Heart failure

Article written and reviewed by Dr Luca Moretti

Heart failure is a complex clinical syndrome in which a structural or functional abnormality of the heart compromises ventricular filling, blood ejection or both, producing symptoms and signs driven by increased intracardiac pressures, congestion and, in more severe forms, inadequate tissue perfusion. The diagnosis is not defined by a single instrumental measurement: it requires convergence between clinical manifestations and objective demonstration of heart disease capable of explaining them. The Second Universal Definition of 2026 considers heart failure a dynamic condition, influenced by etiology, trajectory and the patient’s context, moving beyond an interpretation rigidly dependent on isolated ejection fraction thresholds. The course may progress from a stage of risk to asymptomatic pre-heart failure, become clinically manifest, improve with treatment, enter remission or progress to advanced disease. Functional recovery and cure are not synonymous, because the biological substrate may remain active. The term cardiac insufficiency describes the inability of the cardiovascular system to adequately meet the body’s needs without relying on pathologically elevated filling pressures. Cardiac output may be reduced at rest, appear preserved through neurohormonal compensation or become insufficient only during exercise. For this reason, cardiovascular reserve and the behavior of filling pressures during exertion may reveal the syndrome when resting parameters are only mildly abnormal.

Left ventricular ejection fraction allows recognition of phenotypes with reduced or preserved function and, together with the longitudinal trajectory, improved function; it remains essential for applying therapeutic evidence. However, it depends on preload, afterload, geometry, rhythm and the measurement method; it is not equivalent to contractility, does not describe the right ventricle and may be normal in the presence of severe diastolic dysfunction. Its interpretation must include volumes, stroke volume, myocardial deformation, valves, atria, pulmonary pressures and the clinical picture; congestion is the main reason for symptoms and hospitalization, but has different mechanisms. A gradual increase in total body sodium expands extracellular volume; rapid venous redistribution, mediated mainly by splanchnic vasoconstriction, may transfer blood toward the thorax and abruptly increase pulmonary pressures without a large increase in weight. Interstitial, intravascular and organ congestion do not always run in parallel and require multimodal assessment. Epidemiologically, prevalence increases with age and with survival after myocardial infarction, valvular disease and cardiomyopathies, while hypertension, diabetes, obesity and kidney disease particularly increase the burden of preserved-ejection-fraction phenotypes. The HF STATS 2024 report estimates a prevalence of approximately 6.7 million adults in the United States and a lifetime risk close to one in four people; the global distribution varies with access to care, rheumatic heart disease, infections, genetic etiologies and social determinants.

Despite therapeutic advances, the syndrome retains high mortality and a substantial risk of recurrent hospitalizations, functional decline and multiorgan failure. Prognosis is not uniform: reversible etiologies, early introduction of disease-modifying therapies and correction of valvular disease may produce reverse remodeling, whereas persistent hypotension, right ventricular dysfunction, refractory congestion, renal or hepatic deterioration and drug intolerance identify an unfavorable trajectory.

Etiology, pathogenesis and pathophysiology

Heart failure represents the point of convergence of many heart diseases. Coronary artery disease may cause it through acute or chronic myocardial loss, repeated ischemia, post-infarction remodeling, ventricular aneurysm, ischemic mitral regurgitation and arrhythmias. Dysfunction may reflect an irreversible scar, potentially recoverable hibernating myocardium or a combination; the mere presence of coronary stenoses does not establish that the entire cardiomyopathy is ischemic. Arterial hypertension imposes chronic pressure overload. Increased systolic stress promotes concentric hypertrophy, interstitial fibrosis, ventricular stiffness, slowed relaxation and atrial dilation; ventricular dilation and reduced ejection fraction may develop at a more advanced stage. Hypertensive crises and abrupt increases in afterload may also precipitate pulmonary edema even in a normal-sized ventricle; valvular heart diseases produce pressure overload, volume overload or both. Aortic and pulmonary stenosis increase the workload of their respective ventricles; aortic and mitral regurgitation overload the left ventricle; tricuspid and pulmonary regurgitation overload the right ventricle. A valve may be the primary cause of the syndrome or become regurgitant secondary to ventricular and annular dilation, creating a cycle of progression.

Dilated cardiomyopathies include genetic, inflammatory, autoimmune, toxic, nutritional, metabolic, peripartum and idiopathic forms. Variants in TTN, LMNA, FLNC, DSP and numerous other genes modify the risk of dysfunction and arrhythmias; penetrance is variable, and the environment may act as a second insult. A negative family history does not rule out a genetic cause, because de novo variants, small families and minimally symptomatic phenotypes are frequent. Viral or immune-mediated myocarditis may cause myocyte injury, edema, necrosis and subsequent fibrosis; presentation ranges from chest pain with preserved function to fulminant myocarditis with shock, conduction block or ventricular arrhythmias. Demonstration of inflammation on magnetic resonance imaging does not automatically identify the causative agent, and immunosuppression is not indicated in every form; endomyocardial biopsy and specific therapy depend on the clinical context. Alcohol, cocaine, methamphetamines, anthracyclines, trastuzumab, immune checkpoint inhibitors and numerous other agents may cause dysfunction through different mechanisms; cardiotoxicity may be dose-dependent, idiosyncratic, inflammatory, ischemic or mediated by hypertension and arrhythmias. Early recognition of the exposure allows the agent to be discontinued or modified, cardioprotection to be used and oncological care to be coordinated, without attributing every instance of dysfunction to the drug.

Persistent tachycardias, a high burden of premature ventricular contractions, rapid atrial fibrillation and nonphysiological right ventricular pacing may produce arrhythmia-induced cardiomyopathy. Recovery after rhythm control or correction of dyssynchrony retrospectively supports the diagnosis, but a pre-existing myocardial predisposition may have favored the arrhythmia. Severe bradycardia and loss of atrioventricular synchrony may also reduce cardiac output and worsen filling pressures; hypertrophic and restrictive cardiomyopathies impede filling, reduce compliance and may compromise cardiac output reserve. Transthyretin or light-chain amyloidosis, sarcoidosis, hemochromatosis, Fabry disease and other infiltrative cardiomyopathies require an etiological diagnosis because prognosis and treatment differ radically. Increased wall thickness does not necessarily equate to cardiomyocyte hypertrophy, as it may reflect extracellular deposition. Constrictive pericarditis, tamponade and large effusions limit filling through an extracardiac mechanism. In pericardial constriction, respiratory ventricular interdependence and dissociation between intrathoracic and intracardiac pressures distinguish the condition from restrictive cardiomyopathies, although they may coexist. Identification is essential because pericardiectomy may be curative in appropriate patients.

Operated or unoperated congenital heart disease, shunts, a systemic right ventricle, Fontan circulation and coronary anomalies produce phenotypes that are not always adequately described by traditional categories. The physiology may depend on a single ventricle, pulmonary vascular resistance, conduits, valves and surgical scars; assessment must be entrusted to centers with specific expertise in adult congenital heart disease. In high-output heart failure, the initial problem often lies outside the heart. Severe anemia, thyrotoxicosis, large arteriovenous fistulas, beriberi, sepsis, extensive Paget disease and certain liver diseases reduce vascular resistance or increase demand. Plasma volume expansion and persistent circulatory demand cause dilation, increased pressures and ultimately relative cardiac insufficiency, despite a high absolute cardiac output. The initial injury reduces performance or increases filling pressures, activating compensatory systems intended to preserve blood pressure and perfusion. Arterial baroreceptors sense a reduction in effective circulating volume and increase sympathetic tone; the kidneys and juxtaglomerular apparatus activate the renin-angiotensin-aldosterone system; vasopressin and endothelin pathways promote vasoconstriction and retention. These mechanisms, useful in the immediate setting, become maladaptive when they persist.

Norepinephrine increases heart rate, contractility and systemic vascular resistance but, over time, increases oxygen consumption, arrhythmias, beta-receptor downregulation, apoptosis and ischemia. Angiotensin II and aldosterone promote vasoconstriction, sodium retention, fibrosis and remodeling; the prognostic efficacy of beta-blockers, ACE inhibitors, receptor blockers, ARNIs and mineralocorticoid antagonists provides clinical evidence of the causal role of neurohormonal activation. In opposition, natriuretic peptides, nitric oxide, adrenomedullin and other pathways promote natriuresis, vasodilation and limitation of fibrosis. BNP and NT-proBNP result from proBNP processing in response to wall stress and neurohormonal signals. Neprilysin degrades several vasoactive peptides; its inhibition must be combined with angiotensin receptor blockade to avoid the effects of the concomitant increase in angiotensin II. Ventricular remodeling encompasses changes in size, shape, mass, matrix and cellular composition. After myocardial infarction, thinning and dilation of the necrotic segment increase stress on the remaining regions; in diffuse cardiomyopathies, myocyte elongation and loss of organized matrix favor a spherical geometry. Treatment-induced reverse remodeling may reduce volumes and functional valvular regurgitation, but does not necessarily eliminate scar and arrhythmic risk.

Laplace’s law relates wall stress to pressure, radius and thickness; dilation increases stress and oxygen demand, reduces mechanical efficiency and promotes further dilation. Initial hypertrophy reduces stress per unit area but increases stiffness, oxygen diffusion distance and ischemic vulnerability; these adaptations explain why the same insult may evolve from compensation to progressive failure. Systolic dysfunction is not simply a reduction in the force of contraction. Abnormalities in excitation-contraction coupling, calcium handling, sarcomeric protein phosphorylation, energy metabolism, mitochondrial density and beta-adrenergic reserve reduce the ability to generate work. Mechanical inefficiency increases when dyssynchrony, mitral regurgitation or dilation converts part of the energy into non-ejective work. Diastolic dysfunction results from slowed active relaxation, increased passive stiffness or both. Ischemia and energy deficiency delay calcium reuptake; hypertrophy, fibrosis, titin abnormalities and amyloid deposition increase stiffness. Atrial pressure must then rise to maintain filling, transmitting the increase to the pulmonary circulation. During tachycardia or exercise, shortening of diastole reveals limited diastolic reserve.

In HFpEF, obesity, hypertension, diabetes, kidney disease and aging produce a systemic phenotype with inflammation, microvascular endothelial dysfunction, arterial stiffness, impaired peripheral vasodilation and skeletal myopathy. Not all patients share the same mechanism: amyloidosis, valvular disease, hypertrophic cardiomyopathy and constriction are phenocopies or specific causes that must be recognized, not merely comorbidities of generic HFpEF. Ventricular-arterial coupling influences efficiency. A stiff arterial system increases late systolic load and makes blood pressure highly sensitive to small changes in volume; a stiff ventricle produces large pressure increases in response to modest changes in filling. The interaction between ventricular and vascular stiffness explains the sudden onset of hypertensive pulmonary edema and poor tolerance of changes in preload. The right ventricle faces a normally low-resistance circulation and is particularly sensitive to an acute increase in afterload. Postcapillary pulmonary hypertension, embolism, pulmonary vascular diseases and high-pressure ventilation may reduce right ventricular output; dilation and tricuspid regurgitation increase venous pressure. Ventricular interdependence through the septum and pericardium means that right ventricular overload also reduces left ventricular filling.

Systemic venous congestion produces organ dysfunction independently of cardiac output. Increased renal pressure reduces the filtration gradient, interstitial edema compromises the parenchyma, hepatic congestion causes cholestasis and fibrosis, while intestinal wall edema promotes malabsorption and translocation of microbial products. Central venous pressure is therefore a pathophysiological determinant, not simply a peripheral sign; reduced cardiac output activates vasoconstriction and redistributes flow toward the heart and brain. In the early stages, blood pressure may remain normal, masking renal, muscular and splanchnic hypoperfusion; with progression, cold skin, oliguria, confusion, lactic acidosis and shock appear. Cardiac output must be indexed to body surface area and interpreted in relation to hemoglobin, oxygen consumption and metabolic demand. Skeletal muscle contributes to exercise intolerance through reduced capillary and mitochondrial density, a shift toward glycolytic fibers, endothelial dysfunction and deconditioning; the ergoreflex may disproportionately increase ventilation and vasoconstriction. For this reason, functional capacity does not depend solely on ejection fraction and may improve with physical training even without major changes on echocardiography.

Anemia and iron deficiency reduce oxygen transport and utilization; iron is also required by mitochondrial enzymes, so deficiency may limit muscle function independently of hemoglobin. Inflammation, reduced absorption, gastrointestinal losses and kidney disease contribute to deficiency. Correction with intravenous iron in selected patients improves symptoms and reduces some events, whereas erythropoiesis-stimulating agents are not a general treatment for heart failure. Progression is not inevitably linear. Elimination of tachycardia, alcohol, ischemia, inflammation or valvular overload may allow recovery; neurohormonal treatments reduce cell death and hemodynamic load; resynchronization corrects dyssynchrony in appropriate phenotypes. Conversely, persistence of fibrosis, mutations, vascular disease and comorbidities explains the residual risk even after apparent normalization of function. Peripartum cardiomyopathy develops toward the end of pregnancy or in the months after delivery in the absence of another identifiable cause. Oxidative stress, prolactin fragments, vascular susceptibility and variants in cardiomyopathy genes may converge in the same phenotype. Recovery is variable, and a subsequent pregnancy may cause relapse, even after normalization of function, making multidisciplinary preconception counseling necessary.

Takotsubo syndrome produces transient regional dysfunction, often triggered by physical or emotional stress, with apical, midventricular, basal or focal patterns. Catecholamine excess, microvascular dysfunction and neurocardiac vulnerability contribute to its pathogenesis. Pulmonary edema, shock, dynamic obstruction, mitral regurgitation and arrhythmias may complicate it; its transient nature does not equate to a benign course, and acute treatment depends on hemodynamics. Diabetes and obesity do not act solely through coronary artery disease and hypertension. Insulin resistance, lipotoxicity, mitochondrial abnormalities, glycation products, adipose tissue inflammation and microvascular dysfunction promote fibrosis and stiffness; epicardial and visceral adiposity may impose pericardial restraint and amplify ventricular interdependence, defining a cardiometabolic phenotype that is particularly common in HFpEF. Chronic kidney disease increases volume, blood pressure, anemia, uremic toxins, inflammation and vascular calcification. An arteriovenous fistula for hemodialysis may add a high-output load; an access with very high flow requires hemodynamic measurements and assessment of the ratio of access flow to cardiac output. Access revision must not be decided solely on the presence of cardiac dilation.

Endocrine disorders include thyrotoxicosis, hypothyroidism, pheochromocytoma, acromegaly, hypercortisolism, hyperaldosteronism and diabetes; excess thyroid hormone increases heart rate, cardiac output and the risk of atrial fibrillation; hypothyroidism slows relaxation and may cause an effusion. Catecholamines from pheochromocytoma may produce hypertension, ischemia or stress cardiomyopathy; treatment of the hormonal cause may allow substantial recovery. Thiamine deficiency impairs pyruvate dehydrogenase and oxidative metabolism, causing peripheral vasodilation, retention and high-output heart failure; a fulminant form may present with lactic acidosis and shock. Malnutrition, alcoholism, bariatric surgery and prolonged diuretic use increase the risk. When suspicion is high, thiamine is administered promptly without waiting for tests that are not readily available. Hemochromatosis and transfusional iron overload cause iron deposition in myocytes, generating oxidative stress, diastolic dysfunction, dilation and arrhythmias. T2* magnetic resonance imaging quantifies myocardial iron and guides chelation in appropriate populations. An isolated elevation in ferritin during inflammation or congestion does not establish overload and must be distinguished from the common condition of functional iron deficiency.

Cardiac sarcoidosis may produce atrioventricular block, ventricular tachycardia, aneurysms and dysfunction. Fluorodeoxyglucose PET assesses inflammatory activity when preparation adequately suppresses physiological uptake; magnetic resonance imaging identifies scar. Immunosuppression, antiarrhythmics and devices are selected according to activity, conduction, function and risk of sudden death; neuromuscular and mitochondrial diseases combine cardiomyopathy, conduction disorders and respiratory or skeletal muscle weakness. Duchenne and Becker muscular dystrophies, myotonic dystrophy, Friedreich ataxia and laminopathies require specific surveillance; exercise limitation may simultaneously reflect cardiac, muscular and ventilatory impairment, making NYHA class alone inadequate. Sepsis and systemic inflammation may cause reversible myocardial depression, vasoplegia, right ventricular dysfunction and impaired microcirculation. Elevated troponin and peptide levels are common but do not automatically define myocarditis or primary heart failure. Fluids, vasopressors and ventilation modify preload and afterload; septic cardiomyopathy must be interpreted in the context of the overall distributive shock state.

Obstructive sleep apnea produces intermittent hypoxia, pressure fluctuations and sympathetic activation, promoting hypertension, atrial fibrillation and dysfunction. Central sleep apnea and Cheyne-Stokes respiration may instead result from congestion and instability of ventilatory control; the two forms may coexist and require characterization through a sleep study before ventilatory therapy is selected. Social and environmental factors are not incidental to pathophysiology. Deprivation, inconsistent access to medications, a poor-quality diet, pollution, extreme heat, isolation and health literacy modify exposures, adherence and the timeliness of treatment. The Second Universal Definition recognizes that the trajectory of heart failure also reflects the care context, not only the myocardium.

Clinical manifestations

Dyspnea is the most common symptom but is not specific. Increased pulmonary venous pressure reduces compliance, stimulates interstitial receptors and increases the work of breathing; endothelial dysfunction, impaired gas exchange, respiratory muscle weakness and an excessive ventilatory response to exertion contribute to the sensation. The correlation between the intensity of dyspnea and the severity of resting congestion is imperfect, especially in adapted patients with chronic disease; exertional dyspnea initially develops above a certain threshold, which may decrease with progression. Orthopnea occurs in the supine position because of increased venous return and redistribution of fluid from the limbs, and is described in terms of the number of pillows used or the need to sleep sitting up. Paroxysmal nocturnal dyspnea wakes the patient after one or more hours of sleep and takes time to subside, distinguishing it from simple, immediate orthopnea. Nocturnal cough, wheezing and a sense of tightness may reflect bronchial wall edema, known as cardiac asthma. Pink, frothy sputum, severe tachypnea, diaphoresis and hypoxemia indicate alveolar edema and require urgent management. The absence of crackles does not rule out elevated filling pressures in patients with chronic disease, in whom lymphatic drainage and pulmonary adaptation may limit auscultatory findings.

Fatigability and reduced exercise tolerance result from an insufficient increase in cardiac output, impaired peripheral oxygen extraction, muscle dysfunction, anemia, iron deficiency, deconditioning and comorbidities. Patients may report slowing down in daily activities, taking frequent breaks, being unable to climb stairs or losing independence rather than a specific cardiac sensation. Functional quantification should use concrete examples and, when necessary, standardized tests; systemic congestion causes weight gain, dependent edema, abdominal tightness, early satiety and nausea. Ascites and congestive hepatomegaly may cause right upper quadrant pain, while intestinal edema and reduced perfusion contribute to anorexia and malabsorption. In older or cachectic patients, substantial fluid retention may be masked by simultaneous loss of lean tissue and may not produce an obvious increase in weight. Nocturia develops when recumbency improves renal perfusion and mobilizes edema; oliguria may predominate in advanced stages. Confusion, drowsiness, agitation and reduced concentration may reflect hypoperfusion, hypoxemia, hyponatremia, drugs or delirium due to acute illness; syncope requires investigation for arrhythmias, aortic stenosis, dynamic obstruction, hypotension, pulmonary embolism and other high-risk causes.

On physical examination, blood pressure, heart rate, rhythm, oxygen saturation, temperature and perfusion status define the context; normal blood pressure does not rule out low cardiac output, while a narrow pulse pressure may suggest a low stroke volume. Cold extremities, prolonged capillary refill time, mottling, oliguria and altered mental status indicate hypoperfusion; warm skin does not rule out severe congestion; jugular venous pressure is one of the most informative signs of right-sided congestion. It should be assessed with the patient reclined, identifying the internal jugular venous pulsation and measuring its height relative to the sternal angle. A sustained hepatojugular reflux during abdominal pressure indicates limited ability of the right ventricle to accommodate increased venous return. Obesity, a short neck and altered ventilation may make estimation difficult. The third heart sound, caused by rapid filling of a dilated ventricle or one with elevated pressures, is relatively specific but has low sensitivity and depends on the examiner’s experience. The fourth heart sound reflects atrial contraction against a stiff ventricle and is absent in atrial fibrillation. Mitral or tricuspid regurgitation murmurs may be functional and change with loading conditions and treatment; a soft murmur does not rule out severe regurgitation in a low-output state.

A laterally displaced apical impulse suggests ventricular dilation, while a sustained impulse may indicate hypertrophy; a parasternal heave indicates right ventricular overload. An accentuated P2, splitting of heart sounds, rubs and prosthetic valve sounds point toward specific causes or complications; the cardiovascular examination must always include peripheral pulses, signs of vascular disease and a search for asymmetric hypoperfusion or acute aortic conditions. Bibasal crackles, pleural effusion and reduced oxygen saturation support pulmonary congestion, but crackles may arise from pneumonia or interstitial lung disease. Bilateral dependent edema is also common in venous insufficiency, with vasodilator drugs, in cirrhosis and in nephrotic syndrome. Specificity increases when several signs of elevated filling pressures are concordant. Left-sided heart failure tends to produce dyspnea and pulmonary congestion; right-sided failure produces jugular venous distension, edema, ascites, hepatic congestion and reduced left ventricular filling. In practice, phenotypes are often biventricular. A severely impaired right ventricle may present with low cardiac output and relatively clear lungs, especially in right ventricular infarction, precapillary pulmonary hypertension or embolism.

NYHA class categorizes limitation caused by physical activity from I to IV and retains prognostic and therapeutic value, but is subjective and variable. The six-minute walk test measures submaximal performance influenced by age, motivation and comorbidities; cardiopulmonary exercise testing quantifies oxygen consumption, the VE/VCO2 slope and limiting mechanisms. No single method replaces assessment of functional capacity in real life. Frailty, sarcopenia, depression and cognitive decline may dominate the geriatric presentation. Falls, reduced appetite, weight loss or inability to manage medications may precede obvious congestion. These factors modify adherence, device candidacy and hospitalization risk and should be considered parts of the syndrome, not merely ancillary problems. Signs of instability include dyspnea at rest or rapidly progressive dyspnea, chest pain, syncope, hypoxemia, hypotension, confusion, oliguria, sustained arrhythmia and a rapid increase in edema. The appearance of these findings requires distinguishing an exacerbation from a coronary syndrome, pulmonary embolism, infection, tamponade, aortic dissection or another emergency; recognition of the time course is as decisive as the intensity of an individual symptom.

The presentation may be modified by the phenotype. Hypotension, autonomic neuropathy, carpal tunnel syndrome, biceps tendon rupture and intolerance of vasodilators are frequent in amyloidosis; conduction block and arrhythmias may predominate in sarcoidosis; in hypertrophic cardiomyopathy, dyspnea, angina and syncope also depend on obstruction. These extracardiac clues prevent every case from being reduced to generic congestion. Chest pain may indicate epicardial or microvascular ischemia, pericarditis, embolism or increased wall stress. In a patient with heart failure and coronary artery disease, a recent change in the symptom threshold or prolonged pain requires assessment for a coronary syndrome; the absence of pain does not rule out ischemia, especially in older people, patients with diabetes or those with low cardiac output. Palpitations may reflect premature beats, atrial fibrillation or sustained tachycardia, but also heightened awareness of the normal adrenergic response; sudden onset with a rapid, regular pulse points in a different direction from a persistently irregular heart rate. Correlating symptoms with rhythm by ECG, telemetry or ambulatory monitoring avoids attributing every palpitation to a causative arrhythmia.

Pulsus alternans, with beat-to-beat variation in amplitude during a regular rhythm, suggests severe systolic dysfunction; marked pulsus paradoxus points toward tamponade, severe asthma or pronounced ventricular interdependence. These traditional findings are sought less often, but retain value when correctly elicited and linked to hemodynamic physiology. Cheyne-Stokes periodic breathing alternates a crescendo-decrescendo ventilatory pattern with central apneas, especially in advanced heart failure with increased CO2 sensitivity and prolonged circulation time. It may occur at night or be observed while awake and is associated with an unfavorable prognosis. It should not be confused with terminal irregular breathing or obstructive apnea. In right-sided failure, a prominent jugular v wave indicates tricuspid regurgitation; Kussmaul’s sign, an inspiratory increase or failure of venous pressure to decrease, suggests limited right ventricular filling, as in constriction, restriction or right ventricular infarction. Its absence does not rule out these conditions, and its presence must be interpreted in relation to rhythm, ventilation and intrathoracic pressure.

NYHA class does not describe congestion: a patient may be in class II but markedly hypervolemic, or in class III because of lung disease without elevated pressures. Similarly, ACC/AHA stage classification does not simply regress when symptoms improve, because it retains the history of heart disease. Distinguishing stage from current status makes clinical communication more precise; involuntary weight loss, reduced arm circumference, weakness and reduced appetite indicate catabolism; edema and ascites may conceal them. Nutritional assessment should follow decongestion and include grip strength, muscle mass and intake; obesity does not protect against sarcopenia: the sarcopenic obesity phenotype may feature a high BMI with limited functional reserve.

Investigations and diagnosis

Diagnosis begins with estimation of pretest probability. Known heart disease, myocardial infarction, hypertension, diabetes, cardiotoxic exposure, a family history of cardiomyopathy, orthopnea, elevated jugular venous pressure and a third heart sound increase probability; another complete explanation for the symptoms reduces it. The presence of the syndrome, its etiology, hemodynamic phenotype, severity and precipitating factors must be assessed simultaneously; the electrocardiogram may show previous or acute myocardial infarction, hypertrophy, bundle branch blocks, conduction delays, atrial fibrillation, tachycardias, bradycardias and signs of infiltration. A completely normal ECG makes heart failure with reduced ejection fraction less likely, but does not rule out HFpEF. QRS duration and morphology are essential for assessing resynchronization, while the QT interval and conduction disturbances influence treatment and arrhythmic risk. Chest radiography may document cardiomegaly, vascular redistribution, Kerley lines, alveolar edema and effusions; it also allows recognition of pneumonia, pneumothorax or other diseases. A normal cardiac silhouette does not rule out heart failure, especially in acute, restrictive or preserved-ejection-fraction forms; findings depend on the time course of development, and radiographic congestion may persist or resolve on a different timescale from symptoms.

BNP and NT-proBNP are released in response to myocardial stress and have a high rule-out value when low. Values increase with age, atrial fibrillation, renal insufficiency, pulmonary hypertension, embolism and sepsis; they decrease in obesity and may be less elevated in extremely rapid-onset pulmonary edema or some forms of constriction. Sacubitril/valsartan may transiently increase BNP because of reduced degradation, whereas NT-proBNP is not a neprilysin substrate. Peptide thresholds differ between nonacute and acute settings and must not be applied without considering rhythm, renal function and body mass index. An elevated value supports hemodynamic stress but does not identify its cause; a decreasing trend often accompanies decongestion, without constituting a treatment target on its own. Biological variability requires caution when interpreting small serial differences; the complete blood count identifies anemia, infection and hematological abnormalities; ferritin and transferrin saturation define iron deficiency according to criteria used in trials. Creatinine, eGFR, urea, sodium, potassium, bicarbonate and magnesium guide diuretic and neurohormonal therapy; increased bilirubin and alkaline phosphatase suggest hepatic congestion, while very high aminotransferases may indicate hypoxic injury.

Blood glucose, glycated hemoglobin, the lipid profile and TSH identify modifiable causes and comorbidities. Troponin may be elevated because of a coronary syndrome, myocarditis, tachycardia, embolism or chronic myocardial injury; it requires serial assessment, while an ischemic context is necessary to diagnose myocardial infarction. Serum and urine electrophoresis with immunofixation and free light chains are necessary when AL amyloidosis is suspected, before attributing a positive scintigraphy result to transthyretin. Transthoracic echocardiography is the cornerstone examination. It must quantify volumes and ejection fraction using an appropriate method, describe regional wall motion, wall thickness, mass, atria, valves, pericardium and the visualized aorta, and assess the right ventricle and vena cava. Two-dimensional ejection fraction has inherent variability; echocardiographic contrast, three-dimensional imaging or magnetic resonance imaging may improve accuracy when a decision depends on a therapeutic threshold. Diastolic function is estimated by integrating mitral inflow, tissue e’ velocity, the E/e’ ratio, atrial volume, tricuspid regurgitation velocity and other findings. No index perfectly measures filling pressure in every condition; mitral regurgitation, atrial fibrillation, pacing, annular calcification and valvular disease modify the signals. Assessment must be consistent with age, rhythm and individual physiology.

The right ventricle requires multiple measurements: dimensions, tricuspid annular plane systolic excursion, S’ velocity, fractional area change, strain, septal shape and estimated pulmonary pressure. Right ventricular-pulmonary arterial coupling may be approximated by ratios such as TAPSE/PASP, but depends on the accuracy of both components; an echocardiographic estimate does not replace catheterization when a precise distinction between precapillary and postcapillary pulmonary hypertension is required. Global longitudinal strain may reveal subclinical dysfunction despite preserved ejection fraction and show suggestive patterns, such as relative apical sparing in amyloidosis. However, it is not etiologically specific and depends on image quality and software; serial changes are useful in cardio-oncology and cardiomyopathies if acquisition and analysis remain comparable. Lung ultrasound identifies B-lines and effusions with high sensitivity for extravascular water, but B-lines also occur in interstitial lung diseases, ARDS and infections. Vena cava diameter and collapsibility are influenced by respiration, ventilation, abdominal pressure and right ventricular function. Point-of-care assessment improves speed when integrated with the clinical examination, not when it reduces diagnosis to an isolated image.

Magnetic resonance imaging provides reproducible measurements of volumes and function and tissue characterization through late gadolinium enhancement, T1/T2 mapping and extracellular volume. A subendocardial or transmural pattern points toward ischemia; midwall, subepicardial, diffuse or multifocal distributions point toward different cardiomyopathies. Edema and fibrosis help identify myocarditis, sarcoidosis, amyloidosis, Fabry disease and iron overload, but the final diagnosis requires clinical integration; coronary assessment depends on the probability of disease, symptoms, renal function, anatomy and the feasibility of revascularization. CT angiography is useful when probability is low to intermediate and anatomy is favorable; stress imaging assesses ischemia and viability; invasive coronary angiography is indicated when the result may change the strategy. The finding of coronary artery disease must be correlated with the distribution of dysfunction and scar burden before an ischemic etiology is established; cardiopulmonary exercise testing distinguishes cardiac, ventilatory, peripheral and motivational components of limitation. Peak VO2, percentage of the predicted value, the VE/VCO2 slope, oscillatory ventilation, oxygen pulse and blood pressure response have diagnostic and prognostic significance. In candidates for transplantation or mechanical support, values must be interpreted considering beta-blockade, sex, age, obesity, the protocol and maximal effort documented by the respiratory exchange ratio.

Right heart catheterization measures right atrial, pulmonary artery and wedge pressures, cardiac output and vascular resistance. It is not necessary in every patient, but is indicated when volume status is uncertain, shock is unresponsive, pulmonary hypertension is suspected, advanced therapy is being considered or there is discordance between clinical and instrumental findings. Zeroing errors, overwedging or underwedging, ventilation and the choice of cardiac output measurement method may profoundly alter hemodynamic interpretation. In HFpEF with equivocal resting findings, exercise echocardiography or exercise catheterization may demonstrate a pathological increase in pressures. The H2FPEF and HFA-PEFF scores structure probability assessment and identify patients who need functional testing; they are not interchangeable and do not replace the search for phenocopies. Obesity may reduce peptide levels and make diagnosis particularly dependent on the response to exercise. Endomyocardial biopsy is reserved for situations in which a timely histological diagnosis changes treatment, such as certain fulminant, eosinophilic or giant cell myocarditides, sarcoidosis or infiltrative diseases. Sampling may miss focal lesions and carries risks. It is not a routine test for stable dilated cardiomyopathy without specific warning signs.

Genetic testing is indicated in many cardiomyopathies and must be accompanied by pretest and post-test counseling. A pathogenic variant may guide family screening, arrhythmic risk assessment and sometimes treatment; a variant of uncertain significance must not guide irreversible interventions. The familial phenotype should be reconstructed using a pedigree, ECG and imaging in appropriate relatives, with variant interpretation updated over time; the differential diagnosis of dyspnea includes COPD, asthma, interstitial lung diseases, pulmonary embolism, anemia, obesity, deconditioning, ischemia, dysautonomia and neuromuscular disorders. Edema also results from venous insufficiency, cirrhosis, nephrosis and drugs; elevated peptide levels occur in numerous conditions. Correct diagnosis avoids both overdiagnosis of HFpEF in every older person with dyspnea and failure to identify a syndrome with less conspicuous findings. After confirming the syndrome, its stage must be defined: ejection fraction and trajectory, functional class, congestion, perfusion, rhythm, renal and hepatic function, pulmonary pressure, valves and comorbidities. Etiological assessment must be explicit and not limited to the label “nonischemic”; a complete phenotypic diagnosis allows coherent selection of treatment, devices, follow-up and family screening.

Ambulatory rhythm monitoring is selected according to symptom frequency: short Holter monitoring for daily episodes, prolonged recordings for less frequent events and a loop recorder for unexplained syncope or a suspected rare arrhythmia. The burden of atrial fibrillation and premature beats must be quantified, because tachycardia-mediated cardiomyopathy may not be apparent on an occasional ECG; congestion assessment must not rely solely on weight. Jugular venous pressure, edema, orthopnea, lung ultrasound, vena cava assessment, bioimpedance and biomarkers describe different compartments; weight loss may be minimal during effective decongestion because of redistribution and simultaneous nutritional changes. A multiparametric approach reduces the risk of discharging a patient who remains congested. Bone-tracer scintigraphy may noninvasively diagnose transthyretin cardiac amyloidosis when myocardial uptake is of an appropriate grade and monoclonal proteins have been excluded. The presence of gammopathy instead requires hematological characterization and often biopsy, because AL and ATTR may coexist with age-related monoclonal gammopathy. Amyloid typing is mandatory before treatment.

In sarcoidosis, magnetic resonance imaging and PET provide complementary information on scar and inflammation. Inadequate PET preparation may lead to diffuse physiological uptake and an uninterpretable scan; extracardiac biopsy is often safer than endomyocardial biopsy. Arrhythmic risk may be high even when ejection fraction is not severely reduced, in the presence of extensive late enhancement. In iron overload, ferritin and transferrin saturation guide the selection of investigations, but inflammation and liver disease alter values; myocardial T2* measures the magnetic effect of iron and predicts dysfunction in transfusional forms. Liver biopsy does not necessarily quantify cardiac iron, because the two compartments may have different kinetics. When pheochromocytoma, thyroid disease, acromegaly or another endocrinopathy is suspected, testing must take sampling conditions, medications and pretest probability into account. Mildly elevated metanephrines during critical illness do not confirm a tumor; abnormal TSH may reflect drugs or nonthyroidal illness syndrome; a targeted etiological investigation avoids an indiscriminate panel of false positives.

In peripartum cardiomyopathy, preeclampsia, embolism, ischemia, sepsis and pre-existing heart diseases are excluded; magnetic resonance imaging may clarify alternative diagnoses, but gadolinium use and timing must be discussed during pregnancy. Genetic counseling is reasonable, especially with a family history or incomplete recovery, because some patients have variants shared with dilated cardiomyopathy; valvular assessment must quantify severity under the appropriate loading conditions. Functional regurgitation may decrease after diuresis and treatment, while low cardiac output may make the gradients of severe stenosis appear modest. Transesophageal echocardiography, stress testing, CT and catheterization resolve discrepancies. Before intervention, primary valvular disease must be distinguished from a consequence of remodeling. Estimated pulmonary pressure is derived from tricuspid regurgitation velocity and estimated right atrial pressure, both subject to error. Catheterization distinguishes mean pressure, wedge pressure, gradient and vascular resistance and may include exercise or fluid challenge. Hemodynamic definition is essential before labeling a patient as having pulmonary arterial hypertension and prescribing specific drugs.

When constriction is suspected, echocardiography looks for septal shift, respiratory variations in flow, preserved or increased medial e’ and diastolic flow reversal in the hepatic veins; CT and magnetic resonance imaging assess thickness and inflammation. A pericardium that is not thickened does not rule out constriction; invasive hemodynamic assessment documents respiratory ventricular discordance when imaging remains uncertain. Myocardial viability assessment identifies scar and potentially recoverable dysfunctional myocardium, but must not be used as an automatic trigger for revascularization. Coronary anatomy, symptoms, ischemia, procedural risk and trial evidence must be integrated; contractile recovery may take months, and its absence does not necessarily imply the absence of a benefit in terms of ischemia in prognostically relevant coronary anatomies. Echocardiographic reassessment is appropriate after treatment initiation and titration, a clinical change, revascularization or valve correction, especially if the result changes device decisions. Overly frequent serial imaging in a stable patient rarely adds value. Measurements should report the method and conditions, because a change of a few points may fall within interstudy variability.

Treatment and prognosis

The goals are to prevent progression, treat the cause, reduce mortality and hospitalizations, relieve congestion and symptoms, and preserve organ function and quality of life. The strategy must combine interventions with prognostic benefit, symptomatic therapy, devices and management of comorbidities. The concept of evidence-based therapy entails targeting multiple complementary pathways early at tolerated doses, rather than waiting for the sequential failure of a single drug. Prevention begins before symptoms. Control of hypertension, treatment of diabetes with SGLT2 inhibitors in appropriate patients, prevention of ischemia, smoking cessation and management of obesity reduce the risk of heart failure. In pre-heart failure with reduced ejection fraction, ACE inhibitors and beta-blockers are indicated in defined settings, especially after myocardial infarction; timely correction of valvular disease and cardiotoxicity may prevent progression to the clinical stage. Loop diuretics reduce filling pressure and extracellular volume. The dose should achieve euvolemia while avoiding both residual congestion and excessive depletion; after compensation is achieved, the lowest effective dose is sought, with weight self-monitoring and individualized instructions. Furosemide, torsemide and bumetanide differ in bioavailability and duration, but there is no definitive evidence that one agent universally improves survival over the others.

Diuretic resistance may result from reduced intestinal absorption, renal perfusion, distal nephron hypertrophy, elevated venous pressure, hypoalbuminemia, NSAIDs, excess sodium or nonadherence. Increasing the dose, intravenous administration and sequential nephron blockade with a thiazide, metolazone or acetazolamide in appropriate settings may restore natriuresis. Sodium, potassium, magnesium, renal function and acid-base status require close monitoring. In HFrEF, the first pillar is inhibition of the renin-angiotensin system, with a preference for sacubitril/valsartan in appropriate patients. The ARNI reduces events compared with enalapril; it may be initiated at 24/26 or 49/51 mg twice daily and titrated to 97/103 mg twice daily according to blood pressure, renal function and potassium. After an ACE inhibitor, an interval of at least 36 hours is essential to limit the risk of angioedema; an ACE inhibitor or an ARB remains an alternative when an ARNI is not feasible. Previous ACE inhibitor-related angioedema, pregnancy and significant bilateral renal artery stenosis require particular caution or contraindicate specific therapeutic pathways. A moderate increase in creatinine after RAAS blockade may reflect the expected hemodynamic effect and must be distinguished from hypovolemia, hypotension, NSAID use or clinically significant hyperkalemia.

The beta-blockers with evidence of prognostic benefit are bisoprolol, carvedilol and extended-release metoprolol succinate; nebivolol has supporting data in older patients and a role in European recommendations. They should be started at low doses in clinically stable patients without severe congestion, then titrated; a transient increase in fatigue does not equate to permanent intolerance; symptomatic bradycardia, hypoperfusion or advanced conduction block require reassessment. The mineralocorticoid receptor antagonists spironolactone and eplerenone reduce mortality and hospitalizations in symptomatic HFrEF. They are generally used when eGFR is above 30 mL/min/1.73 m² and potassium is below 5.0 mmol/L at initiation, with early and serial monitoring. Gynecomastia and sexual dysfunction are more frequent with spironolactone; hyperkalemia should not be prevented by unnecessarily discontinuing all drugs with prognostic benefit. Dapagliflozin and empagliflozin, 10 mg once daily, rapidly reduce cardiovascular death or worsening heart failure in HFrEF regardless of the presence of diabetes. SGLT2 inhibitors cause a modest initial fall in eGFR that tends to stabilize and protect the kidneys and heart over time. They should be temporarily withheld during prolonged fasting or critical illness because of the risk of euglycemic ketoacidosis; genital infections and volume status must be managed.

The four pillars should be introduced over weeks, without necessarily bringing each individual agent to its maximum dose before adding the next. Asymptomatic low blood pressure does not automatically require dose reduction; nonessential vasodilators should be eliminated, hypovolemia corrected and doses spaced out. The individualized sequence considers heart rate, potassium, renal function, blood pressure, congestion and access to medications while maintaining the goal of rapidly covering all pathways. Ivabradine reduces hospitalizations in selected patients with an ejection fraction no greater than 35%, sinus rhythm and a heart rate of at least 70/min despite the maximum tolerated beta-blockade. The hydralazine-isosorbide dinitrate combination is useful in Black patients with advanced HFrEF despite optimal treatment and when RAAS blockade is contraindicated. Vericiguat may be considered after recent worsening in stabilized high-risk patients. Digoxin may reduce hospitalizations in symptomatic HFrEF and control heart rate in atrial fibrillation when other options are insufficient, but does not improve survival. Renal function, age, lean body mass, potassium and interactions determine toxicity risk; low concentrations are preferable. Nausea, visual disturbances, bradyarrhythmias and tachyarrhythmias may signal digitalis toxicity.

Nonsteroidal anti-inflammatory drugs, thiazolidinediones and some calcium channel blockers may worsen fluid retention or prognosis in HFrEF. Verapamil and diltiazem are generally avoided in systolic dysfunction because of their negative inotropic effect. Nitrates must not be combined with phosphodiesterase-5 inhibitors; supplements, herbal products and over-the-counter medications must be included in medication reconciliation. In HFrEF with LVEF 41-49% and HFpEF, dapagliflozin and empagliflozin reduce the risk of the composite of worsening heart failure or cardiovascular death across the entire ejection fraction range studied, with benefit driven mainly by fewer heart failure events. Finerenone reduced total worsening heart failure events and cardiovascular death in patients with an ejection fraction of at least 40% in the FINEARTS-HF trial and has been approved in the United States for this indication; it requires monitoring of potassium and renal function. The choice must comply with national regulatory approvals, contraindications and availability. An ARNI or ARB may be useful in subgroups with an ejection fraction toward the lower end, hypertension or other indications; mineralocorticoid antagonists are recommended in symptomatic heart failure regardless of ejection fraction. Diuretics treat congestion in every phenotype. Blood pressure control is essential and should avoid both overload and hypotension, while atrial fibrillation, ischemia, sleep apnea, anemia and kidney disease require integrated management.

In the obesity-related HFpEF phenotype, intentional weight loss may improve symptoms and physical capacity. Semaglutide improved health status and function in the STEP-HFpEF trials; tirzepatide in the SUMMIT trial reduced the composite of cardiovascular death or worsening heart failure events and improved quality of life. These therapies require attention to gastrointestinal tolerability, cholelithiasis, loss of lean mass, frailty and regulatory indications; atrial fibrillation requires rate or rhythm control, anticoagulation according to thromboembolic risk and correction of precipitants. Catheter ablation may improve outcomes in selected patients with HFrEF, especially when the arrhythmia causes or aggravates the cardiomyopathy. Amiodarone is often the antiarrhythmic drug that can be used in systolic dysfunction, but has thyroid, pulmonary, hepatic, ocular and neurological toxicity that requires surveillance. Revascularization, valve interventions and treatment of specific cardiomyopathies must be selected according to the mechanism; revascularization is not indicated solely because ejection fraction is reduced, but may improve prognosis or symptoms in appropriate coronary anatomies. Transcatheter mitral edge-to-edge repair reduces events in selected patients with severe secondary regurgitation, persistent symptoms, suitable anatomy and a ventricle that is not excessively dilated, after optimized treatment.

An implantable cardioverter-defibrillator prevents arrhythmic death in selected patients with ischemic or nonischemic HFrEF, persistently reduced ejection fraction despite at least approximately three months of treatment, and an expected functional survival of more than one year. It is not routinely implanted in the first 40 days after myocardial infarction. Age, etiology, scar, comorbidities and the risk of nonarrhythmic death should inform shared decision-making. Resynchronization offers the greatest benefit in sinus rhythm, with an ejection fraction no greater than 35%, left bundle branch block and a QRS duration of at least 150 ms despite optimal treatment. Benefit decreases with a narrower QRS or non-LBBB morphology and depends on lead position, pacing percentage, rhythm and scar. In patients with an anticipated high pacing requirement, physiological pacing strategies or CRT may prevent dyssynchrony-induced cardiomyopathy. Adapted aerobic and resistance exercise improves functional capacity and quality of life in stable patients; rehabilitation combines training, education, nutrition and support. Prolonged inactivity accelerates deconditioning and sarcopenia. During unstable phases, exercise is temporarily reduced, but early mobilization after stabilization limits decline, especially in older patients.

Sodium restriction should be reasonable and individualized: excess promotes retention, but extreme restriction may worsen appetite and diet quality and activate neurohormonal responses. Fluid restriction is reserved mainly for hyponatremia or difficult-to-control congestion. Alcohol must be stopped in alcoholic cardiomyopathy; vaccination, smoking cessation and infection prevention reduce avoidable precipitants; iron deficiency is assessed using ferritin and transferrin saturation. Intravenous ferric carboxymaltose or ferric derisomaltose has improved functional status and reduced hospitalizations in selected populations, whereas oral iron is often poorly effective in heart failure. Transfusions, erythropoietin and supplementation in the absence of deficiency are not general strategies and carry specific risks; follow-up must monitor symptoms, weight, blood pressure, heart rate, congestion, renal function, electrolytes, iron status, adherence and access to care. Telemonitoring of weight alone has not produced consistent benefits; structured systems and hemodynamic monitoring of pulmonary artery pressure may reduce hospitalizations in selected patients. Technology works when incorporated into a clinical pathway capable of interpreting data and intervening promptly.

After hospitalization, the vulnerable phase requires follow-up within one or two weeks, often sooner, and rapid optimization. STRONG-HF demonstrated that a high-intensity strategy with early treatment titration and frequent visits reduces death or rehospitalization at 180 days in selected, monitored patients. The model must not be copied without observing its stability and laboratory safety criteria. In advanced heart failure, early assessment prevents renal, hepatic or pulmonary dysfunction or frailty from becoming irreversible. Continuous inotropes may serve as a bridge to transplantation or mechanical support, as a bridge to decision or for palliation, but increase arrhythmias and are not routine chronic therapy. Ventricular assist devices and transplantation require multidisciplinary selection, psychosocial assessment and planning for long-term complications; palliative care is appropriate throughout the trajectory when there is a symptom burden, not only in the final days. Management of dyspnea, pain, anxiety, depression and insomnia may coexist with drugs that improve prognosis and with devices. In terminal stages, resuscitation, hospitalizations, inotropes, deactivation of defibrillator shocks and place of care are discussed, respecting the patient’s values and goals.

Prognosis is estimated from the clinical trajectory, hospitalizations, functional class, blood pressure, sodium, renal and hepatic function, peptide levels, oxygen consumption, right ventricular function and treatment tolerance. Models such as the Seattle Heart Failure Model and MAGGIC help, but may be less accurate in populations different from those in which they were developed; honest communication uses ranges and scenarios, avoiding turning a probabilistic score into an individual deadline. Optimization requires distinguishing a true contraindication, a manageable adverse effect and a temporal association. An increase in creatinine after diuresis, low systolic blood pressure without symptoms or a single mildly elevated potassium measurement does not necessarily justify permanent abandonment of treatment. Repeating blood sampling, reviewing diet and medications, and selective use of potassium binders may preserve therapies with prognostic benefit. Renal function is not a uniform limitation on SGLT2 inhibitors, because trials and indications allow use down to low eGFR levels depending on the agent and context. The initial decline reflects a glomerular hemodynamic change and must not be confused with progression of kidney disease. In dialysis, pregnancy, type 1 diabetes or previous ketoacidosis, use requires exclusion or specialist assessment.

In symptomatic hypotension, hypovolemia, infection, bleeding and nonessential drugs are sought. Nitrates, calcium channel blockers or alpha-blockers without a prognostic indication are reduced first, and the diuretic dose is reassessed if the patient is euvolemic. Maintaining small doses of several drug classes may preserve broader biological coverage than complete withdrawal of one pathway; an elevated heart rate in sinus rhythm may reflect congestion, anemia, hyperthyroidism or a reduced beta-blocker dose. Before ivabradine is used, these causes must be treated and rhythm and adherence verified. A very low heart rate requires investigation for conduction block and interactions between a beta-blocker, digoxin and amiodarone, with pacing considered only when there is an independent indication. Diabetes control should prioritize drugs with cardiovascular safety; SGLT2 inhibitors are central; metformin can generally be used in stable heart failure with adequate renal function; thiazolidinediones are avoided because of retention. Insulin may promote weight gain and sodium retention but remains necessary when indicated. The glycemic target should avoid hypoglycemia in frail patients and those with a limited prognosis.

Hypertension in HFpEF is treated with drugs selected also according to comorbidities: RAAS inhibitors, diuretics, MRAs and other appropriate agents; excessively low blood pressure may reduce perfusion and exercise tolerance, especially in stiff ventricles and older patients. Home and orthostatic measurements distinguish true control, the white coat effect and postural hypotension; coronary artery disease requires statins and antithrombotic prevention according to coronary indications, not for heart failure alone. Beta-blockade may treat angina and dysfunction; nitrates relieve symptoms but have not demonstrated routine benefit in HFpEF and may reduce activity. The choice of PCI or bypass surgery should be guided by anatomy, ischemia, function and the Heart Team. Severe primary valvular diseases are corrected before ventricular damage and pulmonary hypertension become irreversible. TAVI or surgery for aortic stenosis, mitral repair or replacement, tricuspid procedures and transcatheter interventions depend on age, anatomy, risk and the expected duration of benefit. Diuretics relieve congestion but do not halt a severe mechanical lesion.

In ATTR amyloidosis, tafamidis stabilizes transthyretin and reduces mortality and hospitalizations in appropriate patients; gene-silencing therapies are expanding options according to phenotype and regulatory approvals. In AL amyloidosis, the priority is rapid suppression of the plasma cell clone in collaboration with hematology. Beta-blockers, ACE inhibitors and vasodilators may be poorly tolerated because of low cardiac output and autonomic neuropathy; active sarcoidosis may require corticosteroids and steroid-sparing immunosuppressants, guided by disease activity, function and arrhythmias, without a guarantee of eliminating scar. Giant cell, eosinophilic or checkpoint inhibitor-associated myocarditis requires specific urgent protocols. In presumed viral lymphocytic myocarditis, generalized empirical immunosuppression is not supported without an appropriate diagnosis. In peripartum cardiomyopathy, therapies compatible with pregnancy or breastfeeding are used according to the phase; ACE inhibitors, ARBs, ARNIs, MRAs and SGLT2 inhibitors are contraindicated during pregnancy. Bromocriptine is used in selected protocols and requires consideration of antithrombotic therapy. Contraception and the risk of another pregnancy should be discussed after recovery with a cardio-obstetric team.

Treatment of high-output forms is directed at the cause: correction of anemia without volume overload, control of thyrotoxicosis, thiamine in beriberi, treatment of sepsis or a fistula, and management of liver disease. Neurohormonal vasodilators may worsen already extreme vasodilation; measurement of cardiac output and vascular resistance avoids mistaking a hyperdynamic circulation for conventional HFrEF. Continuous positive airway pressure treats obstructive sleep apnea and improves sleepiness and blood pressure, but its effect on heart failure events depends on adherence and phenotype. In central sleep apnea with HFrEF, adaptive servo-ventilation is not used indiscriminately because of signals of harm in a study population. Optimization of heart failure remains the first intervention for periodic breathing; influenza, pneumococcal, COVID and other vaccines according to age and risk reduce infections capable of precipitating heart failure. Fever, tachycardia and the inflammatory response increase demand and alter volume; prevention is particularly important in older patients. Vaccination should be incorporated into discharge planning rather than left to a generic future follow-up.

Depression and anxiety require screening and compatible psychological or pharmacological treatment. Tricyclic antidepressants may worsen conduction, hypotension and arrhythmias; SSRIs generally have a more favorable profile but do not directly improve heart failure. Rehabilitation and caregiver support reduce isolation and improve self-management; self-care includes recognition of dyspnea, edema and rapid weight gain, adherence, blood pressure monitoring and a contact plan. Diuretic self-adjustment regimens are appropriate only for educated patients with defined thresholds, avoiding automatic responses to every weight change. Scales, apps and devices do not replace an accessible care contact; polypharmacy is reviewed at every transition. Duplicate RAAS therapies, potassium supplements that are no longer needed, NSAIDs, sympathomimetic decongestants and QT-prolonging drugs are frequent problems. The clinical pharmacist can check doses, interactions and medication packs, turning reconciliation from a formal list into event prevention.

Home care, day-hospital care and outpatient diuretics may prevent some hospitalizations in selected patients, but are not suitable in the presence of hypoxemia, shock, ischemia, unstable arrhythmias or lack of support. The care setting must reflect clinical risk and monitoring capacity, not merely a preference to reduce hospitalization. Response to treatment is judged by survival, hospitalizations, symptoms, functional capacity, quality of life, congestion, organ function and remodeling; a drug may improve clinical events without substantially changing ejection fraction, and a symptomatic therapy may not alter mortality. Separating clinical endpoints from surrogates avoids incorrect conclusions about individual benefit. In patients with improved ejection fraction, the therapy that promoted recovery is generally continued. TRED-HF showed frequent relapses after treatment withdrawal in recovered dilated cardiomyopathy; blood pressure, rhythm, peptide levels and imaging may deteriorate before symptoms; remission therefore requires lifelong surveillance, not permanent discharge from cardiology care.

Complications

The most frequent complication is congestive exacerbation, often preceded by increases in intracardiac pressures days or weeks before symptoms. Ischemia, arrhythmias, infections, hypertension, progression of valvular disease, renal dysfunction, drugs and nonadherence may precipitate it; persistent congestion at discharge is associated with rehospitalization and death, making confirmation of true euvolemia essential. Acute pulmonary edema produces severe hypoxemia, increased work of breathing and possible ventilatory exhaustion. In hypertensive crises, it may depend mainly on redistribution and afterload, whereas forms with increased volume require more prolonged decongestion. Acute mitral regurgitation, myocardial infarction and arrhythmias must be recognized because treating the edema alone does not correct the mechanical cause; progression to low cardiac output may culminate in cardiogenic shock. Hypoperfusion induces anaerobic metabolism, acidosis, inflammation, endothelial dysfunction and multiorgan failure; initial vasoconstriction further increases afterload. Some patients maintain apparently acceptable systolic blood pressure in the early stages, so lactate, urine output, mental status and peripheral signs must be assessed serially.

Renal dysfunction is driven by venous congestion, reduced perfusion pressure, RAAS activation, drugs and pre-existing kidney disease. An increase in creatinine during effective fluid removal may be functional and compatible with a better prognosis than stable creatinine in the presence of residual congestion. Persistent oliguria, an abnormal urinary sediment or consistent biomarkers instead suggest intrinsic kidney injury. Chronic hepatic congestion causes centrilobular fibrosis, cholestasis and, in advanced cases, cardiac cirrhosis; acute hypoperfusion causes hypoxic hepatitis with very high aminotransferases. Coagulopathy, hypoalbuminemia and ascites may simultaneously reflect the heart, liver, nutrition and anticoagulants; MELD-XI and other indices help in advanced assessment but do not replace etiological analysis. Dilutional hyponatremia results from vasopressin and reduced free water excretion and is a marker of severe disease. Hyperkalemia limits RAAS inhibitors and MRAs; diuretic-induced hypokalemia and hypomagnesemia increase arrhythmias. Overly rapid sodium correction exposes patients to osmotic demyelination, while routine use of vasopressin antagonists has not demonstrated a general benefit in survival.

Atrial fibrillation reduces the atrial contribution to filling, increases heart rate and increases thromboembolism; ventricular tachycardia and ventricular fibrillation cause sudden death. Bradycardia, conduction block and sinus node dysfunction may be spontaneous or drug-induced. Myocardial scar is an arrhythmic substrate that may persist even after ejection fraction improves, which is why risk is not reassessed solely on the basis of the ejection fraction measurement. Intracardiac thrombi and stasis increase embolic risk, especially with atrial fibrillation, an apical aneurysm or severe dysfunction. Heart failure in sinus rhythm is not in itself a universal indication for anticoagulation, because the reduction in ischemic events may be offset by bleeding. A documented ventricular thrombus requires a distinct strategy based on morphology, etiology and imaging follow-up. Secondary mitral and tricuspid regurgitation may progress with dilation and dyssynchrony, further increasing volume and pressures; severe tricuspid regurgitation reduces the accuracy of some echocardiographic indices and promotes refractory congestion. The timing of intervention is complex: treating a valve too late may fail to reverse already advanced ventricular dysfunction.

Pleural effusions and ascites may limit ventilation; ascites and massive edema may limit mobility; peripheral edema promotes skin lesions and infections, while intestinal edema may alter drug absorption. Paracentesis or thoracentesis may be necessary in selected cases, but mechanical fluid removal does not replace control of venous pressures. Unilateral effusions, fever or atypical features require a differential diagnosis. Frailty, sarcopenia and cardiac cachexia reduce strength, immune competence and treatment tolerance; weight loss may be hidden by edema and become apparent only after decongestion. Nutritional interventions alone are often insufficient if intestinal congestion, inflammation and neurohormonal activation persist; resistance exercise and treatment of the cause must be integrated. Sleep-disordered breathing, pulmonary hypertension and right ventricular dysfunction worsen prognosis. Adaptive servo-ventilation is not recommended in HFrEF with predominant central sleep apnea; in predominant obstructive sleep apnea, it may be considered to improve sleep quality, quality of life and symptoms. Pulmonary vasodilators are not routinely indicated in postcapillary pulmonary hypertension and may cause pulmonary edema.

Depression, anxiety, cognitive decline and social isolation increase poor adherence, hospitalizations and mortality. Polypharmacy, costs, health literacy and caregiver capacity influence the real-world effectiveness of treatment; a theoretically optimal but inaccessible prescription does not constitute effective treatment; simplification, social support and shared decisions are components of clinical safety. Repeated hospitalizations accelerate deconditioning, muscle loss and delirium risk. Each episode may mark a trajectory of progression, but not all hospitalizations indicate irreversibility: a correctable precipitant and underused therapy offer scope for recovery. However, failure to reassess appropriate patients for advanced therapies may close the window of opportunity. Death may result from progressive pump failure, arrhythmia, myocardial infarction, stroke, infection or multiorgan failure, and the mode varies with phenotype and etiology. Contemporary treatment reduces sudden death and death from pump failure in HFrEF, but increases the relevance of comorbidities and noncardiovascular causes in older patients. Prognosis must therefore be periodically updated together with goals of care.

Nonocclusive mesenteric ischemia is a rare but devastating complication of low cardiac output and intense vasoconstriction. Disproportionate abdominal pain, rising lactate, distension and intolerance of nutritional support require urgent assessment. More common intestinal congestion may produce similar but less fulminant symptoms; delaying imaging in the presence of warning signs exposes patients to intestinal necrosis; chronic congestion and immobility promote skin ulcers, cellulitis and venous thromboembolism. Antithrombotic prophylaxis is used in hospitalized patients at risk and without contraindications, but does not replace mobilization. Massive edema makes the skin fragile, and rapid volume removal may change its tension; dressings and limb care are part of management. Stroke may result from atrial fibrillation, ventricular thrombus, atherosclerosis or procedures; acute neurological deficits must not be attributed to global hypoperfusion without imaging, because reperfusion is time-dependent. After a stroke, blood pressure, swallowing and anticoagulation require a balance between the brain and heart and neurocardiological coordination.

Infections are both precipitants and complications. Pulmonary edema, aspiration, catheters and deconditioning increase pneumonia and bacteremia; fever may be absent in older patients. Elevated inflammatory biomarkers also occur in sterile heart failure, while radiographic infiltrates may represent edema. Cultures and antibiotics should be guided by a reasoned assessment of infection probability; excessive diuresis may cause hypotension, metabolic alkalosis, hypokalemia, renal deterioration and gout. Volume contraction and increased bicarbonate reduce the natriuretic response; acetazolamide may correct part of this physiology in selected settings. The goal is not to maximize the liters removed, but to achieve safe euvolemia while preserving perfusion; implantable devices have their own complications: infection, hematoma, pneumothorax, perforation, lead malfunction, inappropriate shocks and worsening tricuspid regurgitation. Ineffective biventricular pacing due to atrial fibrillation or premature beats reduces benefit. Remote and outpatient checks must assess not only the battery but also delivered therapy, arrhythmias and pacing percentage.

Ventricular assist support exposes patients to bleeding, pump thrombosis, stroke, driveline infection, aortic regurgitation, arrhythmias and right ventricular failure; loss of pulsatility modifies hemostasis and vascularization; anticoagulation and blood pressure require specific protocols. The patient and caregiver must have technical skills and a plan for power interruptions and emergencies. After transplantation, rejection, graft vasculopathy, infections, malignancies, nephrotoxicity and metabolic complications replace part of the risk of native heart failure; denervation modifies the response to exercise and the perception of ischemia. Immunosuppression and surveillance are lifelong, so transplantation is a replacement therapy, not the end of care. Sudden death may occur because of tachyarrhythmia, bradyarrhythmia, electromechanical dissociation or an ischemic event. In advanced phenotypes, the proportion of deaths that cannot be prevented by a shock increases, reducing the relative benefit of an ICD. This explains why life expectancy, frailty and preferences are integral to selection and future deactivation of shocks.

The terminal phase may be characterized by refractory dyspnea, uncontrollable congestion, hypotension, multiorgan failure and frequent hospitalizations. Low-dose opioids may be used for refractory dyspnea in palliative care with appropriate monitoring; oxygen is indicated mainly in hypoxemia. Palliative sedation is reserved for refractory symptoms according to ethical protocols and must not be confused with intentional hastening of death.