Congestive Heart Failure
Congestive heart failure (CHF), often referred to simply as heart failure (HF), is a serious and chronic cardiovascular condition where the heart is unable to pump enough blood to meet the body’s metabolic demands[1]. This inability can stem from various underlying conditions, including systemic hypertension, coronary artery disease, and cardiac valvular disease[2]. HF represents a significant public health burden globally, with studies indicating that approximately 1 in 5 individuals will develop heart failure in their lifetime[2]. In the United States alone, nearly 6 million Americans are affected by this condition [1].
Biologically, the long-term strain on the heart, regardless of its initial cause, triggers maladaptive changes in cellular function and growth within the myocardial tissue. Over time, these changes can lead to irreversible myocardial injury, further impairing the heart’s ability to pump blood effectively [3]. Genetic factors are recognized as contributors to HF susceptibility, with an estimated 18% of the risk potentially attributable to a parental history of heart failure[4]. Understanding these genetic contributions, including the influence of specific single nucleotide polymorphisms (SNPs), is crucial for identifying individuals at higher risk and developing targeted interventions.
Clinically, CHF is characterized by symptoms such as shortness of breath, chronic fatigue, and peripheral edema, which can profoundly impact a patient’s quality of life. The prognosis for individuals diagnosed with HF is a major concern; approximately 1 in 5 patients die within one year of diagnosis, often due to sudden cardiac death, which occurs 6 to 9 times more frequently in HF patients than in the general population[1]. The social importance of CHF is immense, not only due to its high prevalence and significant mortality but also because of the substantial healthcare costs and the profound impact it has on patients, their families, and public health systems. Continued research into genetic predispositions and novel therapeutic targets is vital for improving the prevention, diagnosis, and treatment strategies for this debilitating condition.
Limitations
Section titled “Limitations”Genetic studies on congestive heart failure face several methodological and interpretative challenges that influence the generalizability and certainty of findings. These limitations are crucial for understanding the scope of current research and guiding future investigations.
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The vast number of genetic variants analyzed in genome-wide association studies introduces a significant statistical hurdle, as detecting even one genome-wide significant single nucleotide polymorphism (SNP) might be expected by chance alone given millions of tests[5]. This necessitates independent replication of initial findings to confirm their validity and determine their true biological relevance. Furthermore, the quality of SNP imputation, particularly for variants not directly genotyped, can vary, leading to reduced statistical power for detecting associations, especially for poorly imputed SNPs [5]. The exclusion of SNPs with low minor allele frequency (MAF) from meta-analyses due to potential inaccuracies in statistical model assumptions for rare variants also means that some genetic effects might be overlooked [5].
Phenotypic Heterogeneity and Ancestry-Specific Challenges
Section titled “Phenotypic Heterogeneity and Ancestry-Specific Challenges”Research is often complicated by inconsistencies in how heart failure events are classified across different study cohorts, introducing heterogeneity that can diminish the power to detect genetic associations[5]. A lack of comparable and comprehensive data on the specific type of heart failure, such as systolic versus diastolic dysfunction, further limits the ability to conduct detailed genetic analyses for these distinct clinical presentations[5]. Genetic differences between populations, including varying MAF and distinct patterns of linkage disequilibrium, make direct cross-ancestral comparisons challenging to interpret [6]. Moreover, studies often exhibit limited statistical power in certain ancestry groups, such as those of African ancestry, meaning that smaller effect sizes might not be detectable, potentially leading to an incomplete understanding of genetic influences across diverse populations [5].
Confounding Factors and Remaining Knowledge Gaps
Section titled “Confounding Factors and Remaining Knowledge Gaps”Non-genetic factors significantly influence heart failure prognosis and can confound genetic association studies. For instance, various heart failure treatments are known to affect patient survival, and access to care and treatment practices can differ substantially across regions and ethnic groups[6]. These environmental and socioeconomic variables introduce variability that can obscure or interact with genetic predispositions. Despite identifying specific genetic variants, there remains a need to clarify their precise functional role in the development and progression of clinical heart failure, highlighting an ongoing knowledge gap in understanding the biological mechanisms linking genetic variation to disease manifestation[5].
Variants
Section titled “Variants”Genetic variations play a significant role in an individual’s predisposition to complex diseases like congestive heart failure (CHF), a chronic condition where the heart struggles to pump enough blood to meet the body’s needs. These variations, known as single nucleotide polymorphisms (SNPs), can influence gene activity, protein function, and biological pathways, thereby affecting cardiac structure, function, and the development of related risk factors. Understanding these genetic underpinnings provides insights into the intricate mechanisms contributing to heart failure.
Several variants are associated with fundamental aspects of cardiac development, rhythm, and direct cardiovascular risk. ThePITX2 gene encodes a transcription factor crucial for early cardiac development, particularly in establishing left-right asymmetry and atrial formation. Variants in the PITX2 locus, such as rs76229004 , rs9685830 , and rs2129981 , are strongly linked to atrial fibrillation, a common arrhythmia that significantly increases the risk of stroke and can lead to or worsen congestive heart failure. These SNPs may influence PITX2 expression or its interaction with the long non-coding RNALINC01438, thereby impacting the heart’s electrical stability and structural integrity. Similarly, the LPAgene encodes apolipoprotein(a), a key component of lipoprotein(a) [Lp(a)], a lipid particle whose elevated levels are an independent risk factor for atherosclerosis. The variantrs10455872 is associated with higher Lp(a) concentrations, which promote inflammation and plaque buildup in arteries, leading to coronary artery disease—a primary cause of congestive heart failure.
Other genetic variations influence cellular processes such as growth, senescence, and metabolism, indirectly impacting cardiac health by modulating major cardiovascular risk factors.CDKN1A, also known as p21, is a central regulator of the cell cycle, DNA repair, and cellular senescence. The variant rs3176326 could potentially alter p21 activity, affecting the aging and stress response of cardiac cells. Accelerated senescence in cardiomyocytes or vascular cells contributes to cardiac remodeling and impaired function, increasing susceptibility to heart failure. Adjacent to the important cell cycle regulators CDKN2A/B, the long non-coding RNACDKN2B-AS1 (ANRIL) is implicated in cell proliferation and senescence. Variants like rs4977575 and rs1333047 in this region are associated with coronary artery disease and type 2 diabetes, both significant risk factors for heart failure, by influencing vascular health and cardiac remodeling. Furthermore, variants in theFTO gene, such as rs1421085 and rs62048402 , are strongly linked to obesity and increased body mass index. Obesity is a major contributor to hypertension, type 2 diabetes, and dyslipidemia, all conditions that heighten the risk and severity of congestive heart failure by increasing cardiac workload and promoting adverse structural changes.
Finally, a diverse set of genes with roles in cellular structure, metabolism, and broader systemic functions can also influence cardiac health. SYNPO2L(synaptopodin 2-like) is involved in organizing the actin cytoskeleton, a critical structural element in muscle cells, including those of the heart. The variantrs7915134 , located in or near SYNPO2L and its antisense RNA SYNPO2L-AS1, may affect the integrity and contractility of cardiomyocytes, potentially contributing to the structural and functional changes observed in heart failure. ThePGAP3 gene plays a role in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors and lipid metabolism. Variants like rs12150603 and rs2517953 could impact these processes, potentially altering cell signaling or lipid profiles, which are crucial for cardiovascular health.BBS9, part of the Bardet-Biedl syndrome (BBS) complex, is involved in cilia function. BBS is a disorder often associated with obesity, diabetes, and cardiomyopathy, which can directly lead to heart failure. The variantrs111739575 in BBS9 may subtly influence cilia-related pathways, affecting metabolic regulation and cardiac integrity. Lastly, GTF2IRD2 encodes a transcription factor with broad roles in development and gene regulation. Variants such as rs800997 and rs202209188 could potentially impact the expression of genes vital for cardiac development or stress responses, thus contributing to the complex etiology of congestive heart failure.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs3176326 | CDKN1A | atrial fibrillation hypertrophic cardiomyopathy QRS duration PR interval electrocardiography |
| rs1421085 rs62048402 | FTO | body mass index obesity energy intake pulse pressure measurement lean body mass |
| rs4977575 rs1333047 | CDKN2B-AS1 | Abdominal Aortic Aneurysm pulse pressure measurement coronary artery disease subarachnoid hemorrhage aortic aneurysm |
| rs10455872 | LPA | myocardial infarction lipoprotein-associated phospholipase A(2) measurement response to statin lipoprotein A measurement parental longevity |
| rs76229004 rs9685830 rs2129981 | PITX2 - LINC01438 | congestive heart failure |
| rs111739575 | BBS9 | congestive heart failure |
| rs7915134 | SYNPO2L, SYNPO2L-AS1 | atrial fibrillation prothrombin time measurement congestive heart failure cardiac arrhythmia |
| rs800997 rs202209188 | GTF2IRD2 | congestive heart failure |
| rs12150603 rs2517953 | PGAP3 | congestive heart failure |
| rs2957657 | SBF2 | congestive heart failure |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Congestive heart failure (CHF), often referred to simply as heart failure (HF), is a complex clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood .
Typical Presentations: Common presentations often include:
- Respiratory symptoms:Shortness of breath, particularly during ordinary exertion or at night (paroxysmal nocturnal dyspnea)[7]. A nocturnal cough may also be present [7]. Severe cases can involve acute pulmonary edema, where fluid builds up in the lungs[7].
- Fluid retention:Swelling, commonly observed as bilateral ankle edema, and signs of systemic congestion such as neck vein distention, an enlarged liver (hepatomegaly), or fluid around the lungs (pleural effusion)[7]. Visceral congestion, affecting internal organs, can also occur [7]. Rapid weight loss of 4.5 kg or more in response to diuretic treatment can be a significant sign [7].
- Cardiac findings: A rapid heart rate (≥120 beats/min), the presence of a third heart sound upon auscultation, and an elevated jugular venous pressure of 16 cm or greater are indicative findings [7]. Rales, or crackling sounds in the lungs, can also be detected [7].
Measurement Approaches: The identification of CHF often relies on a combination of clinical assessment and objective measurements:
- Diagnostic criteria:One widely recognized approach, originating from the Framingham study, defines heart failure based on the concurrent presence of two major criteria or one major plus two minor criteria[7]. Minor criteria are considered only if they cannot be attributed to another underlying disease[7].
- Imaging:Chest radiography can reveal cardiomegaly (an enlarged heart) or evidence of pulmonary edema[7]. Autopsy findings can also confirm cardiomegaly or visceral congestion [7].
- Physiological assessments: Measurements include vital capacity, which may be decreased by one-third from previous maximum levels, and heart rate [7]. Clinical examinations also involve assessing for hepato-jugular reflux and jugular venous pressure [7].
- Medical record review: Case identification can be achieved through the review of medical records and sometimes through central adjudication processes, distinct from hospital discharge diagnoses [8]. Guidelines for the diagnosis and treatment of chronic heart failure also provide frameworks for assessment[9].
Variability:The presentation and management of heart failure can be influenced by various factors, including age[10]. The natural history of congestive heart failure, as observed in studies like the Framingham study, demonstrates the evolving nature of the condition’s presentation over time[2]. Different diagnostic criteria sets may also lead to variations in case identification [7].
Congestive heart failure (HF) is a serious cardiovascular condition that affects approximately 1 in 5 individuals during their lifetime. It arises primarily from the burden of systemic hypertension, coronary ischemia, or cardiac valvular disease[3]. The long-term strain on the heart can trigger maladaptive cellular function and growth, potentially leading to irreversible myocardial injury [3].
Environmental Factors
Section titled “Environmental Factors”The primary environmental and acquired factors contributing to heart failure include systemic hypertension, coronary ischemia, and cardiac valvular disease[3]. These conditions place significant strain on the heart, which over time can diminish its pumping efficiency and lead to permanent damage to the heart muscle[3].
Genetic Factors
Section titled “Genetic Factors”Genetic factors contribute to the onset of heart failure[4]. Research indicates that approximately 18% of the risk for developing heart failure may be attributed to a parental history of the condition[4]. Approaches to identifying genetic variants associated with heart failure risk have historically focused on candidate genes. These include genes primarily related to the renin-angiotensin-aldosterone system, adrenergic receptors, and proteins forming sarcomeres and the cytoskeleton[11].
Biological Background
Section titled “Biological Background”Congestive heart failure (HF) is a severe cardiovascular condition characterized by the heart’s inability to pump sufficient blood to meet the body’s demands[6]. This condition affects a significant portion of the population during their lifetime [6]. The primary causes of heart failure include systemic hypertension, coronary ischemia, and cardiac valvular disease[6]. Regardless of the specific clinical cause, prolonged strain on the heart leads to detrimental cellular changes and growth, which can result in irreversible damage to the myocardium, the muscular tissue of the heart [3].
Cellular and Molecular Mechanisms
Section titled “Cellular and Molecular Mechanisms”At the cellular level, failing human hearts exhibit myocyte (heart muscle cell) death through various mechanisms[12]. There is also an increased expression of proteins that make up the cytoskeleton, linkage proteins, and extracellular matrix within the failing myocardium [13]. Autophagy, a cellular process involving the degradation and recycling of cellular components, has been identified as an adaptive response in specific forms of cardiomyopathy, such as desmin-related cardiomyopathy[14].
Studies have also shown altered gene expression profiles in peripheral blood mononuclear cells of patients with chronic heart failure[15]. Molecular investigations have identified components of maxi KCa channels in human coronary smooth muscle, predominantly alpha + beta subunit complexes[16].
Genetic Contributions
Section titled “Genetic Contributions”Genetic factors play a role in the development of heart failure[6]. Research indicates that approximately 18% of the risk for heart failure may be linked to a parental history of the condition[4]. Early approaches to identify genetic variants associated with heart failure risk focused on candidate genes, particularly those involved in the renin-angiotensin-aldosterone system, adrenergic receptors, sarcomeres, and cytoskeletal proteins[11].
More recently, genome-wide association studies (GWAS) have identified specific genetic regions associated with incident heart failure. A significant association was found forCMTM7, a gene encoding a chemokine-like factor located on chromosome 3p22 [6]. The protein produced by CMTM7 is highly expressed in leukocytes and also in the heart. While its exact function is not fully understood, it may act as a chemoattractant, guiding cell migration within the heart [6]. Chemokines are known to function as pro-inflammatory markers in immune responses and can promote angiogenesis (new blood vessel formation) during heart failure[6]. Furthermore, chemokine receptor gene expression is upregulated in heart failure patients compared to controls[15].
Other genomic regions identified in these analyses include chromosome 1q41 and 12q24 [6]. Genes such as OTUD7A and FBXO34have been suggested to influence heart failure progression and survival by affecting the degradation of proteins[6].
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Congestive heart failure (CHF) involves a complex array of molecular and physiological changes that contribute to the progressive decline in cardiac function.
- Cellular Remodeling and Death:In failing human hearts, heart muscle cells, known as myocytes, undergo death through multiple mechanisms[12]. Additionally, cellular processes such as autophagy, an adaptive response involving the self-digestion and recycling of cellular components, have been observed in certain types of cardiomyopathy that can lead to heart failure[14].
- Protein Expression Changes: The myocardium of a failing heart exhibits altered protein expression. Specifically, there is an increased expression of cytoskeletal, linkage, and extracellular proteins [13]. These changes suggest significant structural and functional remodeling within the heart tissue.
- Systemic Molecular Alterations:Beyond the heart itself, studies have revealed altered gene expression profiles in peripheral blood mononuclear cells of patients with chronic heart failure[17]. This indicates broader systemic molecular involvement in the disease’s progression.
- Biomechanical Factors:The overall pathophysiology of heart failure is understood to involve a range of biomechanical and molecular mechanisms[3].
Clinical Relevance
Congestive heart failure (CHF) presents significant clinical challenges, making its study crucial for patient care and public health. Understanding the lifetime risk and epidemiology of heart failure is fundamental for preventive strategies and resource allocation[18]. Identifying predictors of CHF, particularly in the elderly, enables earlier detection and targeted interventions [19]. Insights into the natural history of CHF provide a framework for anticipating disease progression and guiding long-term management[2].
The accuracy of diagnostic criteria for CHF holds clinical importance, as these criteria are associated with patient survival [7]. Furthermore, the method of case identification, such as central adjudication versus hospital discharge diagnoses, influences the understanding of CHF incidence and prognosis [8].
Clinical practice is informed by guidelines for the diagnosis and treatment of chronic heart failure[9]. Patient management strategies for heart failure are influenced by age, indicating a need for tailored approaches[10]. Pharmacotherapies, including beta-blockers, are central to treatment, with studies tracking their usage trends in older adults with CHF [20]. The differentiation of CHF based on left ventricular ejection fraction—whether normal or reduced—is clinically relevant for understanding variations in prevalence and mortality within patient populations[21].
Frequently Asked Questions About Congestive Heart Failure
Section titled “Frequently Asked Questions About Congestive Heart Failure”These questions address the most important and specific aspects of congestive heart failure based on current genetic research.
1. Does my family history make me more likely to get heart failure?
Section titled “1. Does my family history make me more likely to get heart failure?”Yes, your family history can definitely increase your risk. About 18% of the risk for heart failure is linked to having a parent who experienced it. This suggests that certain genetic predispositions can run in families, making you more susceptible if your close relatives have been affected.
2. Can a DNA test tell me if I’m at risk for heart failure?
Section titled “2. Can a DNA test tell me if I’m at risk for heart failure?”Yes, genetic testing can help identify if you carry certain variants that increase your susceptibility to heart failure. While no single test gives a definitive “yes” or “no,” understanding your genetic profile can help identify individuals at higher risk. This information can be crucial for your doctor to recommend targeted screening or preventive strategies.
3. Can a healthy lifestyle really overcome my family’s heart problems?
Section titled “3. Can a healthy lifestyle really overcome my family’s heart problems?”A healthy lifestyle plays a significant role, but it’s a complex interaction. While genetic factors contribute to your risk, non-genetic factors like diet, exercise, and managing underlying conditions profoundly influence heart failure prognosis. Even with a genetic predisposition, proactive lifestyle choices can help mitigate your risk and improve your overall heart health.
4. Does my ethnic background change my heart failure risk?
Section titled “4. Does my ethnic background change my heart failure risk?”Yes, your ethnic background can influence your heart failure risk. Genetic differences exist between populations, affecting the frequency of certain risk variants and how they are linked. Research often has limited power in certain ancestry groups, like those of African ancestry, meaning our understanding of genetic influences might be incomplete across diverse populations.
5. Why do some people develop heart failure at a younger age?
Section titled “5. Why do some people develop heart failure at a younger age?”Genetics can play a role in the timing of heart failure onset. Some individuals may inherit specific genetic variants that predispose them to earlier cardiac issues or accelerate the progression of the disease. These underlying genetic factors can interact with environmental influences to manifest symptoms at a younger age compared to others.
6. Does my family history of irregular heartbeats increase my heart failure risk?
Section titled “6. Does my family history of irregular heartbeats increase my heart failure risk?”Yes, it can. Variants in genes like PITX2 are strongly linked to atrial fibrillation, a common type of irregular heartbeat. Atrial fibrillation significantly increases your risk of developing heart failure over time, so a family history of such arrhythmias suggests a potential genetic predisposition that warrants closer monitoring.
7. Why do some people seem to avoid heart failure despite bad habits?
Section titled “7. Why do some people seem to avoid heart failure despite bad habits?”Individual genetic variations can offer some people a degree of natural resilience. While unhealthy habits generally increase risk, some individuals may have protective genetic profiles that make them less susceptible to the damaging effects of these behaviors. However, even with genetic advantages, consistently poor lifestyle choices will eventually take a toll on heart health.
8. Could a genetic test help my doctor treat my heart better?
Section titled “8. Could a genetic test help my doctor treat my heart better?”Yes, potentially. Identifying specific genetic contributions can help your doctor understand your individual risk profile and guide more personalized, targeted interventions. This could mean earlier screening, more specific preventive advice, or even help in tailoring treatment strategies based on your unique genetic makeup.
9. If I’m diagnosed, will my kids definitely get heart failure too?
Section titled “9. If I’m diagnosed, will my kids definitely get heart failure too?”Not necessarily, but their risk will be higher. While genetic factors contribute to heart failure susceptibility, it’s not a simple inheritance pattern. About 18% of the risk is linked to parental history, meaning your children will have an increased predisposition, but many other genetic and non-genetic factors will also influence their individual risk.
10. Why do heart failure medications work better for some people than others?
Section titled “10. Why do heart failure medications work better for some people than others?”Individual genetic differences can influence how your body processes and responds to medications. Variations in genes can affect drug metabolism and how your cells react to therapies. This genetic variability can lead to different effectiveness or side effect profiles for the same treatment among patients, impacting how well a medication works for you.
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] The Cardiovascular Health Study. “Surveillance and ascertainment of cardiovascular events.”Annals of Epidemiology, vol. 5, 1995, pp. 278–285.
[2] McKee PA, Castelli WP, McNamara PM, Kannel WB. “The natural history of congestive heart failure: the Framingham study.”N Engl J Med 1971;285:1441–1446.
[3] Mann, D. L., and M. R. Bristow. “Mechanisms and models in heart failure: the biomechanical model and beyond.”Circulation, vol. 111, 2005, pp. 2837–2849.
[4] Lee, Daniel S., et al. “Association of parental heart failure with risk of heart failure in offspring.”New England Journal of Medicine, vol. 355, 2006, pp. 138–147.
[5] Smith, Nicholas L., et al. “The 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 CHARGE Consortium.”
[6] Morrison, Alanna C., et al. “Genome-Wide Association Study of Incident Heart Failure.”Circulation: Cardiovascular Genetics, 2011.
[7] Schellenbaum G, Rea T, Heckbert S, Smith N, Lumley T, Roger V, Taylor H, Kitzman D, Levy D, Psaty B. “Survival associated with two sets of diagnostic criteria for congestive heart failure.”American Journal of Epidemiology 2004;160:628–635.
[8] Schellenbaum G, Heckbert S, Smith N, Rea T, Lumley T, Kitzman D, Roger V, Taylor H, Psaty B. “Congestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses.”Annals of Epidemiology 2006;16:115–122.
[9] Remme WJ, Swedberg K. “Guidelines for the diagnosis and treatment of chronic heart failure.”Eur Heart J 2001;22:1527–1560.
[10] Forman D, Cannon C, Hernandez A, Liang L, Yancy C, Fonarow G. “Influence of age on the management of heart failure: findings from Get With the Guidelines - Heart Failure (GWTG-HF).”American Heart Journal 2009;157:1010–1017.
[11] Karkkainen, S, and K Peuhkurinen. “Genetics of dilated cardiomyopathy.”Ann Med, vol. 39, 2007, pp. 91–107.
[12] Kostin, S., et al. “Myocytes die by multiple mechanisms in failing human hearts.” Circulation Research, vol. 92, 2003, pp. 715–724.
[13] Heling, A., et al. “Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium.” Circulation Research, vol. 86, 2000, pp. 846–853.
[14] Tannous, P., et al. “Autophagy is an adaptive response in desmin-related cardiomyopathy.”Proceedings of the National Academy of Sciences, USA, vol. 105, 2008, pp. 9745–9750.
[15] L, Brugaletta S, et al. “Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients.”Physiological Genomics, 2009.
[16] Tanaka, Yasuhiro, et al. “Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant alpha + beta subunit complexes.”The Journal of Biological Chemistry.
[17] Brugaletta, S., et al. “Gene expression profiles in peripheral blood mononuclear cells of chronic heart failure patients.”Physiological Genomics, 2009.
[18] Lloyd-Jones, D. M., et al. “Lifetime risk for developing congestive heart failure: the Framingham Heart Study.”Circulation, vol. 106, 2002, pp. 3068–3072.
[19] Gottdiener, John S., et al. “Predictors of Congestive Heart Failure in the Elderly: The Cardiovascular Health Study.”Journal of the American College of Cardiology, vol. 35, 2000, pp. 1628–1637.
[20] Vasan, Ramachandran S., et al. “Time Trends in the Use of Beta-Blockers and Other Pharmacotherapies in Older Adults with Congestive Heart Failure.”American Heart Journal, vol. 148, 2004, pp. 710–717.
[21] Vasan, R. S., et al. “Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population- based cohort.”J Am Coll Cardiol, vol. 33, 1999, pp. 1948–1955.