Heart Failure
Introduction
Section titled “Introduction”Heart failure (HF) is a complex and progressive clinical syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s metabolic demands, leading to a range of symptoms such as shortness of breath, fatigue, and fluid retention.[1], [2]It represents a significant global health challenge, associated with substantial morbidity, mortality, and economic burden on healthcare systems.[1], [2]The incidence and prevalence of heart failure are steadily increasing worldwide, largely due to an aging population and improved survival rates from other cardiovascular diseases that can contribute to its development.[1], [2]
Biological Basis
Section titled “Biological Basis”The biological basis of heart failure involves fundamental alterations in cardiac structure and function, particularly affecting the left ventricle (LV). These changes can impair the heart’s ability to contract effectively (systolic dysfunction, often with reduced ejection fraction) or to relax and fill properly (diastolic dysfunction, frequently with preserved ejection fraction).[1], [2]Understanding the genetic architecture underlying these cardiac structural and functional parameters is crucial for deciphering the disease’s pathogenesis. Studies aim to identify common genetic variations that influence traits such as left ventricular mass, dimensions, wall thickness, and ejection fraction.[3]For example, specific single nucleotide polymorphisms (SNPs) in genes likeHSPB7 and FRMD4Bhave been linked to advanced heart failure.[4] The BAG3 and HSPB7loci are also implicated in various forms of systolic heart failure.[2] Research has also highlighted the importance of genes such as MYRIP, TRAPPC11, and SLC27A6in left ventricular hypertrophy, a condition that can precede heart failure.[5]Furthermore, shared genetic pathways contribute to the risk of cardiomyopathies, such as hypertrophic and dilated cardiomyopathies, which are significant causes of heart failure.[6] The GOSR2locus is another genetic region associated with mixed etiology heart failure and dilated cardiomyopathy.[7]
Clinical Relevance and Social Importance
Section titled “Clinical Relevance and Social Importance”Given the profound impact of heart failure on individuals and healthcare systems, its prevention and treatment are major public health priorities.[1]Diagnosis and management of heart failure often rely on a comprehensive assessment of left ventricular functional and structural parameters, typically obtained through cardiac imaging techniques.[8]Identifying the genetic and environmental determinants of heart failure is essential for developing more effective preventative strategies, personalized treatments, and ultimately, reducing the global burden of this debilitating condition.[1]
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Research into heart failure genetics faces several methodological and statistical challenges that can impact the interpretation of findings. Studies often contend with relatively small sample sizes, which can limit statistical power and increase the likelihood of false negative findings (Type II errors) for genetic associations of smaller magnitude.[9] The extensive multiple testing inherent in genome-wide association studies (GWAS) also presents a challenge, potentially increasing false positive results if not adequately addressed, and in some cases, explicit multiplicity adjustments are not performed.[9] Furthermore, issues such as genomic inflation have been observed, which can lead to an overestimation of effect sizes.[6] Another significant limitation pertains to the need for replication and the reliance on specific study designs. The validation of findings, such as the utility of cardiac sphericity for clinical risk prediction, necessitates replication in additional, diverse cohorts.[10] Some studies have also reported a limited ability to replicate previously identified associations, partly due to partial coverage of genetic variation by the genotyping platforms used.[3]Additionally, the reliance on diagnostic codes from sources like the UK Biobank to identify disease cases introduces a risk of misclassification, which can weaken observed associations and affect the accuracy of findings, even with curated outcome sets.[10]
Phenotypic and Generalizability
Section titled “Phenotypic and Generalizability”The generalizability of findings in heart failure research is often constrained by the demographic characteristics of study populations. For instance, some genome-wide association studies have been conducted primarily on subsets of participants of similar European ancestry to mitigate population substructure, which limits the direct applicability of these findings to more diverse global populations.[10] This lack of diverse representation can hinder the identification of ancestry-specific genetic variants or effect modifications, impacting the broader utility of discovered markers.
Phenotypic and definition also pose limitations. The use of uniform thresholds for physiological measurements, such as normal left ventricular (LV) size and function, without accounting for sex-specific differences, can lead to the inclusion of subjects whose measurements fall just outside the normal range when sex-specific criteria are applied.[10]While models may adjust for these factors, the initial approach can subtly affect cohort definition and subsequent analyses. Furthermore, the reliance on broad diagnostic codes to identify disease outcomes, even when curated, carries an inherent risk of misclassification, potentially obscuring true associations or weakening their observed strength.[10]
Environmental Interactions and Unexplained Heritability
Section titled “Environmental Interactions and Unexplained Heritability”A significant limitation in understanding the etiology of heart failure lies in the complex interplay between genetic and environmental factors, which is often not fully explored. Genetic variants may influence phenotypes in a context-specific manner, with their effects modulated by environmental influences such as dietary intake.[3]Studies frequently do not undertake explicit investigations of these gene-environmental interactions, leaving a gap in understanding how lifestyle and environmental exposures modify genetic predispositions to heart failure.[3] For instance, the associations of ACE and AGTR2 with LV mass have been reported to vary according to dietary salt intake.
This omission contributes to the broader challenge of unexplained heritability and remaining knowledge gaps in heart failure genetics. Without a comprehensive understanding of these interactions, the full spectrum of genetic and environmental determinants of conditions like left ventricular mass or diastolic function remains incomplete.[3]Consequently, the development of precise risk prediction models and targeted interventions is hampered by the incomplete picture of how various factors synergistically contribute to disease risk and progression.
Variants
Section titled “Variants”Genetic variations play a significant role in an individual’s susceptibility to heart failure by influencing diverse biological pathways, including metabolism, cardiac structure and function, and general cardiovascular health. Understanding these variants helps to elucidate the complex genetic architecture underlying heart failure risk.
Several variants are implicated in metabolic and lipid pathways, which are critical determinants of cardiovascular health. For instance, variants in theFTO (Fat Mass and Obesity-associated) gene, such as rs56094641 , rs11642015 , and rs1861867 , are strongly associated with obesity and type 2 diabetes, conditions that are major independent risk factors for heart failure due to increased cardiac workload and metabolic stress.[11] The GCKR (Glucokinase Regulator) gene, with variant rs780094 , plays a pivotal role in regulating glucokinase activity, impacting glucose and triglyceride metabolism, and thereby influencing liver fat and insulin resistance, which can contribute to cardiometabolic disease and subsequent heart failure.[12] Variants in CELSR2 (Cadherin EGF LAG Seven-Pass G-Type Receptor 2), including rs629301 and rs660240 , are part of a genetic cluster known to influence LDL cholesterol levels, a key factor in the development of atherosclerosis and coronary artery disease, a leading cause of heart failure.[13]Furthermore, the cholesteryl ester transfer protein (CETP), near which rs247617 is located (and also involving HERPUD1), is central to lipid transfer and HDL cholesterol metabolism, with specific alleles influencing cardiovascular disease risk and indirectly affecting heart health.
Other variants influence fundamental aspects of cardiac structure, function, and cellular regulation. The PITX2 gene, a crucial transcription factor for cardiac development and electrical rhythm, has variants such as rs78229461 , rs2634071 , and rs59788391 that are notably associated with atrial fibrillation, a common arrhythmia that can precipitate or exacerbate heart failure.[14] The long non-coding RNA LINC01438, including variant rs1906592 , can regulate gene expression and may influence cardiac remodeling and disease progression. TheCDKN1A (Cyclin Dependent Kinase Inhibitor 1A, also known as p21) gene, with variants like rs3176326 and rs4135240 , is a critical cell cycle inhibitor involved in cellular senescence and apoptosis, processes that contribute to myocardial fibrosis and dysfunction in heart failure.[3] Additionally, ZPR1 (rs964184 ) is generally involved in cell proliferation and survival, and its dysregulation could impact cardiomyocyte integrity or repair mechanisms relevant to heart failure.
A significant locus for cardiovascular disease risk is theCDKN2B-AS1 (ANRIL) region on chromosome 9p21. Variants in this area, including rs7859727 , rs1556516 , and rs7857118 , are strongly associated with coronary artery disease and myocardial infarction, both major contributors to heart failure.[13] This long non-coding RNA is believed to regulate nearby tumor suppressor genes involved in cell cycle control and cellular senescence, directly impacting vascular health. While the CDKN2BAS gene, as mentioned in studies, has variants like rs10757270 and rs10757272 associated with intracranial aneurysms, the broader locus has well-established implications for overall cardiovascular health.[15] The locus THEMIS3P - AKR1B1P6, with variant rs8082812 , involves pseudogenes; however, the related functional gene AKR1B1(Aldose Reductase) is implicated in diabetic complications, a significant risk factor for heart failure, suggesting potential regulatory or functional proximity effects.
Key Variants
Section titled “Key Variants”Fundamental Concepts in Cardiovascular Assessment
Section titled “Fundamental Concepts in Cardiovascular Assessment”Cardiovascular disease (CVD) is a broad term encompassing various conditions affecting the heart and blood vessels.[16]Within this domain, specific physiological and structural measurements are routinely assessed to understand cardiac health. Key among these are the left ventricular mass (LV mass) and left atrial size (LA size), which represent important indicators of heart chamber dimensions and muscle development.[16]These measurements contribute to the conceptual framework of cardiac remodeling, where changes in heart structure can signify underlying pathological processes relevant to conditions like heart failure.
Biomarkers of Cardiac Function
Section titled “Biomarkers of Cardiac Function”Beyond structural assessments, biochemical markers provide insights into the heart’s physiological state. The atrial natriuretic peptide, specifically its N-terminal pro-atrial natriuretic peptide form, is a crucial biomarker.[16]This peptide is released in response to cardiac stretch and stress, serving as an operational indicator of ventricular wall tension and volume overload. Its offers a quantitative approach to evaluating cardiac function and is widely used in clinical and research settings to reflect myocardial strain.[16]
Electrophysiological Measures
Section titled “Electrophysiological Measures”The electrical activity of the heart is another vital aspect of cardiovascular assessment. Electrocardiographic conduction measures provide detailed insights into the heart’s electrical pathways and rhythm.[17] These measures are obtained through non-invasive techniques and are fundamental for diagnosing a range of cardiac conditions. Analyzing these conduction patterns helps in understanding the heart’s overall functional integrity and identifying potential abnormalities in electrical signal propagation, which can be relevant in the context of various cardiac pathologies.[17]
Signs and Symptoms
Section titled “Signs and Symptoms”Heart failure is a clinically heterogeneous condition associated with substantial morbidity and mortality, presenting with a wide spectrum of clinical features.[8] Its diagnosis and management are complex, relying on a combination of subjective symptoms, objective signs, and advanced diagnostic tools to characterize its diverse phenotypes.[18], [19]The increasing prevalence of heart failure, particularly in an aging population, underscores the importance of understanding its varied presentations and diagnostic approaches.[1]
Clinical Presentation and Phenotypic Diversity
Section titled “Clinical Presentation and Phenotypic Diversity”The clinical presentation of heart failure encompasses a range of symptoms and signs, which can vary significantly between individuals and across different heart failure phenotypes. Patients commonly report physician-documented symptoms indicative of cardiac dysfunction, such as dyspnea or fatigue.[20]Heart failure is broadly categorized into those with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), each exhibiting distinct clinical features and underlying pathophysiologies, necessitating differentiated diagnostic approaches.[19], [21]The burden of both systolic and diastolic ventricular dysfunction contributes to the overall clinical picture of heart failure in the community.[22]
Objective Assessment of Cardiac Structure and Function
Section titled “Objective Assessment of Cardiac Structure and Function”The diagnosis and treatment of heart failure are heavily reliant on the objective assessment of left ventricular (LV) functional and structural parameters derived from various cardiac imaging modalities.[8]Echocardiography (ECHO) is a primary diagnostic tool, providing measurements of LV mass, LV diastolic internal dimension, LV wall thickness, aortic root, and left atrial size, as well as evaluating LV systolic dysfunction, typically defined by an ejection fraction below 50%.[3]Modern evaluation of left ventricular diastolic function also extensively utilizes Doppler echocardiography, along with two-dimensional echocardiography, for noninvasive assessment.[23], [24], [25]Advanced imaging techniques, such as cardiovascular magnetic resonance (CMR), overcome some limitations of 2-dimensional ECHO by providing more standardized and comprehensive assessments of LV phenotypes, including global longitudinal and circumferential strain derived from speckle-tracking echocardiography and feature-tracking cardiac magnetic resonance imaging, which can correlate with invasive diastolic functional indices.[8], [26], [27] Additionally, fractal dimension analysis on cardiac CT images can provide further insights into cardiac structure.[7] and standardized recommendations exist for chamber quantification.[28]
Biomarkers and Prognostic Indicators
Section titled “Biomarkers and Prognostic Indicators”Beyond imaging, specific biomarkers play a crucial role in the diagnosis and prognostic assessment of heart failure. Laboratory measurements of brain natriuretic peptide (BNP) are routinely extracted and utilized to aid in diagnosis and monitor disease severity.[20]These objective biochemical measures complement clinical symptoms and imaging findings, particularly in cases of underdiagnosed heart failure, such as those with supranormal left ventricular ejection fraction (snLVEF) where elevated BNP levels may indicate underlying cardiac stress despite seemingly preserved function.[20]Furthermore, polygenic risk scores derived from left ventricular phenotypes have shown promise as predictive indicators for heart failure events, operating independently of traditional clinical risk factors and offering insights into the genetic basis of prognostically important LV phenotypes.[8]
Causes of Heart Failure
Section titled “Causes of Heart Failure”Heart failure is a complex syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s metabolic demands, leading to substantial morbidity and mortality. Its development is influenced by a confluence of genetic predispositions, environmental exposures, developmental factors, and acquired comorbidities, underscoring the importance of understanding these determinants for effective prevention and treatment.[1]
Genetic Predisposition and Cardiac Architecture
Section titled “Genetic Predisposition and Cardiac Architecture”Genetic factors play a significant role in susceptibility to heart failure, with an increased risk observed in offspring of parents with the condition.[29] Large-scale genome-wide association studies (GWAS) have identified numerous common genetic variants that influence cardiac structure and function, including left ventricular (LV) dimensions, systolic function, and diastolic function.[1]These genetic insights have led to the development of polygenic risk scores, which can predict future heart failure events by integrating the effects of multiple associated loci.[8]Specific genes and loci are implicated in the development of various forms of heart failure and related cardiac conditions. For instance, studies have identified 14 genome-wide significant loci impacting LV end-diastolic volume, end-systolic volume, mass, and ejection fraction, with candidate genes likeTTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11 being enriched in cardiac developmental pathways and contractile mechanisms.[8] Variants in genes such as BAG3, FHOD3, and PLN are linked to cardiomyopathies and affect diastolic function, with PLN being a critical regulator of sarcoplasmic reticulum calcium-ATPase activity and ventricular filling.[30] Furthermore, rare variants identified through whole-exome sequencing, such as MYRIP, TRAPPC11, and SLC27A6, are associated with left ventricular hypertrophy, while gene-gene interactions, like the epistatic effects ofACE I/D and AGT variants, can influence LV mass in hypertensive patients.[5]
Environmental and Lifestyle Modulators
Section titled “Environmental and Lifestyle Modulators”Environmental factors and lifestyle choices significantly modulate the risk and progression of heart failure. Identifying these determinants is crucial for public health prevention strategies.[1] For example, adverse lipid profiles are strongly associated with detrimental changes in cardiac structure and systolic function, and this causal link extends to impairments in diastolic traits.[30] While the provided studies emphasize genetic aspects, they acknowledge the critical interplay of external factors that can either exacerbate or mitigate inherited predispositions, highlighting the need for comprehensive approaches to risk assessment.
Developmental Origins and Gene-Environment Dynamics
Section titled “Developmental Origins and Gene-Environment Dynamics”The earliest stages of cardiac development are critical, with certain genes playing indispensable roles in shaping heart structure and function, thereby influencing later susceptibility to heart failure. Small heat shock proteinsHspb7 and Hspb12 are known to regulate initial steps of cardiac morphogenesis, with HSPB7 specifically being essential for heart development through its modulation of actin filament assembly.[31], [32]The identified candidate genes from GWAS analyses are frequently enriched in cardiac developmental pathways, suggesting that deviations during cardiac formation can predispose individuals to heart failure.[8]Beyond intrinsic developmental programs, gene-environment interactions represent a dynamic interplay where genetic predispositions are modulated by external exposures throughout life. For instance, a genome-wide meta-analysis revealed significant interactions between specific single nucleotide polymorphisms (SNPs) and antihypertensive medication effects on left ventricular traits, particularly in African American populations.[33]This demonstrates how an individual’s genetic makeup can influence their response to therapeutic interventions or environmental stressors, thereby altering their risk profile for heart failure.
Acquired Conditions and Aging
Section titled “Acquired Conditions and Aging”Heart failure is increasingly prevalent with the aging of the global population, making age a significant contributing factor.[1]In addition to age, various acquired comorbidities commonly contribute to the development and progression of heart failure. Conditions such as type 2 diabetes are associated with a higher prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF).[34]Other significant comorbidities include ventricular stiffness, which serves as a substrate for the evolution of mixed etiology heart failure, and atrial fibrillation, where atrial remodeling causally drives this arrhythmic outcome.[30]Even thyroid hormone levels, within the normal reference range, have been linked to heart rate, cardiac structure, and function in middle-aged individuals, highlighting the systemic influences on cardiac health.[35]The interplay of these acquired conditions, often exacerbated by age-related physiological changes, underscores the multifaceted nature of heart failure pathogenesis, distinguishing between heart failure with preserved versus reduced ejection fraction based on their unique clinical features and predictors.[34]
Biological Background
Section titled “Biological Background”Heart failure (HF) is a complex and prevalent condition associated with substantial morbidity, mortality, and healthcare costs, with its incidence increasing as the global population ages.[1] This necessitates a deeper understanding of its genetic and environmental determinants for effective prevention and treatment, representing a significant public health priority.[1]HF manifests in various forms, broadly categorized into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), each involving distinct but often overlapping disruptions in cardiac function.[1] Both HFrEF and HFpEF are characterized by impaired left ventricular (LV) structure and function, affecting the heart’s ability to pump (systolic function) and fill (diastolic function) efficiently.[1]The progression of diastolic dysfunction, where the heart struggles to relax and adequately fill with blood, is a critical pathway that can lead to overt heart failure.[30]Risk factors such as aging, hypertension, and type 2 diabetes contribute to cardiac dysfunction, often leading to increased vascular stiffness and ventricular stiffness, particularly noted in HFpEF.[30]
Genetic Architecture and Regulatory Networks in Heart Failure
Section titled “Genetic Architecture and Regulatory Networks in Heart Failure”Genetic factors significantly contribute to both the overall susceptibility to heart failure and the inter-individual variability in cardiac structure and function.[1]Large-scale genome-wide association studies (GWAS) have been instrumental in identifying numerous genetic loci associated with left ventricular image-derived phenotypes, providing insights into cardiac morphogenesis and heart failure development.[8]These studies underscore the complex interplay of genetic variations in shaping cardiac health and disease progression.[1] Specific genes like HSPB7 and FRMD4Bcontain common variants that are associated with advanced heart failure, withHSPB7also implicated in various etiologies of systolic heart failure and crucial for heart development by modulating actin filament assembly.[36] Other genes, including MYRIP, TRAPPC11, and SLC27A6, are potentially important for left ventricular hypertrophy, particularly in populations of African ancestry.[5] Genetic polymorphisms can also confer protection, as seen with a GRK5polymorphism that inhibits beta-adrenergic receptor signaling, which is protective in heart failure.[37] The Nppa-Nppbcluster locus plays a vital role during heart development and disease, and epistatic effects ofACE I/D and AGTgene variants have been linked to left ventricular mass in hypertensive patients, demonstrating the complex interplay of genetic factors.[5]
Molecular and Cellular Mechanisms of Myocardial Dysfunction
Section titled “Molecular and Cellular Mechanisms of Myocardial Dysfunction”Heart failure at the cellular level is characterized by profound dysregulation of critical molecular pathways and essential cellular functions within cardiomyocytes. Key biomolecules are central to maintaining the structural integrity and contractile capabilities of the heart. For example,HSPB7, a heat shock protein, is vital for heart development and directly influences actin filament assembly, a fundamental process required for muscle contraction and cellular architecture.[32] The robust function of the heart relies heavily on the intricate organization of the cytoskeleton and cell adhesion structures, such as costameres and integrin-based adhesions, which are crucial for myocyte stability and efficient force transmission.[38] Proteins like talin-1 (TLN1) are indispensable for preserving heart function, as its loss can lead to beta-1 integrin reduction, costameric disruption, myocyte instability, and ultimately, dilated cardiomyopathy.[36] Other structural components, including Filamin 2 (Fln2) and Cysteine and Glycine Rich Protein 3 (CSRP3), also contribute to cardiac health, with mutations in CSRP3being associated with cardiac disease.[39]Signaling pathways are frequently perturbed in heart failure, exemplified by the protective effect of aGRK5 polymorphism inhibiting beta-adrenergic receptor signaling, and the detrimental aldosterone-specific activation of cardiomyocyte mineralocorticoid receptors, while metabolic processes are severely compromised, leading to the characterization of the failing heart as an “engine out of fuel.”.[37] Histone deacetylase (HDAC) inhibition has also shown the ability to reverse pre-existing diastolic dysfunction and block extracellular matrix remodeling, highlighting the importance of epigenetic regulation in cardiac pathology.[40]
Cardiac Development and Pathological Remodeling
Section titled “Cardiac Development and Pathological Remodeling”The intricate process of cardiac morphogenesis, or the proper formation of the heart, is a critical developmental stage profoundly influenced by specific genes and their regulatory networks.[8] Small heat shock proteins, such as Hspb7 and Hspb12, are recognized as crucial regulators of these early steps in cardiac development, ensuring the heart forms correctly.[31] This initial developmental integrity is foundational for lifelong cardiac health.[8]However, disruptions during this developmental phase or later in life can precipitate pathological remodeling, a process where the heart undergoes maladaptive structural and functional alterations in response to chronic stressors. This includes left ventricular hypertrophy, characterized by an abnormal increase in heart muscle mass, which often serves as a precursor to the development of heart failure.[5]In conditions like hypertrophic cardiomyopathy, mutations within sarcomere-encoding genes are frequently implicated, leading to the characteristic thickening of the heart muscle, while dilated cardiomyopathy involves the enlargement and weakening of the heart chambers, often linked to myocyte instability.[41]Initially, these changes may act as compensatory responses to maintain cardiac output, but over time, they become detrimental, leading to a progressive decline in heart function and the onset of overt heart failure.[20]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Heart failure is a complex syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s metabolic demands, driven by a myriad of interconnected molecular pathways and cellular mechanisms. These involve dysregulation of signaling cascades, metabolic shifts, compromised structural integrity, and impaired protein homeostasis, often resulting from a combination of genetic predispositions and environmental factors.
Neurohumoral Signaling and Calcium Dysregulation
Section titled “Neurohumoral Signaling and Calcium Dysregulation”The progression of heart failure is significantly influenced by the dysregulation of neurohumoral signaling pathways, which govern cardiac function and adaptation. Beta-adrenergic receptor signaling, while crucial for normal cardiac contractility, can become maladaptive when persistently activated, contributing to disease progression. A specific polymorphism inGRK5has been identified that inhibits beta-adrenergic receptor signaling, and remarkably, this variant is associated with protection against heart failure, illustrating a critical feedback loop in receptor activation and intracellular signaling cascades.[37]Another key pathway in pathological cardiac remodeling involves the calcineurin/NFAT coupling, which is activated in pathological hypertrophy but not in physiological cardiac growth.[42]Furthermore, the mineralocorticoid receptor, activated by aldosterone, plays a direct role in cardiomyocyte function, contributing to hypertrophy and fibrosis.[43] Calcium handling is also a fundamental regulatory mechanism, and disruptions in its homeostasis are central to contractile dysfunction, with the ion channel Orai1 demonstrating a protective role in angiotensin-II-induced pathological cardiac remodeling.[44]
Myocardial Remodeling and Cytoskeletal Integrity
Section titled “Myocardial Remodeling and Cytoskeletal Integrity”The structural integrity of cardiomyocytes is paramount for efficient cardiac function, and its disruption is a hallmark of heart failure, involving complex gene regulation and protein modifications. Truncations in the giant sarcomeric proteinTitinare a significant genetic cause of dilated cardiomyopathy, directly impacting heart function by altering sarcomere structure and contractility, and these variants are also associated with early-onset atrial fibrillation.[45] Beyond Titin, other critical structural components like Filamin 2 are involved in myofibrillar instability, underscoring the intricate regulation of cardiac architecture.[39] Heat shock proteins (HSPs) function as essential regulatory mechanisms, facilitating protein folding and quality control in response to cellular stress. HSPB7 is indispensable for heart development by modulating actin filament assembly, and its involvement, alongside BAG3, has been linked to various etiologies of systolic heart failure.[32] Additionally, MIM, a tissue-specific regulator of cytoskeletal dynamics, interacts with ATP-actin monomers, further illustrating the precision required for maintaining myocardial structure.[46]
Metabolic Reprogramming and Energy Impairment
Section titled “Metabolic Reprogramming and Energy Impairment”Heart failure is frequently characterized by profound shifts in myocardial energy metabolism, often described as an “engine out of fuel,” where the heart transitions from efficient fatty acid oxidation to less efficient glucose utilization.[47] This metabolic reprogramming involves the dysregulation of fatty acid transport and utilization pathways, with proteins like SLC27A6 (Fatty Acid Transport Protein 6, FATP6) identified as potentially important in left ventricular hypertrophy.[5]Changes in the synthesis of dicarboxylic acylcarnitines also reflect altered lipid metabolism in cardiovascular disease, indicating compromised catabolism and flux control.[48]Furthermore, systemic endocrine signals play a role in metabolic regulation, as thyroid hormone levels, even within the normal reference range, are associated with cardiac structure and function, with the thyroid receptor beta influencing lipid metabolism.[35]These metabolic pathways and their dysregulation represent critical disease-relevant mechanisms that offer potential therapeutic targets for heart failure.
Protein Homeostasis and Ubiquitin-Proteasome System
Section titled “Protein Homeostasis and Ubiquitin-Proteasome System”Maintaining precise protein homeostasis, encompassing synthesis, proper folding, and timely degradation, is fundamental for cardiac health, and its disruption is a key mechanism in heart failure. The ubiquitin-proteasome system (UPS) is a major regulatory mechanism responsible for protein catabolism and post-translational regulation, with its dysregulation implicated in the pathogenesis of cardiovascular disease.[11] This system involves E3 ligases, such as components of the SCF ubiquitin ligase complex, which play critical roles in regulating gene expression by marking specific proteins, including cardiac-specific transcription factors, for degradation.[49] The heart’s response to various stressors, including endoplasmic reticulum (ER) stress, involves adaptive changes in gene expression and can significantly impact protein folding and degradation pathways, highlighting the complex network interactions and hierarchical regulation within the cell.[50]This intricate balance of ubiquitination and deubiquitination is vital for preventing the accumulation of misfolded or damaged proteins, which can lead to pathway dysregulation and contribute to the progression of heart failure.
Genetic Predisposition and Personalized Risk Assessment
Section titled “Genetic Predisposition and Personalized Risk Assessment”Understanding the genetic underpinnings of heart failure (HF) and its related cardiac phenotypes offers significant clinical relevance for prognostic assessment and the development of personalized prevention strategies. Large-scale genome-wide association studies (GWAS) have identified numerous genetic susceptibility loci associated with left ventricular (LV) structural and functional parameters, such as LV end-diastolic volume, LV end-systolic volume, LV mass, and LV ejection fraction.[8] These findings enhance the understanding of the genetic basis of prognostically important LV phenotypes in the general population and highlight the intricate genetic relationship between these endophenotypes and the pathogenesis of HF, paving the way for identifying potential novel therapeutic targets.[8] Polygenic risk scores (PRS) derived from these LV phenotypes have demonstrated predictive value for future HF events, independently of traditional clinical risk factors.[8] This suggests a potential role for PRS in personalized risk stratification, allowing for the identification of high-risk individuals who might benefit from early, targeted interventions or intensified monitoring, although further validation of their clinical robustness is needed.[8]Furthermore, an individual’s genetic risk, such as specific genetic risk scores for supranormal left ventricular ejection fraction (snLVEF), has been associated with decreased survival and underdiagnosed HF, even in the absence of common comorbidities like hypertension.[20] The association of parental HF with an increased risk of HF in offspring further underscores the importance of genetic and familial predispositions in risk assessment.[29]
Advanced Cardiac Imaging for Diagnosis and Monitoring
Section titled “Advanced Cardiac Imaging for Diagnosis and Monitoring”Advanced cardiac imaging techniques play a crucial role in the diagnosis, risk assessment, and monitoring of heart failure, providing detailed insights into cardiac structure and function. Cardiovascular magnetic resonance (CMR) imaging, with its standardized protocols, offers high-resolution assessment of LV phenotypes, overcoming some limitations of traditional 2-dimensional echocardiography (ECHO) that rely on geometric assumptions.[8]Feature-tracking CMR, in particular, shows excellent agreement with speckle-tracking echocardiography and invasive measures of diastolic function, making it a valuable tool for characterizing patients with heart failure with preserved ejection fraction (HFpEF).[30] Echocardiography remains a cornerstone for evaluating diastolic function by characterizing features of ventricular relaxation, stiffness, and recoil.[30]Standardized recommendations for cardiac chamber quantification by echocardiography guide clinicians in assessing parameters like LV mass, LV diastolic internal dimension, and LV ejection fraction, which are critical for diagnosis and monitoring disease progression.[51]Specialized techniques like speckle tracking echocardiography can detect early signs of conditions such as uremic cardiomyopathy and predict cardiovascular mortality, highlighting their utility in identifying high-risk individuals and guiding treatment strategies.[52]
Phenotypic Heterogeneity, Comorbidities, and Prognosis
Section titled “Phenotypic Heterogeneity, Comorbidities, and Prognosis”Heart failure is a clinically heterogeneous condition, and understanding its diverse phenotypes and associations with comorbidities is essential for accurate diagnosis, prognostic assessment, and tailored patient care. Distinguishing between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) is critical, as they present with different clinical features, underlying disease pathogenesis, and predictors of new-onset HF.[53]Furthermore, the phenotype of supranormal ejection fraction (snLVEF), characterized by an unusually high LVEF, is associated with decreased survival and a tendency for underdiagnosis of HF, often accompanied by elevated brain natriuretic peptide (BNP) levels and increased HF symptoms.[20]Comorbidities significantly impact the prognosis and management of heart failure. Hypertension, a common comorbidity, is strongly associated with snLVEF and contributes to decreased survival and a higher burden of HF symptoms.[20]Other conditions such as left ventricular hypertrophy, coronary artery disease, and ventricular dysfunction independently affect survival outcomes, particularly in diverse patient populations.[54] Age and sex also influence left ventricular mechanics and diastolic strain analysis, emphasizing the need for age- and sex-specific considerations in diagnosis and monitoring.[30]
Frequently Asked Questions About Heart Failure
Section titled “Frequently Asked Questions About Heart Failure”These questions address the most important and specific aspects of heart failure based on current genetic research.
1. My dad had heart failure; does that mean I’ll definitely get it too?
Section titled “1. My dad had heart failure; does that mean I’ll definitely get it too?”Not necessarily, but your risk is higher. Genetic factors play a significant role in heart failure development, influencing how your heart’s structure and function change over time. While you inherit some genetic predispositions, lifestyle choices and other environmental factors also heavily influence whether you develop the condition.
2. Why do some healthy-looking people get heart failure while others don’t?
Section titled “2. Why do some healthy-looking people get heart failure while others don’t?”Even in seemingly healthy individuals, subtle genetic variations can increase susceptibility. For example, specific changes in genes like HSPB7 or FRMD4Bare linked to advanced heart failure, and variations in genes such asMYRIPcan lead to conditions like left ventricular hypertrophy, which can precede heart failure without obvious outward signs.
3. Can my daily habits really make a difference if heart failure runs in my family?
Section titled “3. Can my daily habits really make a difference if heart failure runs in my family?”Absolutely. While your genes influence your risk, your daily habits can significantly modify that risk. A healthy lifestyle, including diet and exercise, can help mitigate genetic predispositions by positively impacting cardiac structure and function, potentially delaying or even preventing the onset of heart failure.
4. Does stress actually make my heart weaker and increase my risk?
Section titled “4. Does stress actually make my heart weaker and increase my risk?”Yes, chronic stress can contribute to heart problems. While the article doesn’t detail specific stress-related genes, the complex interplay between environmental factors like stress and your genetic predispositions is recognized as an important aspect of heart health. Managing stress is a key part of a heart-healthy lifestyle.
5. If I keep fit, can I overcome a family history of heart failure?
Section titled “5. If I keep fit, can I overcome a family history of heart failure?”Being physically fit is a powerful protective factor. While you can’t change your genes, regular exercise can strengthen your heart and improve its function, helping to counteract some genetic predispositions. This can reduce the likelihood of developing conditions like left ventricular hypertrophy or other structural changes that lead to heart failure.
6. My doctor said my heart looks “normal.” Am I completely in the clear for heart failure?
Section titled “6. My doctor said my heart looks “normal.” Am I completely in the clear for heart failure?”A “normal” assessment is great news, but it’s not a guarantee for life. Heart failure can develop over time, and genetic factors can influence subtle changes in heart structure and function that may not be immediately apparent or that progress later in life. Ongoing monitoring and maintaining a healthy lifestyle are still important.
7. I’m not of European descent; does my background affect my heart failure risk differently?
Section titled “7. I’m not of European descent; does my background affect my heart failure risk differently?”Yes, your ancestry can play a role. Many genetic studies have focused primarily on populations of European descent, meaning that specific genetic variants or risk factors prevalent in other ethnic groups might not be as well understood. This highlights the importance of diverse research to identify ancestry-specific genetic influences on heart failure.
8. Does my heart just naturally get weaker as I get older, making heart failure more likely?
Section titled “8. Does my heart just naturally get weaker as I get older, making heart failure more likely?”Aging is a risk factor for heart failure, and some age-related changes are natural. However, genetic predispositions can influence how gracefully your heart ages and its susceptibility to decline. Understanding these genetic factors is key to developing strategies to maintain heart health as you get older.
9. Could I have hidden heart changes now that might lead to heart failure later?
Section titled “9. Could I have hidden heart changes now that might lead to heart failure later?”Yes, it’s possible. Genetic factors can contribute to subtle alterations in heart structure, like left ventricular hypertrophy, which might not cause symptoms immediately but can precede heart failure. For instance, genes likeMYRIP have been linked to such changes, highlighting that underlying genetic predispositions can lay the groundwork for future issues.
10. My sibling has heart failure, but I don’t. Why the difference if we share genes?
Section titled “10. My sibling has heart failure, but I don’t. Why the difference if we share genes?”While you share many genes, you don’t share all of them, and environmental factors differ. Variations in specific genes, like BAG3 or HSPB7, can contribute to different forms of heart failure. Additionally, individual lifestyle choices, exposures, and even subtle genetic differences can lead to varying outcomes despite a shared family background.
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.
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