risk profile. For example, individuals with high-risk mutations may benefit from more aggressive interventions, such as implantable cardioverter-defibrillators (ICDs), to prevent abnormal heart beats and potentially sudden cardiac death.
To summarise, hypertrophic cardiomyopathy is a genetically heterogeneous disorder primarily caused by mutations in sarcomeric protein genes. Advancements in genetic research have enhanced our understanding of the disease, leading to improved diagnostic accuracy, risk stratification, and personalized management strategies. Continued research efforts are essential to unravel the complex genetic architecture of HCM and to develop targeted therapies that can modify the disease course and improve patient outcomes.
Arrhythmic Disorders
In addition to cardiomyopathies, inherited arrhythmic disorders also can be diagnosed in patients with heart problems. Conditions such as Long QT Syndrome and Brugada Syndrome, are caused by mutations in genes encoding cardiac ion channels. These conditions can lead to life-threatening arrhythmias and sudden cardiac death. Genetic testing facilitates early diagnosis and guides management strategies, including lifestyle modifications, pharmacotherapy and the use of implantable cardioverter-defibrillators.
Role of Genes in Hypertension
Hypertension, or high blood pressure (BP), is a significant risk factor for various cardiovascular diseases. While lifestyle factors like diet and physical activity are well-known contributors, genetic factors also play a substantial role.
The genetic architecture of hypertension plays an important role in influencing the underlying biological mechanisms that regulate BP. A broad spectrum of genetic variations, ranging from high-impact rare genetic mutations to more common single nucleotide polymorphisms (SNPs), has significantly advanced the understanding of the genetic basis of high BP. These discoveries have opened new questions for researchers, particularly in the field of pharmacogenomics, to explore how genetic variations influence individual responses to antihypertensive therapies and aid in the development of personalised treatment approaches. Understanding the genetic and molecular mechanisms that contribute to BP regulation can be crucial for improving the management, treatment and ultimately wellbeing of patients, who are affected by high BP.
Recent breakthroughs in genomic and epigenomic research have significantly expanded our knowledge of the role of genetic variants, gene-environment interactions, and epigenetic modifications in the causes of high BP. Epigenetics — which involves changes in gene expression without altering the DNA sequence — has been recognised as a dynamic and reversible regulatory mechanism that influences BP. This includes DNA methylation, histone modifications, and non-coding RNAs (such as lncRNAs), which collectively impact gene expression and cellular function. Investigating these epigenetic mechanisms can provide valuable insights into the pathophysiology of hypertension and help identify new potential therapeutic targets to develop precise, individualised medical treatments.
In addition to this, the growing field of pharmacogenomics plays a pivotal role in understanding the variability in BP regulation and response to antihypertensive medications across individual patients. By integrating genetic and epigenetic data, clinicians can better predict which antihypertensive drugs will be most effective for a particular patient, reducing the likelihood of adverse effects and improving treatment outcomes. This shift toward personalised treatment is particularly important, as it offers a more targeted approach to managing high BP based on an individual’s genetic makeup rather than a one-size-fits-all approach.
The relationship between genetic predisposition and environmental factors has also emerged as a key component in understanding BP regulation. Environmental influences such as diet, stress, and physical activity can modulate gene expression through epigenetic modifications, which in turn can affect BP levels. This gene-environment interaction highlights the complexity of hypertension and underscores the need for future research that can further elucidate these mechanisms. By doing so, it may become possible to implement preventive strategies and develop novel therapeutic approaches for individuals at high genetic risk of hypertension.
In particular, understanding epigenetic changes in hypertensive patients has the potential to uncover new molecular targets for therapeutic intervention. Studies on DNA methylation patterns, histone modifications, and long non-coding RNAs (lncRNAs) in hypertensive individuals have already provided promising insights into disease pathogenesis. By targeting these epigenetic alterations, researchers could potentially develop novel therapeutic drugs that reverse or inhibit maladaptive gene expression patterns linked to high BP. This could lead to the development of more effective and personalised treatment regimens tailored to an individual’s genetic and epigenetic profile.
Ultimately, future research efforts must focus on integrating genomic, epigenomic, and transcriptomic data to create a more comprehensive understanding of BP regulation. This interdisciplinary approach holds great promise for identifying new molecular targets for antihypertensive therapies and guiding the development of personalized medicine strategies. Additionally, expanding the use of pharmacogenomics in clinical practice may enable healthcare providers to tailor treatments based on a patient’s genetic profile, minimizing adverse drug reactions and optimizing treatment efficacy. By bridging the gap between basic genetic research and clinical applications, the future of hypertension management could shift towards more precise, individualized, and effective therapies, ultimately improving patient outcomes and reducing the global burden of high BP.
(https://www.ahajournals.org/doi/pdf/10.1161/HYPERTENSIONAHA.124.22072)
Genetic Testing for Cardiovascular Diseases
Advancements in genetic testing have revolutionized the approach to diagnosing and managing cardiovascular diseases. By identifying genetic mutations associated with heart conditions, healthcare providers can potentially implement individualized strategies for prevention and treatment. Although it`s a still developing field, screening patients` relatives for Familial Hypercholesterolaemia, Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy is a well established diagnostic step at present.
Diagnostic Testing
For individuals with a personal or family history suggestive of an inherited heart condition, genetic testing can confirm a diagnosis and identify at-risk family members. The genetic services offer also counselling and explain potential implications if the test comes back positive.
Predictive Testing
Predictive genetic testing assesses the risk of developing certain cardiovascular diseases before symptoms appear. This is a developing field but has a potential to transform a lot of therapies in medicine.
Pharmacogenomics
Genetic testing can also guide medication choices by predicting individual responses to specific drugs. Much research is needed to allow widespread adoption but the idea itself is very promising.
DNA Testing for Cardiovascular Risks
DNA testing has become a valuable tool in assessing cardiovascular risk, enabling early interventions and personalized healthcare strategies.
Pathogenic DNA variants contribute to the development of various cardiovascular disease phenotypes, with familial dyslipidemias, cardiomyopathies, arrhythmias, and aortopathies being among the most recognized. However, the clinical presentation of monogenic cardiovascular diseases often overlaps with conditions arising from complex genetic and non-genetic factors, making it challenging to differentiate between them based on clinical symptoms alone. As a result, genetic testing has become a critical tool for achieving a precise diagnosis, allowing for more tailored management and risk assessment in affected individuals.
The broader integration of genetic testing in cardiovascular care presents a valuable opportunity to enable precision diagnoses that can significantly impact prognosis, management, and the health of family members. While genetic testing is often perceived as a specialized tool primarily utilized by cardiovascular genetic specialists, its growing relevance across a wide range of cardiovascular conditions highlights the need for clinical cardiologists to become familiar with its role in patient care. Cardiologists should be equipped to recognize appropriate indications for genetic testing, understand its clinical implications, and access available resources to facilitate testing. Although widespread adoption of genetic testing in routine cardiovascular practice will take time, expanding education and awareness among cardiologists is a critical first step — ultimately leading to improved patient care and more comprehensive family-centered management.
(https://link.springer.com/article/10.1007/s11886-023-02003-4)
Conclusion
The role of genetics in heart disease is multifaceted, encompassing inherited conditions, genetic predispositions to common cardiovascular diseases, and the potential for personalised medicine through genetic testing. As research advances, our understanding of the genetic factors influencing heart disease continues to deepen, offering new strategies for prevention, diagnosis, and treatment. However, it would be important to approach genetic information with careful consideration, ensuring that individuals receive appropriate counselling and support to make informed decisions about their health and long term wellbeing.
Incorporating genetic testing into routine clinical practice holds promise for reducing the burden of cardiovascular diseases. By identifying individuals at high genetic risk, healthcare providers can implement targeted interventions, potentially improving outcomes and reducing healthcare costs. As the field of genomics evolves, ongoing research and collaboration will be essential to fully harness the potential of genetic information in combating heart disease.
In summary, understanding the role of genetics in heart disease is an important component of modern medicine, paving the way for personalized healthcare and improved cardiovascular outcomes. This field is growing and still requires a lot of research.
