Mastering Heart Failure: A Complete Guide for Healthcare Professionals

Introduction

Heart failure (HF) is a complex clinical syndrome characterized by the heart’s inability to pump or receive blood effectively, leading to inadequate perfusion of organs and tissues.[1] This condition arises when the heart muscle becomes weakened or stiffened, failing to circulate sufficient blood to meet the body’s metabolic demands.[2, 3, 4] HF is a progressive disease, often representing the end stage of various underlying cardiovascular processes, and its risk increases significantly with age.[3] Despite its name, HF does not imply that the heart has ceased functioning entirely, but rather that its pumping action is compromised.[5]

Globally, cardiovascular diseases (CVDs), which include HF, are the leading cause of mortality, accounting for an estimated 17.9 million lives annually.[6] HF alone affects an estimated 64.34 million people worldwide, translating to a prevalence of 8.52 per 1,000 inhabitants as of 2017.[7, 8] This widespread prevalence underscores its status as a global pandemic.[8, 9] The burden of HF is particularly pronounced in individuals over 60 years of age, with 81% of all cases and 87% of all years lost due to disability (YLDs) occurring in this demographic.[7] Over the last 28 years, the prevalence of HF has increased by approximately 36% since 1900, a trend not expected to reverse soon.[7] Projections suggest that by 2030, the global prevalence will rise to 9.81 per 1,000 inhabitants, a 15.1% increase, with a corresponding economic burden estimated to reach nearly $400 billion USD.[7] This escalating prevalence and economic impact highlight the urgent need for enhanced preventive interventions and a re-evaluation of healthcare resource allocation to address this evolving epidemiological challenge.[7]

Classification and Staging

The systematic classification and staging of heart failure are crucial for guiding diagnosis, prognosis, and therapeutic strategies. Major international guidelines, including those from the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA) and the European Society of Cardiology (ESC), provide frameworks for understanding the progression and phenotypic variations of HF.[10, 11]

ACC/AHA/HFSA and ESC Guidelines for Classification and Staging

Both American and European guidelines delineate the stages of HF to reflect disease progression, from risk factors to advanced symptomatic disease.[10]

• Stage A: This initial stage identifies individuals at risk for HF who do not yet exhibit symptoms, structural heart disease, or elevated cardiac biomarkers. Risk factors include hypertension, coronary artery disease, diabetes, obesity, exposure to cardiotoxic agents, and a family history of cardiomyopathy.[10, 11, 12, 13] The primary objective at this stage is risk factor modification to prevent disease progression.[11]
• Stage B (Pre-HF): This stage encompasses patients without current or prior HF symptoms but with evidence of structural heart disease, increased ventricular filling pressures, or elevated natriuretic peptides/troponin levels.[10, 11, 12, 13, 14] Management focuses on treating these underlying conditions to prevent the onset of symptomatic HF.[11]
• Stage C (Symptomatic HF): Patients in this stage have structural heart disease and current or previous symptoms of heart failure, such as shortness of breath, fatigue, or edema.[10, 11, 12, 13]
• Stage D (Advanced HF): This represents the most severe form, where patients experience marked HF symptoms that significantly interfere with daily life and lead to recurrent hospitalizations despite optimized medical therapy.[10, 11, 12, 13]

Ejection Fraction (EF) Based Classification

Beyond staging, HF is also classified based on the left ventricular ejection fraction (LVEF), which quantifies the percentage of blood ejected from the left ventricle with each beat.[15, 16] This classification is critical because different EF categories often necessitate distinct therapeutic approaches.[16]

• Heart Failure with Reduced Ejection Fraction (HFrEF): Defined by an LVEF ≤40%.[2, 10, 11, 12, 14, 15, 16] In HFrEF, the left ventricle’s pumping capacity is compromised, often due to weakened heart muscle, leading to insufficient blood circulation and fluid accumulation.[2, 16]
• Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF): Characterized by an LVEF between 41% and 49%.[2, 10, 11, 12, 14, 15, 16] This category was more recently recognized and often includes evidence of increased left ventricular filling pressures.[3, 11, 14]
• Heart Failure with Preserved Ejection Fraction (HFpEF): Defined by an LVEF ≥50%.[3, 10, 11, 12, 14, 15, 16] In HFpEF, the primary issue is the heart’s inability to fill efficiently due to stiffness, even though its pumping action (ejection) remains relatively normal.[2, 16]
• Heart Failure with Improved Ejection Fraction (HFimpEF): A newer classification introduced by ACC/AHA/HFSA guidelines, defined by a previous LVEF ≤40% that has since improved to >40%.[10, 11, 12, 14] Continuation of HFrEF guideline-directed medical therapy (GDMT) is recommended for these patients to reduce relapse risk.[10]

NYHA Functional Classification

Complementing the ACC/AHA staging, the New York Heart Association (NYHA) Functional Classification provides a subjective assessment of a patient’s functional capacity and symptom severity, particularly for those in ACC/AHA stages C and D.[3, 13] This classification is an independent predictor of mortality and helps guide therapeutic interventions.[3]

• Class I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or shortness of breath.[13]
• Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, shortness of breath, or chest pain.[13]
• Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, shortness of breath, or chest pain.[13]
• Class IV: Inability to carry on any physical activity without discomfort. Symptoms of heart failure are present even at rest; if any physical activity is undertaken, discomfort is increased.[13]

While the NYHA classification is widely used, its subjective nature can lead to variability. Studies have shown significant overlap in objective measures like natriuretic peptide levels, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and 6-minute walk distances between different NYHA classes, particularly between classes I and II.[17, 18] This suggests that while it remains a powerful predictor of cardiovascular events, its ability to precisely stratify risk in milder forms of HF may be limited, advocating for integration with more objective measures.[18]

Etiology and Risk Factors

Heart failure is a multifaceted syndrome resulting from various conditions that damage or overwork the heart, often influenced by a combination of predisposing factors. Understanding these etiologies and risk factors is fundamental for both prevention and targeted management.

Primary Causes of Heart Failure

The causes of heart failure can be broadly categorized as intrinsic heart diseases and other pathologies that strain the cardiovascular system.[2, 19]

• Coronary Artery Disease (CAD) and Myocardial Infarction (Heart Attack): Ischemic heart disease, often caused by CAD, is the most common cause of HF.[2, 14, 19] A heart attack occurs when coronary arteries become blocked by a clot, preventing adequate blood supply to the heart muscle, leading to damage or weakening.[2, 4]
• Hypertension (High Blood Pressure): Uncontrolled high blood pressure is a major contributor to HF, even in the absence of CAD.[2, 4, 12, 14, 19, 20] It causes mechanical stress by increasing afterload and induces neurohormonal changes that increase ventricular mass, leading to a stiffer heart that cannot fill efficiently (HFpEF).[4, 19, 20]
• Valvular Heart Disease: Damaged or diseased heart valves (e.g., mitral or aortic stenosis/regurgitation) can impede proper blood flow, forcing the heart to work harder and eventually leading to failure.[2, 12, 19] Rheumatic heart disease is a common cause of valvular disease, particularly in younger populations globally.[19]
• Cardiomyopathy: This is a heterogeneous group of heart muscle diseases where the heart walls become stiff, stretched, or thickened, reducing pumping efficiency.[2, 19] Types include dilated, hypertrophic, and restrictive cardiomyopathies, many of which have a genetic basis.[19]
• Abnormal Heart Rhythm (Arrhythmia): Irregular heart rhythms can impair the heart’s electrical system, leading to inefficient pumping.[2, 14] Tachycardia-related cardiomyopathy is one example where persistently fast heart rates can weaken the heart muscle.[21]
• Congenital Heart Disease: Structural heart problems present at birth can lead to HF.[2, 4]
• Inflammatory Conditions: Myocarditis, often caused by viral infections (e.g., adenoviruses, enteroviruses, HIV, COVID-19), can lead to inflammatory cardiomyopathy and HF.[2, 19] Chagas disease is a significant cause in Latin America.[19]
• Other Causes: These include childbirth (peripartum cardiomyopathy), overactive thyroid (hyperthyroidism), excessive alcohol consumption (alcohol-induced cardiomyopathy), certain cancer medications (cardiotoxicity), and recreational drug use.[2, 4, 12] Chronic obstructive pulmonary disease (COPD) is also a common etiology, particularly for right-sided heart failure.[4, 19]

Major Risk Factors for Heart Failure Development

Several factors increase the likelihood of developing heart failure, with the risk escalating as more contributing factors are present.[4] These can be broadly categorized into modifiable and non-modifiable factors.

Modifiable Risk Factors:

• High Blood Pressure (Hypertension): A primary risk factor that strains the heart and blood vessels.[5, 6, 14, 22, 23] Optimal control of blood pressure is a Class 1 recommendation in guidelines for HF prevention.[14]
• High Blood Cholesterol/Dyslipidemia: Unhealthy cholesterol levels contribute to atherosclerosis, narrowing arteries and increasing heart disease risk.[22, 23]
• Diabetes Mellitus: Both Type 1 and Type 2 diabetes significantly increase HF risk. Poor glycemic control is associated with worse outcomes.[5, 14, 22, 23, 24] SGLT2 inhibitors are recommended for patients with Type 2 diabetes and cardiovascular disease or high risk for CVD to reduce HF risk.[12, 14]
• Obesity and Overweight: Excess body fat is linked to higher “bad” cholesterol, triglycerides, high blood pressure, and diabetes, all contributing to heart disease.[5, 14, 22, 23] Obesity is also a chronic systemic inflammatory state that directly stresses the cardiovascular system.[3]
• Unhealthy Diet: Diets high in saturated fats, trans fats, cholesterol, and excessive sodium contribute to heart disease and elevated blood pressure.[6, 22] Healthy dietary patterns, such as the Mediterranean and DASH diets, are recommended.[10, 25, 26]
• Physical Inactivity: Lack of physical activity leads to heart disease and increases the risk of obesity, high blood pressure, high cholesterol, and diabetes.[6, 22, 23] Regular physical activity is emphasized for prevention.[10, 12, 14, 26]
• Tobacco Use: Smoking damages the heart and blood vessels, increasing the risk of atherosclerosis and heart attack. Nicotine raises blood pressure, and carbon monoxide reduces oxygen-carrying capacity. Exposure to secondhand smoke also poses a risk.[5, 6, 22, 23] Smoking cessation is strongly recommended.[14, 26]
• Harmful Alcohol Use: Excessive alcohol consumption can raise blood pressure, increase triglycerides, and lead to cardiomyopathy.[2, 6, 22, 23] Avoiding excessive intake is advised.[10, 14]
• Stress: Stressful situations can raise heart rate and blood pressure, increasing the heart’s oxygen demand and potentially injuring artery linings.[23]
• Exposure to Cardiotoxic Agents: Certain cancer treatments (radiation and chemotherapy) can injure the heart.[2, 4, 12, 14]

Non-Modifiable Risk Factors:

• Age: The risk of HF increases significantly with age, particularly after 60 years, as the heart naturally weakens and stiffens.[4, 5, 7, 22, 23]
• Genetics and Family History: A family history of heart disease or certain genetic mutations can increase susceptibility to HF.[4, 5, 14, 19, 22, 23] Genetic screening and counseling are recommended for cardiomyopathies in first-degree relatives.[14]
• Sex: Heart failure is common in both men and women. Men often develop HFrEF at a younger age, while women more commonly experience HFpEF and may have worse symptoms.[4, 7] While prevalence is higher in females, years lost due to disability (YLDs) are marginally higher in men.[7]
• Race/Ethnicity: Certain racial and ethnic groups, such as Black and African American individuals in the U.S., have a higher likelihood of developing HF, often with more severe cases and at a younger age.[4, 22]

Pathophysiology

Heart failure is a complex clinical syndrome arising from intricate pathophysiological processes that impair ventricular structure or function, leading to the heart’s inability to effectively pump or receive blood.[1, 3] These impairments result in inadequate organ perfusion and the characteristic symptoms of dyspnea, fatigue, and congestion.[3]

Mechanisms of Cardiac Dysfunction

The fundamental mechanisms of cardiac dysfunction in HF involve a decline in stroke volume due to either systolic dysfunction, diastolic dysfunction, or a combination thereof.[27]

• Systolic Dysfunction: Primarily associated with HFrEF, this involves a loss of intrinsic myocardial contractility (inotropy). It can be caused by disease-induced alterations in signal transduction mechanisms, acute or chronic ischemia, or the loss of viable muscle following a myocardial infarction.[27] The left ventricle typically enlarges and weakens, leading to reduced stroke volume and elevated left ventricular end-diastolic pressure.[1]
• Diastolic Dysfunction: Predominantly seen in HFpEF, this occurs when the ventricle becomes less compliant or “stiffer,” impairing its ability to relax and fill efficiently.[27, 28, 29] This reduced filling capacity results in less blood being ejected, even if the ejection fraction is preserved.[27, 28] Common histopathological findings in HFpEF include fibrosis, hypertrophy, and inflammation, all contributing to decreased distensibility and elasticity.[1, 29]

Both systolic and diastolic dysfunction lead to an increase in ventricular end-diastolic pressure. This initially acts as a compensatory mechanism, utilizing the Frank-Starling mechanism to augment stroke volume. However, under chronic conditions, these compensatory changes can ultimately worsen cardiac function.[27]

A significant area of research indicates that cardiac dysfunction is intimately linked to abnormalities in calcium handling within cardiac cells.[30] The sarcolemma, sarcoplasmic reticulum, and mitochondria play crucial roles in regulating intracellular Ca2+ concentration, and their remodeling due to changes in gene expression or protein-phospholipid interactions contributes to impaired myofibrillar interaction with Ca2+ in the failing heart.[30]

Ventricular Remodeling: Pathological Changes in Heart Structure and Function

Ventricular remodeling, or cardiac remodeling, refers to detrimental changes in the heart’s size, shape, structure, and function.[31, 32] This pathological process typically follows an injury to the heart muscle, such as a myocardial infarction, or chronic conditions that impose increased pressure or volume overload, like hypertension or valvular heart disease.[32]

After an insult, the left ventricular myocardium undergoes a series of histopathological and structural alterations that progressively diminish its performance.[32] This can manifest as ventricular hypertrophy (thickening of the muscle walls) or ventricular dilation (stretching of the chambers).[32] In HFrEF, eccentric hypertrophy is common, characterized by increased chamber size without proportional wall thickening, leading to increased left ventricular end-diastolic volume.[29] Conversely, HFpEF often involves concentric hypertrophy, where the ventricular wall thickens relative to chamber size, resulting in increased left ventricular mass but normal or slightly reduced end-diastolic filling volume.[3, 29]

Myocardial necrosis and thinning of the heart wall can occur post-myocardial infarction, leading to chamber dilatation. While initial remodeling may be beneficial for maintaining cardiac output, prolonged remodeling causes the heart to become less elliptical and more spherical, increasing ventricular mass and volume, which adversely affects function.[32] Cellular abnormalities, such as increased cardiomyocyte diameter in HFpEF and disruptions in extracellular matrix proteins and fibrosis in HFrEF, contribute to these structural changes.[29] Fibroblast activation and increased collagen synthesis lead to fibrosis, further stiffening the heart.[32]

Neurohumoral Activation: Role of SNS, RAAS, and AVP Systems

In heart failure, a critical compensatory response involves the activation of several neuroendocrine systems, including the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS), and the arginine vasopressin (AVP) system.[27, 33, 34] While initially adaptive, prolonged activation of these systems plays a key role in the progression of HF and the perpetuation of its pathophysiology.[27, 33]

• Sympathetic Nervous System (SNS) Activation: Elevated catecholamine levels and SNS activation are consistently observed in HF patients, leading to excessive vasoconstriction, persistent tachycardia, and cardiac arrhythmias.[33] This hyperactivity can deplete myocardial norepinephrine stores, making the heart dependent on circulating catecholamines, which paradoxically increase vascular resistance and afterload, worsening cardiac performance.[33] Chronic SNS activation also contributes to maladaptive remodeling and arrhythmogenicity.[33]
• Renin–Angiotensin–Aldosterone System (RAAS) Activation: Reduced renal perfusion in HF activates the RAAS. Angiotensin II, a potent vasoconstrictor, promotes fibrosis in the heart and kidneys and exacerbates neurohormonal activation.[33] Aldosterone further enhances sodium retention, potassium excretion, and contributes to myocardial and vascular fibrosis.[33] Chronic overactivation of RAAS leads to significant salt and water retention and left ventricular hypertrophy.[33]
• Arginine Vasopressin (AVP) System Activation: High plasma AVP concentrations are found in congestive HF patients. AVP contributes to disease progression through V1a receptor activation (vasoconstriction, increased afterload, myocardial hypertrophy) and V2 receptor activation (fluid retention, edema, hyponatremia).[33]

These neurohumoral responses, while initially attempting to maintain cardiac output and arterial blood pressure, can ultimately aggravate HF by increasing ventricular afterload and preload, leading to pulmonary or systemic congestion and edema.[27] Therapeutic interventions often target these systems to attenuate their deleterious effects.[27]

Diastolic Dysfunction in HFpEF: Impaired Relaxation and Reduced Compliance

Diastolic dysfunction is a hallmark of Heart Failure with Preserved Ejection Fraction (HFpEF), affecting approximately 50% of HF patients.[3, 28] It describes changes in ventricular diastolic properties that adversely impact ventricular filling and stroke volume, even when the LVEF is normal (≥50%).[28, 29]

The pathophysiology of diastolic dysfunction in HFpEF involves two primary mechanisms:

1. Reduced Ventricular Compliance: This is most commonly a consequence of left ventricular hypertrophy, where the ventricle becomes stiffer.[28] This increased stiffness elevates the end-diastolic pressure-volume relationship, resulting in less ventricular filling (decreased end-diastolic volume) and a higher end-diastolic pressure.[1, 28] This can arise from chronic hypertension or aortic valve stenosis.[28] The elevated left ventricular filling pressure is then transmitted backward, increasing left atrial, pulmonary venous, and pulmonary arterial pressures, potentially leading to pulmonary congestion and edema.[28]
2. Impaired Ventricular Relaxation (Reduced Lusitropy): This non-anatomical mechanism involves a decreased rate and extent of myocyte relaxation.[28] Proper relaxation requires the sarcoplasmic reticulum to actively sequester Ca++, allowing actin and myosin to disengage. If this process is impaired (e.g., by reduced Ca++ uptake), ventricular filling is reduced, especially during the rapid filling phase.[28]

At the cellular level, cardiomyocytes in HFpEF show increased diameter (consistent with concentric hypertrophy), and while fibrotic changes are variable, an increased amount of collagen is typically observed, contributing to ventricular stiffening.[29] A pro-inflammatory state may also contribute by inducing endothelial changes, reducing nitric oxide availability, and promoting hypertrophic changes and fibrosis.[29] The elevated left ventricular filling pressures induce structural remodeling of the left atrium, leading to smaller left atrial volumes but increased left atrial peak pressures and stiffness, making patients more prone to atrial fibrillation.[3] Pulmonary hypertension is common in HFpEF patients, linked to increased morbidity and mortality, and often leads to right ventricular dysfunction, further worsening prognosis.[3, 29]

Clinical Manifestations and Diagnosis

Recognizing the clinical manifestations and accurately diagnosing heart failure are critical for timely intervention and improved patient outcomes. The symptoms of HF can be subtle or easily dismissed, often progressing gradually over time.[5]

Symptoms and Signs of Heart Failure

Common symptoms and signs of heart failure reflect the heart’s diminished ability to pump blood effectively and the resulting fluid buildup in the body.[1, 5, 35]

• Shortness of Breath (Dyspnea): A key symptom, particularly noticeable during activity, when lying down (orthopnea), or waking up at night gasping for breath (paroxysmal nocturnal dyspnea).[1, 5, 35, 36] This occurs as blood backs up into the lungs, causing fluid to accumulate in the air sacs (pulmonary edema).[37, 38]
• Fatigue and Weakness: Feeling unusually tired or weak, even with minimal activity, is a common sign due to the body not receiving enough oxygen-rich blood.[1, 5, 35, 38]
• Swelling (Edema): Accumulation of fluid, most commonly in the legs, ankles, and feet, but also potentially in the abdomen (ascites).[1, 5, 35] This is caused by increased pressure in the veins as the heart struggles to circulate blood.[37]
• Persistent Cough or Wheezing: A cough, especially one that produces white or pink, foamy mucus, can indicate fluid buildup in the lungs.[5, 35] Wheezing can also be a sign of pulmonary congestion.[5, 35]
• Rapid or Irregular Heartbeat (Palpitations): The heart may race, pound, or have an irregular rhythm as it tries to compensate for its reduced pumping efficiency.[5, 35]
• Reduced Exercise Capacity: Patients often experience a diminished ability to perform physical activities.[5, 35]
• Loss of Appetite or Nausea: These vague symptoms can be related to fluid buildup affecting the digestive system.[1, 5, 35]
• Sudden Weight Gain: Especially if accompanied by swelling, this can indicate fluid retention.[5, 35] Daily weight monitoring is crucial for early detection of fluid retention.[26]
• Night-time Urination (Nocturia): Increased need to urinate at night can be an indirect sign of fluid redistribution.[5]
• Chest Pain: If HF is caused by a heart attack or coronary artery disease, chest pain, particularly during physical activity, may be present.[5]
• Difficulty Concentrating or Decreased Alertness: Reduced blood flow to the brain can cause cognitive impairments.[1, 5]

It is imperative to consult a healthcare professional if any combination of these symptoms is persistent or worsening, as early detection and treatment significantly improve quality of life and prognosis.[5] Emergency medical help should be sought for severe symptoms such as chest pain, fainting, severe shortness of breath with foamy mucus, or a rapid/irregular heartbeat accompanied by other serious signs.[5]

Diagnostic Criteria and Tools

The diagnosis of heart failure relies on a comprehensive evaluation combining clinical assessment, laboratory tests, and advanced imaging. International guidelines from ACC/AHA/HFSA and ESC provide evidence-based recommendations for this process.[11]

Initial Investigations for Suspected or Newly Diagnosed HF:

• History and Physical Examination: Crucial for identifying symptoms, signs of congestion (e.g., jugular vein distension, rales, edema), and underlying etiologies.[11, 14, 36]
• 12-Lead Electrocardiogram (ECG): Recommended for all patients with HF to assess heart rhythm and identify potential abnormalities.[11, 14, 39]
• Blood Tests: A comprehensive panel is recommended to differentiate HF from other conditions, provide prognostic information, and guide therapy. This includes:
  • Natriuretic Peptides (BNP or NT-proBNP): These biomarkers are elevated in response to cardiac wall stress and are highly useful for ruling out HF, especially HFrEF, when levels are below certain cut-offs (e.g., BNP <35 pg/mL or NT-proBNP <125 pg/mL).[11, 36, 40, 41] Elevated levels support the diagnosis, particularly for patients presenting with dyspnea or for risk stratification in chronic HF.[11, 36] However, NP levels can be lower in HFpEF and consistently lower in obese patients, necessitating careful interpretation and often requiring further imaging.[36, 41, 42]
  • Serum electrolytes, blood urea nitrogen, creatinine, full blood count, lipid profile, liver function tests, iron studies, and thyroid-stimulating hormone.[11, 14, 39]
• Transthoracic Echocardiography (TTE): Considered the cornerstone of non-invasive investigation, TTE is essential for determining Left Ventricular Ejection Fraction (LVEF) and identifying the underlying etiology of HF.[11, 36, 39, 41, 43] It provides detailed information on cardiac structure and function, including systolic, diastolic, left atrial, and right ventricular function.[41, 43]
  • For HFrEF, an LVEF <40% is diagnostic.[41]
  • For HFpEF, diagnosis is more challenging, requiring LVEF ≥50% along with evidence of cardiac dysfunction such as abnormal LV filling, elevated filling pressures (e.g., E/e′ ≥13 or ≥15), left atrial dilation, or LV hypertrophy.[29, 36, 39, 41, 43] Stress echocardiography can reveal abnormalities exaggerated during exercise that are not discernible at rest.[29] Newer modalities like Global Longitudinal Strain (GLS) by speckle-tracking echocardiography offer more sensitive markers of LV systolic function and prognostic value, even with normal LVEF.[41, 43]
• Chest X-ray: Provides supportive evidence of HF and helps rule out alternative causes of breathlessness. Common findings include cardiomegaly, pleural effusions, Kerley B lines (interstitial edema), and upper lobe pulmonary venous congestion.[11, 39, 44, 45, 46]
• Cardiac Magnetic Resonance (CMR) Imaging: Recommended for assessing myocardial structure and function when TTE image quality is inadequate or for characterizing myocardial tissue in suspected infiltrative, inflammatory, or genetic diseases (e.g., amyloid, sarcoidosis, myocarditis).[11, 39, 47] CMR is considered the gold-standard non-invasive modality for characterizing diseases causing HF, offering high spatial and temporal resolution, and the ability to non-invasively interrogate myocardial tissue composition using techniques like late gadolinium enhancement (LGE) and parametric mapping.[47]
• Invasive Testing:
  • Cardiac Catheterization and Coronary Angiography: Recommended for patients with persistent angina and intermediate to high pre-test probability of CAD who are suitable for revascularization.[11, 39] Right heart catheterization is used in selected patients with persistent or worsening symptoms where hemodynamics are uncertain, or for those with severe HF being evaluated for heart transplant or mechanical circulatory support.[11, 36, 39]
  • Cardiopulmonary Exercise Testing (CPET): Recommended in selected ambulatory patients to determine appropriateness for advanced treatments (e.g., LV assist device, heart transplant) and to assess functional capacity and cause of dyspnea.[11, 39] Invasive exercise testing with right heart catheterization is considered the gold standard to confirm HFpEF as the cause of symptoms by directly assessing elevated PCWP at rest (≥15 mmHg) or during exercise (≥25 mmHg).[36]

Integrated Diagnostic Approaches:

Scoring systems like the H2FPEF score (combining obesity, AF, age, etc.) and the HFA-PEFF score (ESC/HFA) are available to aid in risk stratification and guide the diagnostic workup for HFpEF, reserving more costly tests for intermediate pre-test probability patients.[36, 39]

Management Strategies

The management of heart failure is a multi-pronged approach encompassing pharmacological, non-pharmacological, and advanced device/surgical interventions, all aimed at improving symptoms, quality of life, and survival, while reducing hospitalizations.

Pharmacological Treatment

Pharmacological interventions form the cornerstone of HF management, with distinct guideline-directed medical therapies (GDMT) tailored to different EF phenotypes.

Guideline-Directed Medical Therapy (GDMT) for HFrEF (Quadruple Therapy)

For patients with HFrEF (LVEF ≤40%), current guidelines from both ESC and AHA recommend a “quadruple therapy” approach, which has been shown to significantly improve survival and reduce morbidity.[48, 49, 50, 51] This therapy should ideally be initiated during hospitalization and rapidly uptitrated to maximum tolerated doses within weeks after discharge.[48, 49, 50] The four foundational medication classes include:

1. Beta-blockers: These drugs antagonize the effects of catecholamines, leading to reductions in heart rate, blood pressure, and myocardial oxygen demand, while improving left ventricular function and remodeling.[48, 52] Large-scale trials have demonstrated significant reductions in mortality and hospitalization rates with beta-blockers like carvedilol, metoprolol succinate, and bisoprolol.[48]
2. Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) or alternatively ACE inhibitors (ACEIs) or Angiotensin Receptor Blockers (ARBs): ARNIs (e.g., sacubitril/valsartan) work by inhibiting neprilysin, which prevents the degradation of natriuretic peptides, and blocking angiotensin II, leading to natriuresis, diuresis, and vasodilation.[53, 54] ACEIs and ARBs block the renin-angiotensin system, reducing vasoconstriction and fluid retention.[27, 53] Guidelines recommend de novo ARNI initiation or switching from ACEI/ARB to ARNI for symptomatic patients.[10]
3. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: This class of drugs (e.g., empagliflozin, dapagliflozin) was initially developed for diabetes but has shown remarkable benefits in HFrEF, irrespective of diabetic status.[48, 52, 55] Their mechanisms include improved energy metabolism, increased natriuresis/diuresis, decreased inflammation, weight loss, and improved cardiac remodeling.[48, 52] SGLT2 inhibitors are strongly recommended (Class 1 indication) for reducing HF hospitalization and death.[48, 56]
4. Mineralocorticoid Receptor Antagonists (MRAs): MRAs (e.g., spironolactone, eplerenone) block aldosterone’s effects, reducing sodium retention, myocardial fibrosis, and vascular injury.[33, 50] They are recommended for patients with Class II-IV HF.[50]

Despite the profound benefits, including an estimated 8-year survival improvement for a 55-year-old HF patient on quadruple therapy, adoption remains poor, with less than 10% of eligible patients receiving this comprehensive treatment.[48, 49, 51] Strategies for rapid initiation in the hospital are being advocated to improve implementation.[49]

Pharmacological Therapies for HFpEF

Effective treatment options for HFpEF have historically been limited, with a growing understanding that therapies effective in HFrEF often do not show comparable benefits in HFpEF.[56, 57] However, recent trials have expanded the pharmacological armamentarium for HFpEF.

• SGLT2 Inhibitors: These are supported by the most robust evidence for HFpEF.[56] Trials like EMPEROR-Preserved and DELIVER have shown that SGLT2 inhibitors improve cardiovascular mortality and HF events by approximately 20% in patients with symptomatic HF and LVEF ≥40%.[56] They are recommended as Class 1 (ESC) or Class 2a/1 (ACC/AHA/HFSA) indications for reducing HF events and cardiovascular death in HFpEF.[10, 56, 58]
• Mineralocorticoid Receptor Antagonists (MRAs): MRAs have shown some reduction in hospitalization rates for HFpEF, particularly in a prespecified subgroup analysis, and receive a Class 2b recommendation in both ACC/AHA/HFSA and ESC guidelines.[3, 10]
• Angiotensin Receptor-Neprilysin Inhibitors (ARNIs): While not as strongly supported as SGLT2 inhibitors, ARNIs like sacubitril/valsartan have shown a tendency to lower the risk of HF-related hospitalizations in HFpEF, particularly in women.[3, 56] They receive a Class 2b recommendation in ACC/AHA/HFSA guidelines.[10]
• Diuretics: These remain a crucial first-line treatment for managing acute congestion and improving symptoms in HFpEF, with loop diuretics being preferred.[3, 56] Thiazide diuretics may be added for synergistic effects in cases of insufficient response.[56]
• Antihypertensive Therapies: Optimal blood pressure control (below 130/80 mm Hg) is a goal, with diuretics, ARNIs, ARBs, and MRAs being preferred pharmacologic interventions for uncontrolled hypertension in HFpEF.[3] Beta-blockers may also be beneficial, especially for patients with concomitant coronary artery disease.[3]

Non-Pharmacological Management and Lifestyle Modifications

Lifestyle modifications are integral to HF management, complementing pharmacological treatments to slow disease progression, alleviate symptoms, and improve quality of life.[26, 59]

• Sodium Restriction: Aims to reduce fluid retention and volume overload. While international guidelines recommend sodium restriction (e.g., <2g/day for moderate-severe HF by KSHF, avoiding >5g/day by ESC, avoiding excessive sodium by AHA/ACC), its efficacy, particularly in malnourished patients, is debated, with some studies suggesting no long-term quality of life improvement and potentially increased mortality/readmission risk.[26] An individualized approach is often more beneficial.[26]
• Fluid Restriction: The benefit of routine fluid restriction is also debated, with inconsistent evidence. Guidelines offer no clear universal recommendations, suggesting consideration on a case-by-case basis (e.g., 1.5-2L for severe HF/hyponatremia by ESC).[26]
• Dietary Adjustments: Adherence to heart-healthy, evidence-based diets such as the Dietary Approaches to Stop Hypertension (DASH) diet and the Mediterranean diet is recommended by AHA/ACC.[10, 25, 26, 59] These diets focus on reducing sodium, increasing fruits, vegetables, and low-fat dairy, and incorporating lean proteins and healthy fats.[25, 26, 60] For overweight or obese patients, caloric restriction for weight loss is advised.[26] In advanced HF, managing unintentional weight loss, sarcopenia, and cardiac cachexia with high-calorie, high-protein diets and resistance training is crucial.[26]
• Physical Activity and Cardiac Rehabilitation (CR): Regular physical activity and exercise-based CR programs significantly enhance functional status, exercise capacity, and quality of life, while reducing hospitalizations.[26, 59, 61, 62, 63] CR is a medically supervised program that includes personalized exercise, education on risk factors, nutritional advice, and psychosocial support.[61, 62] Guidelines strongly recommend CR for eligible patients.[26, 59]
• Weight Management: While weight loss is recommended to prevent HF, its efficacy in established HF is less clear due to the “obesity paradox” where lower BMI in mild obesity may be linked to higher mortality.[26, 59] Guidelines vary, with some recommending weight loss for symptom management in certain BMI ranges.[26]
• Substance Use Cessation: Strong advice for cessation of heavy alcohol use, tobacco, cannabis, and cocaine, as they are linked to HF onset and progression.[26, 59] Smoking cessation, in particular, lowers the incidence of adverse cardiovascular events.[26]
• Daily Weight Monitoring: Critical for early detection of fluid retention, which indicates worsening HF. Patients are advised to weigh themselves daily at the same time, using the same scale, and to report significant gains (e.g., 2-3 pounds/day or 5 pounds/week) to their healthcare provider.[25, 26, 59]
• Stress Management: Techniques like mindfulness and stress reduction may be helpful, as anxiety and depression are common in HF patients and can worsen outcomes.[25, 59]
• Immunization: Vaccinations against preventable respiratory illnesses (e.g., influenza, pneumonia) are recommended.[10, 14, 25]

Device Therapies and Surgical Interventions

For patients with advanced heart failure or specific cardiac conditions, device therapies and surgical interventions offer crucial options to manage symptoms, improve heart function, and extend life expectancy.[55, 63, 64, 65]

• Pacemakers: Indicated for patients whose heart beats too slowly. Pacemakers continuously monitor heart rate and deliver electrical pulses to maintain a regular and appropriate rhythm.[64]
• Cardiac Resynchronization Therapy (CRT) Devices: Used when the left ventricle’s walls contract out of sync. CRT, a specialized pacemaker, coordinates ventricular contractions, improving pumping efficiency and reducing symptoms.[53, 55, 63, 64, 65] Guidelines recommend CRT as a Class I indication for patients with sinus rhythm, NYHA Class III or ambulatory IV symptoms, QRS duration ≥120ms (with stronger evidence for ≥150ms), and LVEF ≤35% despite optimal medical therapy.[66, 67] It induces reverse remodeling and reduces mitral regurgitation.[66]
• Implantable Cardioverter Defibrillators (ICDs): Fitted for patients with, or at high risk of, dangerous abnormal heart rhythms (ventricular tachyarrhythmias) to prevent sudden cardiac arrest.[53, 63, 64, 65] An ICD monitors heart rhythm and delivers electrical shocks (defibrillation) to restore normal rhythm if a life-threatening arrhythmia is detected.[64, 65, 68, 69] Indications include hemodynamically unstable VT or VF without a reversible cause, stable sustained VT with structural heart disorder, or ischemic/non-ischemic cardiomyopathy with NYHA Class II/III symptoms and LVEF ≤35% despite optimal medical therapy.[69, 70]
• CRT-Ds: Combination devices that provide both cardiac resynchronization and defibrillation for patients who need both therapies.[64, 65]
• Pulmonary Artery Pressure Sensors (e.g., CardioMEMS HF System): A small, wireless sensor implanted in the pulmonary artery to remotely monitor pressure and detect early signs of worsening HF. This proactive approach allows for timely adjustments to medications, helping prevent hospitalizations and offering personalized care.[53, 64, 65]
• Left Ventricular Assist Devices (LVADs): Mechanical blood pumps implanted to assist the left ventricle in pumping blood throughout the body when the heart is too weak.[54, 55, 63, 64, 65] LVADs can serve as a bridge to heart transplantation or as a long-term therapy for patients not eligible for transplant.[54, 55, 64, 65] Advances in LVAD technology have led to smaller, more efficient devices with improved outcomes.[55]
• Heart Transplant: The ultimate treatment for severe, end-stage heart failure that cannot be managed by other therapies.[64, 68, 71, 72] It replaces a failing heart with a healthy donor heart, potentially improving or resolving symptoms.[68] However, it is a complex procedure with risks and limitations, including donor organ availability and lifelong immunosuppression.[64, 68]
• Heart Valve Surgery: If damaged or diseased heart valves contribute to HF, surgical repair or replacement may be recommended.[64, 68]
• Coronary Angioplasty or Bypass Surgery (CABG): For HF caused by coronary artery disease, these procedures can restore blood flow to the heart muscle.[64, 68]
• Percutaneous Valve Interventions: Non-surgical procedures using catheters to widen narrowed valves, reduce leaks in leaky valves, or replace faulty valves.[68]
• Cardiac Contractility Modulation (CCM): A therapy that uses electrical signals to enhance ventricular contractility and promote favorable myocardial remodeling, without increasing oxygen demand. It is an option for HFrEF patients with NYHA Class III/IV symptoms and LVEF 25-45% who are ineligible for or non-responsive to CRT.[73]
• Baroreflex Activation Therapy (BAT): Electrically stimulates the carotid baroreceptor to decrease sympathetic activity and increase parasympathetic activity, alleviating HF symptoms. Approved for symptomatic improvement in HFrEF patients (NYHA Class III/II with recent III history) with LVEF ≤35% and specific NT-proBNP levels, and no Class I CRT indication.[73]
• Mitraclip: A device placed inside the heart to help it pump more effectively, typically used for moderate to severe HF patients unresponsive to other treatments, improving quality of life and reducing hospitalizations.[54]
• V-Wave InterAtrial Shunt Device: An implanted device that redirects blood flow to improve symptoms and quality of life.[54]
• Personalized Volume Management Systems (PVM): Devices that use sensors to continuously monitor hemodynamic parameters and guide clinicians in optimizing fluid status, improving outcomes and reducing hospital admissions.[54]

Prognosis and Complications

The prognosis of heart failure varies significantly, influenced by numerous factors including disease stage, ejection fraction, age, sex, and the presence of comorbidities. HF is a progressive disease, and its complications can profoundly impact patient morbidity, mortality, and quality of life.

Prognosis and Survival Rates

Overall, the outlook for individuals with HF remains challenging despite treatment advancements.[74]

• General Survival Rates: International cohort studies report 1-year survival rates for chronic HF around 80–90% (compared to 97% in the general population) and 5-year survival rates around 50–60% (compared to 85% in the general population).[74, 75] Ten-year survival rates are approximately 27–35%.[74, 75] For acute HF, 30-day post-discharge survival is around 80%.[75]
• Prognosis by Stage (ACC/AHA/HFSA): Survival rates decline significantly with advancing stages.[74]
  • Stage A: 5-year survival rate of 97%.
  • Stage B: 5-year survival rate of 95.7%.
  • Stage C: 5-year survival rate of 74.6%.
  • Stage D: 5-year survival rate of 20%.[74]
• Prognosis by Ejection Fraction (LVEF): While some studies suggest no significant difference in survival rates between HFrEF and HFpEF over time, mortality generally increases with decreasing LVEF.[74, 76]
  • LVEF ≤15%: 51% mortality
  • LVEF 16–25%: 41.7% mortality
  • LVEF 26–35%: 31.4% mortality
  • LVEF 35–45%: 25.6% mortality[74]
• Prognosis by NYHA Functional Class: Higher NYHA classes are associated with worse prognoses and higher mortality rates.[9, 17, 18, 72, 77, 78]
  • Class II (mild symptoms): 1-year mortality 5-10%.[78]
  • Class III (moderate symptoms): 1-year mortality 10-15%.[78]
  • Class IV (severe symptoms): 1-year mortality 30-40%.[78] The prognosis for end-stage HF (NYHA Class IV) is generally poor, with a median survival of approximately 6-12 months without advanced interventions.[72]
• Factors Affecting Survival:
  • Age: Complications and mortality steadily increase with age. While younger patients have lower death rates, they are still significant.[74]
  • Sex: Women with HF tend to live longer than men, especially when the cause is not ischemia.[74]
  • Exercise Tolerance: Reduced exercise tolerance is a key symptom and is associated with poorer quality of life and increased mortality.[74]
  • Hospitalization: HF requiring hospitalization is linked to poor outcomes, with multiple hospitalizations increasing the risk of death.[74]

Impact of Comorbidities on Prognosis

The presence of multiple cardiovascular and non-cardiovascular comorbidities (multimorbidity) is a major issue in HF, complicating management and significantly worsening prognosis.[24, 79, 80, 81] Nearly all HF patients (99.8%) have at least one comorbidity, and over 95% have two or more.[79]

• Hypertension, Chronic Kidney Disease (CKD), and Diabetes: These represent the comorbidity pairs with the greatest population-level risk, accounting for a substantial proportion of deaths in HFpEF patients.[79, 80, 81]
• Polyvascular Disease (Stroke, Peripheral Artery Disease, Coronary Artery Disease) and Chronic Obstructive Pulmonary Disease (COPD): These combinations pose the highest risk at the individual patient level.[79, 80, 81] For instance, stroke and CAD combined resulted in a 61% excess risk of death.[79]
• Anemia and Iron Deficiency: Commonly observed in all HF forms, these conditions have a multifactorial etiology and are responsible for reduced exercise tolerance, impaired quality of life, and poor long-term prognosis.[24, 37] Anemia is an independent prognostic predictor in both HFrEF and HFpEF.[24] Iron deficiency affects 35-55% of chronic HF patients and up to 80% in acute decompensated HF.[24]
• Diabetes Mellitus: Highly prevalent in HF patients (10-30% in HFrEF, ~45% in HFpEF), poor glycemic control is associated with worse outcomes.[24] Diabetic patients with HF have increased rates of major cardiovascular events, hospitalizations, and mortality.[24]
• Atrial Fibrillation (AF): Common in chronic HF (up to 40% in advanced stages), AF increases morbidity and mortality.[21, 24] Its presence worsens symptoms, complicates management, and is a marker of disease severity.[24]

The significant impact of multimorbidity emphasizes the need for an integrated treatment approach that views HF as a multisystem disorder requiring holistic management.[79, 80]

Common Complications of Heart Failure

Heart failure can lead to a cascade of complications affecting various organ systems, further exacerbating the disease and contributing to poor outcomes.[37, 38]

• Abnormal Heart Rhythm (Arrhythmias): The weakened heart is predisposed to various arrhythmias, including supraventricular (e.g., atrial fibrillation, atrial flutter), ventricular (e.g., ventricular tachycardia, ventricular fibrillation), and bradyarrhythmias (e.g., sinus node dysfunction, AV block).[2, 21, 37, 82] Arrhythmias can worsen HF symptoms by decreasing effective cardiac output and carry a substantial risk of mortality, including sudden cardiac death (SCD).[21, 82] Atrial fibrillation, in particular, increases the risk of stroke due to blood clots.[37, 38]
• Cardiorenal Syndrome (CRS): This encompasses a spectrum of disorders where acute or chronic dysfunction in the heart or kidneys leads to dysfunction in the other organ.[37, 83, 84] HF can lead to kidney damage or failure due to reduced blood supply, and conversely, kidney disease can worsen HF by leading to fluid retention and increased blood pressure.[37, 38] Pathophysiology involves complex hemodynamic (reduced cardiac output, elevated central venous pressures) and non-hemodynamic factors (neurohumoral activation, inflammation, oxidative stress).[83, 84]
• Pulmonary Hypertension (PH): Heart failure is the leading cause of PH, which is high blood pressure in the blood vessels carrying blood from the heart to the lungs.[85] As the heart struggles to pump blood from the lungs, blood backs up, increasing pressure in the pulmonary vasculature. This can lead to heart enlargement and right-sided heart failure.[85, 86] The relationship is often a vicious cycle, where each condition exacerbates the other.[85]
• Cardiac Cachexia: A severe, multifactorial condition linked to chronic HF, characterized by involuntary and severe loss of edema-free muscle mass, often without affecting fat tissue.[37, 87, 88] It results from an imbalance between protein synthesis and degradation or intestinal malabsorption, leading to increased morbidity and mortality.[87] A vicious cycle is established between skeletal muscle and cardiac mass loss, further limiting the heart’s pumping capacity.[87]
• Depression and Anxiety: These mental health conditions frequently co-occur with HF, with overlapping symptoms and a worsened prognosis.[35, 89, 90] Depression can inhibit self-care, reduce adherence to treatments, and is independently associated with increased cardiac mortality and physical decline.[89, 90] Stress, inflammation, and neuro-hormonal dysregulation are biological mediators linking these conditions.[89]
• Sleep Apnea: Sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and central sleep apnea with Cheyne-Stokes respiration (CSA-CSR), frequently overlaps with HF.[91, 92] SDB in HF is associated with worse prognosis, including higher mortality.[91] OSA can cause myocardial damage through intermittent hypoxia and increased sympathetic activity, while fluid shifts contribute to its severity.[91] CSA-CSR is linked to hyperventilation and ventilatory instability.[91]

Hospital Readmission Rates and Economic Burden

Hospital readmissions are a significant public health problem in HF, associated with increased illness, death, and substantial healthcare costs.[93, 94, 95]

• Readmission Rates: Nearly 1 in 4 HF patients are readmitted within 30 days of discharge, and approximately half are readmitted within 6 months.[96] For acute decompensated HFpEF, 18.4% of patients were readmitted within 30 days between 2016-2020, with rates increasing from 17.4% to 19.9% over this period.[97] Ninety-day all-cause readmissions for HF increased from 30.9% to 34.6% between 2010 and 2017.[96]
• Economic Burden: HF is one of the most expensive health conditions in the United States, with total healthcare expenditures projected to reach $70 billion by 2030.[94, 95] Hospitalizations are the main contributor to HF-related expenditures.[95] In 2018, 1 million index HF admissions resulted in 233,000 readmissions, costing $3.49 billion.[93] The average cost per readmission ranges from $10,737 to $17,830.[94] Readmission costs often exceed those of the initial hospitalization.[95, 97]
• Predictors of Readmission: Factors associated with increased readmission rates include patients leaving against medical advice, cirrhosis, COPD, cancer, anemia, and longer initial hospital stays.[97] Socioeconomic status also plays a role, with lower income and Medicaid recipients having higher readmission rates.[97]
• Interventions: Remote monitoring devices, such as the Heart Failure Management System (HFMS), have shown promise in reducing hospital readmissions and associated costs by enabling early detection of worsening symptoms.[94] However, studies on transitional care services aimed at reducing readmissions have shown mixed results.[93, 98]

Future Directions in Heart Failure Management

The landscape of heart failure management is rapidly evolving, driven by advancements in scientific understanding, technological innovation, and a growing emphasis on personalized and preventive care. Future directions are focused on developing more targeted therapies, leveraging cutting-edge technologies, and implementing integrated care models.

Novel Pharmacological Targets and Research

Despite significant progress, there is a critical need for novel pharmacological agents, particularly for HFpEF, where effective treatment options remain limited.[57, 73] Research is exploring new targets beyond traditional neurohumoral and hemodynamic modulation, focusing on the direct effects on cardiomyocytes, coronary microcirculation, and myocardial interstitium.[99, 100, 101]

• Myocardial Contractility and Calcium Handling: Abnormal intracellular Ca2+ handling in cardiomyocytes plays a crucial role in impaired cardiac contractility.[30, 100] Novel drugs like istaroxime (a luso-inotropic agent that stimulates SERCA2a ATPase activity) and JTV519 (K201, which consolidates the ryanodine receptor to inhibit Ca2+ leakage) are being investigated to improve Ca2+ cycling and reverse dysfunction.[99, 100] Nitroxyl (HNO) donors (e.g., BMS-986231) also aim to improve cardiomyocyte function by enhancing sarcoplasmic reticulum Ca2+ cycling.[99, 100]
• Fibrosis and Remodeling: Targeting fibroblasts, collagen, and regulatory enzymes involved in collagen synthesis within the myocardial interstitium presents a promising avenue.[99, 100] Chymase inhibitors like fulacimstat are being explored for their anti-remodeling effects post-myocardial infarction.[100]
• Inflammation and Oxidative Stress: Research is identifying agents that can reduce inflammation and oxidative stress, which contribute to disease progression.[99, 100, 101]
• Myocardial Metabolism: New drugs might target cardiac metabolism and mitochondrial function to improve energy efficiency in the failing heart.[99, 101]
• Multi-omics Approaches: Large-scale multi-omics studies are identifying novel drug targets for both HFrEF and HFpEF by analyzing genetic, transcriptomic, and proteomic data. This approach has revealed subtype-specific targets, highlighting the importance of developing tailored therapeutic strategies.[57, 102] For example, lipoprotein(a) (LPA) has emerged as a target for both HFrEF and HFpEF, while other genes like interleukin-6 receptor (IL6R) are specific to HFrEF.[102]

Ongoing clinical trials are actively studying novel medications and repurposing approved drugs for other diseases, including SGLT2 inhibitors, ARNIs, diuretics, and MRAs, to further reduce the impact of HF.[103]

Regenerative Medicine (Stem Cell, Gene Therapy)

Regenerative medicine aims to achieve structural and functional organ restitution in HF, representing a disruptive innovation.[104]

• Stem Cell Therapy: Researchers are investigating the use of stem cells (embryonic, adult, or induced pluripotent stem cells) to regenerate and repair damaged heart tissue.[105, 106] Stem cells can be guided to differentiate into specific cell types, such as heart muscle cells, which can then be implanted to repair injured myocardium.[105] Adult bone marrow cells have shown promise in repairing heart tissue in humans.[105] While initially envisioned for direct muscle rebuilding, current understanding suggests an indirect, paracrine-mediated mode of action, where stem cells stimulate the heart’s natural healing processes.[104, 107] Clinical trials are ongoing to test mesenchymal stem cells for cardiac disorders.[107]
• Exosomes: These cell-derived vesicles are a promising area of research, as they can harness relevant cell therapy features, concentrate active ingredients, and offer flexibility in dosing, potentially leading to more affordable and accessible “off-the-shelf” regenerative products.[104, 107]
• Gene Therapy: Advances in genome editing, particularly CRISPR-Cas9 and base editing, are providing new opportunities for cardiac disease modeling and therapeutic intervention.[108, 109] Gene editing can target disease mediators with high specificity within the injured organ, potentially offering high therapeutic benefit with fewer side effects.[109] For instance, base editing has been used to correct pathogenic mutations in genes like LMNA (linked to progeria, which causes premature HF) and RBM20 (linked to dilated cardiomyopathy), showing improved cardiac function and extended lifespan in mouse models.[108] A first-in-human gene therapy trial (MUSIC-HFpEF) is evaluating SRD-002 for HFpEF, showing early encouraging results in improving NYHA class, 6-minute walk test, and biomarkers by directly addressing impaired myocardial relaxation.[110] RNA therapy is also being explored to instruct the heart to repair itself.[111]
• Mass Customization and Equitable Care: The future aims for streamlined production of affordable cardiac repair-competent cells and cell-free products to overcome variability and ensure broad accessibility, ultimately leading to equitable regenerative care.[104]

Precision Medicine and Genomics

Precision medicine involves tailoring treatment to a patient’s unique genetic makeup, lifestyle, and environment, moving beyond a one-size-fits-all approach.[60, 112, 113] Genomics, the study of genomes, is revolutionizing this field by identifying genetic variants associated with HF risk, improving diagnosis, risk stratification, and treatment.[112]

• Genetic Basis of HF: HF has a complex genetic component, particularly in cardiomyopathies like hypertrophic and dilated cardiomyopathy, which are caused by mutations in genes encoding critical cardiac proteins.[112]
• Genetic Testing: Essential for patients with a family history of cardiomyopathy or other genetic conditions. Types of tests include targeted gene panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS).[112] A positive result can guide treatment decisions, though interpreting variants can be challenging, and a negative result does not rule out a genetic cause.[112]
• Challenges: Reimbursement issues for genetic testing and counseling services remain a significant barrier to widespread implementation of precision medicine in cardiology.[114] Cost and accessibility also limit current genetic testing.[112]
• Future Outlook: Precision medicine is poised to revolutionize cardiovascular healthcare by integrating “omics” data (genomics, transcriptomics, epigenomics, proteomics, metabolomics, microbiomics) for deep phenotyping, leading to early diagnosis, timely precise interventions, and minimal side effects.[113, 115]

Emerging Technologies (Wearable Devices, AI/Machine Learning, Organoids)

Technological advancements are transforming HF management, offering new tools for continuous monitoring, early detection, and personalized care.[55, 116, 117, 118]

• Wearable Devices and Remote Monitoring: These devices collect and analyze long-term continuous data on physiological parameters (e.g., heart rate, rhythm, blood pressure, oxygen saturation, sleep, activity).[116, 117, 118] They can detect subtle changes indicating impending HF exacerbation, allowing for timely intervention and potentially preventing hospitalizations.[116, 117] Examples include smartwatches, activity trackers, and specialized patches.[116, 118] Remote monitoring technology is envisioned to empower patient self-management.[119, 120]
• Artificial Intelligence (AI) and Machine Learning (ML): AI is playing a dominant role in advancing HF detection, diagnosis, risk stratification, and treatment optimization.[115, 116, 120, 121, 122, 123]
  • Diagnosis: ML algorithms can analyze various diagnostic modalities (ECG, echocardiography, CMR, CT scans) to improve accuracy and efficiency in HF diagnosis, including image segmentation, disease detection, and prognostication.[116, 121, 122, 123] AI-driven models have reported diagnostic accuracies as high as 99.9%.[121]
  • Risk Stratification: ML can develop predictive models using clinical, imaging, and genomic data to identify high-risk patients for hospitalization or mortality, enabling targeted interventions and resource allocation.[115, 116, 123] Risk scores like the Seattle Heart Failure Model (SHFM) and Get With The Guidelines Heart Failure (GWTG-HF) risk score are examples of ML applications.[115, 123]
  • Treatment Optimization: AI can provide personalized treatment recommendations by analyzing individual patient characteristics and predicting outcomes, including potential adverse events from medications.[115, 116, 123]
  • Challenges: Data quality, algorithmic transparency, model bias, and regulatory approval are significant challenges for clinical integration of AI.[116, 120, 121, 123]
• Cardiac Organoids: These miniature, simplified 3D cellular models grown from progenitor or stem cells more accurately mimic the biological characteristics and functions of the human heart than conventional 2D models.[99, 124] They are useful platforms for studying human cardiac biology, pathophysiology, and drug testing.[124] Organoids are being used to model HFpEF, recapitulating structural, functional, and mechanistic features, and hold potential for identifying novel therapeutic targets.[99, 125]

Integrated Care Models and Public Health Initiatives

Effective HF management increasingly emphasizes integrated care models and broader public health initiatives to improve outcomes and address the growing burden of the disease.[6, 60, 126]

• Team-Based Approach: A multidisciplinary team approach is recommended to optimize care, involving physicians, nurses, physical therapists, dietitians, and mental health professionals.[10, 61, 63]
• Care Transitions: Strategies for effective communication and integration of operational processes between clinicians and settings of care (e.g., hospital to home) are crucial to reduce hospital readmissions and adverse outcomes.[127] Mobile integrated health programs, involving in-home visits by paramedics and facilitated telehealth, are an emerging model, showing particular benefit for women and younger patients, though not always significantly reducing overall readmissions.[98]
• Public Awareness and Education: Public awareness campaigns and education for healthcare professionals are needed to aid in the prediction and prevention of HF.[126] Teaching people to recognize symptoms is key for timely treatment.[128]
• Targeted Prevention Strategies: Focus on preventing cardiovascular diseases (e.g., hypertension, diabetes, CAD, MI, AF) to prevent HF onset.[6, 126] This includes lifestyle modifications, pharmacological interventions (statins, antiplatelets, antihypertensives, SGLT2 inhibitors), and earlier biomarker testing (e.g., NT-proBNP).[60, 126]
• Addressing Social Determinants of Health: Factors like nutrition and financial stressors significantly influence patient outcomes outside of clinical visits and need to be addressed in comprehensive care models.[119]

Major Ongoing Clinical Trials (2025-2026)

Research in heart failure is highly active, with numerous ongoing clinical trials exploring novel therapies and optimizing existing treatments.

• Pharmacotherapy Trials: As of August 2023, 119 ongoing clinical trials are studying pharmacotherapy for HF, including novel medications, SGLT2 inhibitors, ARNIs, diuretics, and MRAs.[103] For example, research is being presented on safely simplifying dosing of medications like vericiguat for HFrEF.[110]
• Gene Therapy Trials: The Medera-funded MUSIC-HFpEF trial is a first-in-human gene therapy trial evaluating SRD-002 for HFpEF, showing encouraging early clinical signals in improving NYHA class, 6-minute walk test, and biomarkers.[110] Other gene therapy trials are exploring phosphatase inhibition for non-ischemic HF.[129]
• Device-Based Therapy Trials: Trials are investigating the safety and efficacy of various devices, including transcatheter shunt systems (e.g., Edwards APTURE), Cardiac Contractility Modulation (CCM) therapy for HF with higher ejection fraction, and ventricular restoration systems (e.g., AccuCinch) for HFrEF.[129] Research also continues on optimizing cardiac resynchronization therapy (CRT), such as His bundle pacing.[53, 130]
• Remote Monitoring Trials: Studies like REM-HF are assessing whether remote monitoring of HF patients via implanted devices can reduce hospitalizations.[53, 130]
• Other Areas: Research also covers topics like inflammation and obesity in HF, cardiotoxicity assessment in cancer patients, and the impact of iron supplementation.[53, 110, 129, 130] The Heart Failure Society of America (HFSA) Annual Scientific Meeting in 2025 will feature the latest science, research, and practical management, including a dedicated meeting on device-based care.[131]

Conclusion

Heart failure represents a formidable and escalating global health challenge, marked by its increasing prevalence, substantial economic burden, and profound impact on patient morbidity and mortality. The complexity of HF is underscored by its diverse etiologies, intricate pathophysiological mechanisms involving ventricular remodeling and neurohumoral activation, and varied clinical presentations across different ejection fraction phenotypes.

Current management strategies, guided by international consensus, emphasize early diagnosis through a combination of clinical assessment, biomarker analysis (notably natriuretic peptides), and advanced imaging modalities such as echocardiography and cardiac MRI. Pharmacological treatment for HFrEF has advanced significantly with quadruple therapy, demonstrating remarkable improvements in survival, though its implementation remains a critical area for improvement. For HFpEF, SGLT2 inhibitors have emerged as a pivotal therapy, alongside other agents that manage symptoms and comorbidities. Non-pharmacological interventions, including rigorous lifestyle modifications and cardiac rehabilitation, are indispensable for optimizing patient outcomes and quality of life. Advanced device therapies and surgical interventions offer life-saving options for patients with specific conditions or advanced disease.

Despite these advancements, HF remains associated with a poor prognosis, particularly in later stages and in the presence of multimorbidity. The frequent occurrence of complications such as arrhythmias, cardiorenal syndrome, pulmonary hypertension, cardiac cachexia, and psychological distress further complicates management and contributes to high hospital readmission rates and healthcare costs.

The future of heart failure management is poised for transformative change. Emerging research is focused on identifying novel pharmacological targets, particularly for HFpEF, and harnessing the potential of regenerative medicine, including stem cell and gene therapies, to achieve structural and functional restoration of the heart. Precision medicine, driven by advances in genomics and multi-omics, promises to tailor treatments to individual patient profiles, while artificial intelligence and wearable technologies are set to revolutionize diagnosis, risk stratification, and remote patient monitoring. Finally, integrated care models and public health initiatives are crucial for addressing the holistic needs of patients and mitigating the broader societal impact of this pervasive condition. Continued investment in research and a concerted effort to translate scientific breakthroughs into equitable clinical practice will be paramount in significantly reducing the burden of heart failure worldwide.