Systolic Heart Failure
Introduction
Section titled “Introduction”Background
Section titled “Background”Systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF), is a chronic and progressive condition characterized by the heart’s inability to pump enough blood to meet the body’s metabolic demands. This occurs due to a weakening of the left ventricle, the heart’s main pumping chamber, leading to impaired contractility and a reduced ejection fraction. The compromised pumping action results in less oxygenated blood reaching vital organs and tissues throughout the body, leading to various systemic effects.
Biological Basis
Section titled “Biological Basis”The biological basis of systolic heart failure involves a complex interplay of structural and functional changes within the myocardium. The primary defect is a decrease in the left ventricle’s ability to contract forcefully, often resulting from damage to the heart muscle. Common causes include myocardial infarction (heart attack), prolonged hypertension, valvular heart disease, or other forms of cardiomyopathy. Over time, the heart may attempt to compensate for its reduced pumping efficiency by undergoing remodeling, such as ventricular dilation (enlargement) or hypertrophy (thickening of the walls). While initially adaptive, these changes can ultimately lead to further deterioration of heart function and progression of the disease.
Clinical Relevance
Section titled “Clinical Relevance”Clinically, systolic heart failure manifests through a range of symptoms, including dyspnea (shortness of breath), fatigue, peripheral edema (swelling in the extremities), and reduced capacity for physical activity. It represents a serious cardiovascular condition with profound implications for patient health and quality of life. The prognosis and overall survival are significant concerns for individuals diagnosed with heart failure.[1]Effective management typically involves a combination of pharmacotherapy aimed at improving cardiac function and symptoms, lifestyle modifications, and in select cases, medical devices or surgical interventions. Regular clinical assessment and monitoring are crucial to manage the disease’s progression and prevent acute decompensations.
Social Importance
Section titled “Social Importance”Systolic heart failure carries substantial social importance due to its high prevalence and significant impact on public health worldwide. It affects a considerable portion of the adult population, with studies indicating that heart failure affects 1 in 5 people during their lifetime.[2]The condition leads to a diminished quality of life for affected individuals, often limiting their ability to perform daily activities and work, and places a substantial economic burden on healthcare systems through frequent hospitalizations, long-term care, and various medical treatments. Advancing the understanding of the genetic and environmental factors contributing to systolic heart failure is therefore critical for developing improved prevention strategies, early diagnostic tools, and more targeted and effective therapies.
Limitations
Section titled “Limitations”Statistical Power and Methodological Constraints
Section titled “Statistical Power and Methodological Constraints”Research into the genomic variation associated with heart failure is subject to several statistical and methodological constraints that can impact the interpretation and generalizability of findings. A significant limitation is the restricted statistical power, particularly evident in studies involving individuals of African ancestry where smaller sample sizes, such as 466 participants, inherently limit the ability to detect associations . Alterations here may impair the heart’s ability to regenerate or adapt to injury. Similarly, thers4977575 variant in CDKN2B-AS1, a long non-coding RNA, can modulate the expression of genes involved in cell proliferation and senescence, thereby contributing to the pathological remodeling observed in heart failure.[3] Furthermore, the BAG3 gene, with its rs17617337 variant, is essential for protein quality control and managing cellular stress in heart muscle cells, and its dysfunction can directly lead to weakened heart contractions and familial dilated cardiomyopathy. Thers3807132 variant, located near or within FLNC(Filamin C), influences a critical structural protein in cardiac sarcomeres, and variations here can compromise myocardial integrity, leading to a loss of contractile function characteristic of systolic heart failure.
Other variants influence lipid metabolism and overall metabolic health, indirectly impacting cardiac function. The rs10455872 variant in the LPAgene, encoding apolipoprotein(a), is strongly associated with elevated levels of lipoprotein(a) (Lp(a)), an established risk factor for atherosclerosis and coronary artery disease. Higher Lp(a) levels contribute to the buildup of fatty plaques in arteries, which can restrict blood flow to the heart, eventually leading to heart attacks and subsequent systolic heart failure.[3] Additionally, variants rs11642015 and rs1421085 within the FTOgene are strongly linked to obesity and increased body mass index, a significant risk factor for heart failure. TheseFTOvariants may influence metabolic pathways and energy balance, leading to the metabolic strain on the cardiovascular system.[3]
Beyond structural and metabolic factors, variants impacting ion balance and cellular stress responses are also relevant. The rs945425 variant in CLCNKA, which codes for a chloride channel vital for kidney function, can affect fluid and electrolyte balance in the body. Imbalances here can lead to high blood pressure and increased fluid retention, both of which place additional strain on the heart and can contribute to systolic heart failure.[3] Lastly, the rs56968346 variant in MAP3K7CLmay play a role in modulating cellular signaling pathways involved in stress responses and inflammation, potentially influencing the heart’s resilience to various insults and its susceptibility to developing heart failure.[3]Together, these genetic variations highlight the complex interplay of pathways contributing to the development and progression of systolic heart failure.
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Conceptual Framework and Terminology of Heart Failure
Section titled “Conceptual Framework and Terminology of Heart Failure”Heart failure (HF) represents a complex clinical syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s metabolic demands. Historically, this condition has often been referred to as congestive heart failure, a term reflecting the common symptoms of fluid overload and congestion experienced by patients.[4]The term “heart failure” serves as a broad classification, encompassing various forms of myocardial dysfunction. Within this framework, it is crucial to recognize distinct subtypes, such as systolic heart failure and diastolic heart failure, as these presentations can differ significantly in their underlying mechanisms and associated mortality outcomes.[1]
Diagnostic Criteria and Measurement Approaches
Section titled “Diagnostic Criteria and Measurement Approaches”The diagnosis of heart failure relies on a precise set of clinical criteria, exemplified by the framework established in the Framingham Heart Study. This approach defines HF by the concurrent presence of at least two major criteria, or one major criterion combined with two minor criteria.[5]Major diagnostic indicators include symptoms like paroxysmal nocturnal dyspnea, pulmonary rales, distended jugular veins, acute pulmonary edema, and evidence of an enlarging heart size on chest radiography. Minor criteria, which are considered only if not attributed to another co-existing disease, encompass manifestations such as bilateral ankle edema, nocturnal cough, and shortness of breath on ordinary exertion.[5] These criteria are typically ascertained through comprehensive reviews of medical records, physical examinations, and other available clinical data.
Classification and Phenotypic Subtypes
Section titled “Classification and Phenotypic Subtypes”Within the overarching diagnosis of heart failure, precise classification into phenotypic subtypes is essential for understanding disease progression and prognosis. The primary distinction often made is between systolic heart failure and diastolic heart failure, reflecting different mechanisms of cardiac dysfunction. While diagnostic details for specifically distinguishing systolic heart failure were not universally available across all studies, it is acknowledged that research populations frequently comprise individuals with both systolic and diastolic presentations.[1]The clinical significance of this differentiation is underscored by the observation that these two disease states may be associated with markedly different causes of death.[1] A key diagnostic parameter for differentiating these forms is the left ventricular ejection fraction, which quantifies the heart’s pumping efficiency; however, data availability for this specific measure can be limited in some study cohorts. [1]
Causes of Systolic Heart Failure
Section titled “Causes of Systolic Heart Failure”Genetic Predisposition
Section titled “Genetic Predisposition”Systolic heart failure is influenced by a complex interplay of genetic factors, ranging from single inherited variants to polygenic risk scores. Genome-wide association studies (GWAS) have been instrumental in identifying numerous genetic loci associated with cardiovascular outcomes, including incident heart failure and related conditions.[6]While some severe forms of heart disease, such as certain cardiomyopathies, can be attributed to Mendelian inherited variants within families, the majority of systolic heart failure cases involve a polygenic risk, where multiple common genetic variants, each with small effects, collectively contribute to an individual’s susceptibility.[7]
Genetic variations also contribute to the risk of conditions that frequently precede or exacerbate systolic heart failure. For instance, common variants in several loci have been identified as influencing blood pressure, a primary risk factor for heart failure.[8]Similarly, genetic variants are linked to coronary artery disease, which can lead to myocardial infarction and subsequent heart failure.[9]Variations influencing cardiac ventricular conduction and resting heart rate also underscore the broad genetic influence on cardiovascular function that can ultimately impact the heart’s pumping ability.[10]Studies examining genomic variation in heart failure patients have identified genes related to deubiquitinating activity and potassium channels, though specific findings may vary across ethnic groups due to differences in minor allele frequency and linkage disequilibrium patterns.[1]
Environmental and Lifestyle Influences
Section titled “Environmental and Lifestyle Influences”A range of environmental and lifestyle factors significantly contribute to the development and progression of systolic heart failure. Key among these are lifestyle choices that lead to established risk factors such as hypertension, diabetes, and myocardial infarction.[4]Poor diet, lack of physical activity, and other adverse lifestyle habits can result in elevated blood pressure, unhealthy cholesterol levels, and increased body weight, all of which are closely monitored clinical measures in large-scale studies due to their association with cardiovascular disease.[1]
Beyond individual choices, broader socioeconomic and geographic factors also play a role. Access to adequate healthcare and variations in treatment practices across different regions and ethnic groups can influence the survival and progression of heart failure.[1]These systemic environmental factors can impact the early detection, management, and overall trajectory of the disease, demonstrating how external conditions can shape the natural history of congestive heart failure.[4]
Gene-Environment Interactions
Section titled “Gene-Environment Interactions”The development of systolic heart failure often arises from intricate gene-environment interactions, where an individual’s genetic predisposition is amplified or mitigated by environmental and lifestyle factors. For example, individuals genetically susceptible to elevated blood pressure, as indicated by specific gene variants, may experience a more pronounced increase in blood pressure when exposed to environmental triggers like a high-sodium diet or chronic stress.[8]Conversely, a healthy lifestyle can potentially delay the onset or reduce the severity of heart failure in those with a genetic predisposition.
Studies often account for these interactions by including lifestyle-related comorbidities like diabetes and hypertension, as well as therapeutic interventions such as anti-hypertensive therapy, as covariates in genetic models.[5]This approach acknowledges that while specific genetic variants may confer a risk, the actual manifestation and progression of systolic heart failure are profoundly shaped by how these genetic factors interact with an individual’s environment, including diet, physical activity, and medical management.
Comorbidities and Age-Related Changes
Section titled “Comorbidities and Age-Related Changes”Several comorbidities significantly contribute to the onset and progression of systolic heart failure, acting as primary drivers of cardiac dysfunction. Hypertension, diabetes, and a history of myocardial infarction are among the most critical preceding conditions consistently identified in studies of heart failure populations.[1] These conditions can independently or synergistically damage the heart, leading to structural and functional changes that impair the left ventricle’s ability to pump blood effectively.
Age is another unmodifiable and significant contributing factor to systolic heart failure. The risk of developing heart failure increases with age, reflecting cumulative damage to the cardiovascular system over time, as well as age-related physiological changes.[1]Furthermore, the effects of medications, such as anti-hypertensive therapy, are also relevant considerations in the context of heart failure, as these treatments can modify the disease course and patient outcomes, even as they manage underlying conditions.[5]
Biological Background of Systolic Heart Failure
Section titled “Biological Background of Systolic Heart Failure”Systolic heart failure is a complex condition characterized by the heart’s inability to pump enough blood to meet the body’s metabolic demands, primarily due to impaired contractility of the left ventricle. This reduction in the heart’s ejection fraction has profound consequences at the molecular, cellular, tissue, and organ levels, driven by a combination of genetic predispositions and pathophysiological processes. Understanding these intertwined biological aspects is crucial for comprehending the development and progression of this debilitating disease.
Cardiac Electromechanical Function and Systemic Regulation
Section titled “Cardiac Electromechanical Function and Systemic Regulation”The heart functions as a highly coordinated pump, relying on precise electrical signaling to drive mechanical contraction and maintain systemic circulation. Electrocardiographic (ECG) traits, such as QRS duration and PR interval, reflect the integrity of ventricular and atrioventricular conduction, respectively, and their disruption can predict cardiovascular events, including sudden cardiac death.[11]For example, sodium channels likeNav1.8 play a critical role in cardiac conduction, and pharmacological inhibition of the Nav1.8 channel has been shown to increase QRS and PR duration, indicating slowed electrical impulse propagation. [12] Furthermore, resting heart rate, another fundamental measure of cardiac rhythm, serves as an independent predictive risk factor for sudden death in middle-aged men. [11]
Beyond intrinsic cardiac function, systemic factors like blood pressure are critical determinants of cardiac workload and long-term health. Elevated blood pressure is a significant risk factor for cardiovascular disease, placing chronic stress on the heart and vasculature.[8]The interplay between these electrical and hemodynamic factors underscores the delicate homeostatic balance required for optimal cardiac performance, where perturbations can initiate a cascade leading to pump dysfunction and ultimately, systolic heart failure.
Cellular and Molecular Bases of Myocardial Health
Section titled “Cellular and Molecular Bases of Myocardial Health”At the cellular level, the coordinated function of cardiomyocytes is essential for effective myocardial contraction. These cells rely on intricate molecular pathways for energy metabolism, ion handling, and structural integrity. Disruptions in these processes, such as impaired calcium handling or mitochondrial dysfunction, can lead to reduced contractility. Critical proteins, enzymes, and receptors regulate these cellular functions, ensuring proper electrical excitability and mechanical force generation.
For instance, the connexin-43 (GJA1) gene encodes a gap junction protein vital for intercellular communication and electrical coupling in the heart, and genetic variants near this gene have been associated with resting heart rate. [13] Similarly, the integrity of coronary arteries, influenced by factors like PHACTR1 as a major determinant of coronary artery stenosis [14]is paramount for delivering oxygen and nutrients to cardiomyocytes. When these cellular and molecular mechanisms are compromised, as seen in conditions like coronary artery disease, the heart’s ability to contract efficiently is diminished, contributing to the development of systolic heart failure.
Genetic Architecture of Cardiovascular Risk
Section titled “Genetic Architecture of Cardiovascular Risk”Genetic factors play a substantial role in determining an individual’s susceptibility to cardiovascular diseases and related traits, including those that predispose to systolic heart failure. Studies have demonstrated the notable heritability of various cardiac parameters, with heart rate showing heritability ranging from 32% to 77% in family and twin studies, respectively.[11]Genome-wide association studies (GWAS) have successfully identified numerous genetic loci and variants that influence traits such as coronary artery disease (CAD), blood pressure, and specific electrocardiographic characteristics[9], [11], [14], [15], [16]. [8]
These genetic mechanisms can involve specific gene functions, such as those related to vascular integrity like PHACTR1, or regulatory elements that modulate gene expression patterns, influencing protein abundance or activity. [14] For example, variants near the connexin-43 (GJA1) gene can affect the precise electrical coordination required for cardiac function. [13]The cumulative effect of these genetic variations contributes to an individual’s overall risk profile, dictating their propensity for developing the underlying conditions that lead to systolic heart failure.
Pathophysiological Progression to Systolic Heart Failure
Section titled “Pathophysiological Progression to Systolic Heart Failure”The development of systolic heart failure is often the culmination of various pathophysiological processes, where initial homeostatic disruptions trigger a series of maladaptive changes in the heart. Coronary artery disease (CAD), for example, is a leading cause of cardiovascular morbidity and mortality, characterized by conditions like myocardial infarction or the need for coronary revascularization.[17]This damage to the heart muscle directly impairs its contractile ability, reducing the heart’s ejection fraction. Similarly, chronic hypertension (high blood pressure) imposes a persistent pressure overload on the left ventricle, leading to compensatory hypertrophy where the heart muscle thickens.[8]
While initially a compensatory response to maintain cardiac output, prolonged hypertrophy can eventually become detrimental, leading to ventricular stiffness, reduced filling capacity, and impaired contractility. Over time, these pathological remodeling processes, coupled with other factors like arrhythmias or valvular heart disease, progressively weaken the heart muscle. This decline in pumping efficiency ultimately manifests as systolic heart failure, characterized by a reduced ability to eject blood into the systemic circulation.[2]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Genetic Modulation of Cardiac Electrical Activity
Section titled “Genetic Modulation of Cardiac Electrical Activity”The electrical activity of the heart is precisely regulated, with genetic factors playing a significant role in its various parameters. Studies have demonstrated the heritability of key electrocardiographic (ECG) traits, such as the QT interval duration, which reflects myocardial repolarization, and the RR interval, inversely related to heart rate.[11] Genetic variants located near the connexin-43 gene have been associated with resting heart rate in individuals of African ancestry, indicating a role for intercellular communication pathways in cardiac rhythm control. [13] Furthermore, genome-wide association studies have identified multiple loci influencing QRS duration, which signifies ventricular conduction, and PR interval, associated with atrioventricular conduction, highlighting specific genetic influences on the propagation of electrical signals through the heart [12], [18]. [19]Dysregulation of these electrical pathways can contribute to cardiovascular events, including sudden cardiac death.[11]
Vascular Health and Hemodynamic Regulation
Section titled “Vascular Health and Hemodynamic Regulation”The maintenance of vascular health and stable blood pressure are critical factors influencing cardiac function and the progression of heart disease. Genome-wide association studies have identified several susceptibility loci for coronary artery disease (CAD), includingPHACTR1 as a major determinant of coronary artery stenosis [14], [15], [16]. [9] These genetic predispositions affect the integrity and function of coronary arteries, which are essential for myocardial blood supply. Concurrently, other studies have uncovered numerous genetic variants that influence blood pressure, thereby affecting systemic hemodynamics [8]. [20]Dysregulation in these vascular and hemodynamic pathways creates chronic stress on the heart, contributing to the broader spectrum of cardiovascular illness and disability.[14]
Gene Regulation and Cardiovascular Susceptibility
Section titled “Gene Regulation and Cardiovascular Susceptibility”Genetic regulation plays a foundational role in determining an individual’s susceptibility to various cardiovascular conditions that can collectively impact heart health. Genome-wide association studies have pinpointed specific genomic regions containing variants that are associated with traits like coronary artery disease, blood pressure, and cardiac electrical conduction characteristics[8], [9], [12], [13], [14], [15], [16], [20]. [18]While the precise molecular mechanisms by which all these variants exert their effects are complex, they collectively point to altered gene expression or protein function that can perturb normal cardiac and vascular physiology. For instance, such genetic variations can influence transcription factor regulation or affect structural and functional proteins, thereby modulating the risk for conditions that precede heart failure.[11]
Integrated Cardiovascular Risk Pathways
Section titled “Integrated Cardiovascular Risk Pathways”Cardiovascular disease, including heart failure, arises from the complex interplay and integration of multiple physiological pathways and genetic factors. The collective impact of genetic predispositions influencing cardiac electrical activity, vascular integrity, and systemic blood pressure creates a network of interconnected risks[8], [9], [12], [13], [14], [15], [16], [20]. [18]Dysregulation in one pathway, such as impaired coronary artery flow due to stenosis, can exacerbate issues in another, like increased cardiac workload from hypertension, leading to progressive cardiovascular dysfunction. This systems-level integration of genetic and physiological perturbations manifests as emergent properties, such as a higher incidence of heart failure or increased susceptibility to sudden cardiac death, underscoring the multifactorial nature of advanced heart disease[2]. [11]
Pharmacogenetics for Systolic Heart Failure
Section titled “Pharmacogenetics for Systolic Heart Failure”Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs3176326 | CDKN1A | atrial fibrillation hypertrophic cardiomyopathy QRS duration PR interval electrocardiography |
| rs10455872 | LPA | myocardial infarction lipoprotein-associated phospholipase A(2) measurement response to statin lipoprotein A measurement parental longevity |
| rs4977575 | CDKN2B-AS1 | Abdominal Aortic Aneurysm pulse pressure measurement coronary artery disease subarachnoid hemorrhage aortic aneurysm |
| rs11642015 rs1421085 | FTO | diastolic blood pressure systolic blood pressure pulse pressure measurement mean arterial pressure blood urea nitrogen amount |
| rs945425 | CLCNKA | left ventricular ejection fraction measurement heart function attribute left ventricular diastolic function measurement left ventricular systolic function measurement heart failure |
| rs17617337 | BAG3 | diastolic blood pressure heart failure left ventricular ejection fraction measurement natriuretic peptides B level natriuretic peptides B proteolytic cleavage product level |
| rs56968346 | MAP3K7CL | systolic heart failure |
| rs3807132 | CCDC136 - FLNC | systolic heart failure |
Frequently Asked Questions About Systolic Heart Failure
Section titled “Frequently Asked Questions About Systolic Heart Failure”These questions address the most important and specific aspects of systolic heart failure based on current genetic research.
1. My parents had heart failure. Will I definitely get it too?
Section titled “1. My parents had heart failure. Will I definitely get it too?”No, not necessarily. While genetic variations play a crucial role in your susceptibility to systolic heart failure, having a family history doesn’t guarantee you’ll develop it. It means you may have an increased genetic predisposition, but lifestyle choices and other environmental factors also contribute significantly to whether the condition manifests.
2. Why do some people develop heart failure at a younger age?
Section titled “2. Why do some people develop heart failure at a younger age?”Genetic variations can influence the age at which heart failure might begin. Some specific gene variants can make an individual more susceptible to an earlier onset of the condition, even if other health and lifestyle factors seem similar. This highlights how your unique genetic makeup interacts with various influences over time.
3. Can eating well and exercise really overcome my genetic heart risk?
Section titled “3. Can eating well and exercise really overcome my genetic heart risk?”Absolutely. While your genetic risk factors are an important part of the picture, lifestyle modifications like a healthy diet and regular exercise are incredibly powerful. They can significantly reduce or even mitigate genetic predispositions and improve your overall cardiac function, demonstrating a strong interaction between your genes and your environment.
4. I’m of African ancestry. Is my heart failure risk different?
Section titled “4. I’m of African ancestry. Is my heart failure risk different?”Yes, your genetic risk profile for heart failure can indeed be different. Studies show that genetic variations associated with heart failure often differ in their frequency and impact across various ancestry groups, including those of African descent. This means findings from one population may not directly apply to another, emphasizing the importance of diverse research.
5. Is it true that heart failure is mostly from bad habits, not genes?
Section titled “5. Is it true that heart failure is mostly from bad habits, not genes?”No, that’s a common misconception. Systolic heart failure is a complex condition resulting from an interplay between your inherited genetic predispositions and environmental factors, including lifestyle choices and other medical conditions. Genetic variations play a crucial role in an individual’s susceptibility, working alongside other factors.
6. If I had a heart attack, did that activate my genetic heart risk?
Section titled “6. If I had a heart attack, did that activate my genetic heart risk?”A heart attack (myocardial infarction) causes significant damage to the heart muscle, a primary cause of systolic heart failure. If you have underlying genetic predispositions, this damage could indeed accelerate or trigger the disease’s progression. Your genetic makeup can influence how your heart recovers and remodels after such a significant event.
7. Why do some people with heart failure seem to live longer?
Section titled “7. Why do some people with heart failure seem to live longer?”Survival rates for heart failure can vary considerably, and genetic factors play a significant role. Research has identified specific genomic variations associated with differences in mortality among individuals living with heart failure. These genetic differences can influence disease progression and how well an individual responds to treatment.
8. What would a DNA test tell me about my heart failure risk?
Section titled “8. What would a DNA test tell me about my heart failure risk?”A DNA test could identify specific genetic variations that increase your susceptibility to systolic heart failure. Knowing these predispositions can help you and your doctor better understand your personal risk. This information can then be used to guide early prevention strategies and potentially more targeted management approaches for your health.
9. Can medical conditions like high blood pressure make my genetic risk worse?
Section titled “9. Can medical conditions like high blood pressure make my genetic risk worse?”Yes, definitely. Prolonged high blood pressure (hypertension) is a major contributor to heart muscle damage and can significantly accelerate the development of heart failure. If you also have underlying genetic predispositions, these medical conditions can interact with your genes to further heighten your risk and worsen the disease’s progression.
10. Are there special checks for my family if heart failure runs in it?
Section titled “10. Are there special checks for my family if heart failure runs in it?”If heart failure is common in your family, it’s highly advisable to discuss this with your doctor. While the article highlights the role of genetics, it underscores the importance of advanced understanding of genetic factors for improved prevention and early diagnostic tools. Your doctor can recommend tailored screening and monitoring strategies based on your family history.
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] Morrison, A. C. et al. “Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.”Circ Cardiovasc Genet, 2010.
[2] Smith, N. L. et al. “Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.”Circ Cardiovasc Genet, 2010.
[3] Benjamin EJ, et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S11. PMID: 17903293.
[4] McKee, P. A., et al. “The natural history of congestive heart failure: the Framingham study.”New England Journal of Medicine, 285 (1971): 1441-1446.
[5] Larson, M. G. “Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes.”BMC Medical Genetics, vol. 8, 2007.
[6] Cupples, L. A., et al. “The Framingham Heart Study 100K SNP genome-wide association study resource: Overview of 17 phenotype work group reports.” BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, pp. S1.
[7] Nava, A., et al. “Juvenile sudden death and effort ventricular tachycardias in a family with right ventricular cardiomyopathy.”International Journal of Cardiology, vol. 21, 1988, pp. 111-126.
[8] Ehret, G. B., et al. “Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.”Nature, vol. 478, no. 7367, 2011, pp. 103-109.
[9] Samani, N. J., et al. “Genomewide association analysis of coronary artery disease.”New England Journal of Medicine, vol. 357, no. 5, 2007, pp. 443-453.
[10] Eijgelsheim, M., et al. “Genome-wide association analysis identifies multiple loci related to resting heart rate.” Human Molecular Genetics, vol. 19, no. 20, 2010, pp. 4210-4219.
[11] Newton-Cheh, C. et al. “Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study.”BMC Med Genet, 2007.
[12] Sotoodehnia, N., et al. “Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.” Nature Genetics, vol. 42, no. 12, 2010, pp. 1068-1073.
[13] Deo, R. et al. “Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.” Heart Rhythm, 2013.
[14] Hager, J., et al. “Genome-wide association study in a Lebanese cohort confirms PHACTR1 as a major determinant of coronary artery stenosis.” PLoS One, vol. 7, no. 6, 2012, e38946.
[15] Lu, X., et al. “Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease.” Nature Genetics, vol. 44, no. 8, 2012, pp. 871-75.
[16] Schunkert, H., et al. “Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.” Nature Genetics, vol. 43, no. 4, 2011, pp. 333-38.
[17] Wellcome Trust Case Control Consortium, et al. “Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.” Nature, vol. 447, no. 7145, 2007, pp. 661-78.
[18] Denny, J. C. et al. “Identification of genomic predictors of atrioventricular conduction: using electronic medical records as a tool for genome science.” Circulation, 2010.
[19] Jeff, J. M. et al. “Generalization of variants identified by genome-wide association studies for electrocardiographic traits in African Americans.” Ann Hum Genet, 2013.
[20] Newton-Cheh, C., et al. “Genome-wide association study identifies eight loci associated with blood pressure.” Nature Genetics, vol. 41, no. 6, 2009, pp. 666-676.