Chronic congestive heart failure – etiology, pathogenesis, clinical manifestations

01Definition and overview

Heart failure is a clinical syndrome of symptoms and signs caused by a structural or functional abnormality of the heart that raises the pressures inside it or limits its output, at rest or on exertion. The diagnosis needs objective evidence of congestion, supported by tests: raised natriuretic peptides and an abnormal heart on echocardiography. People with a heart abnormality but no symptoms are at stage A or B, not in heart failure. Chronic heart failure is established heart failure, stable or slowly progressing; "congestive" describes the fluid retention that marks it.

By ejection fraction

A patient whose ejection fraction rises by at least 10 points to above 40 per cent with treatment has heart failure with improved ejection fraction; the heart failure is in remission, not cured.

By stage and by symptoms

• Stage A, at risk: hypertension, diabetes, obesity, coronary disease, cardiotoxic drugs or a family history of cardiomyopathy, with a normal heart.
• Stage B, pre-heart failure: structural or functional heart disease, or raised natriuretic peptides, without symptoms, such as a reduced ejection fraction after an infarction.
• Stage C, heart failure: current or past symptoms.
• Stage D, advanced heart failure: severe symptoms and repeated admissions despite full treatment.

Heart failure is also described by the side that fails. Left heart failure congests the lungs; right heart failure congests the body, and it is usually caused by left heart failure, or by lung disease and pulmonary hypertension (cor pulmonale). High-output heart failure occurs when a normal heart cannot meet a very high demand, in severe anaemia, thyrotoxicosis, arteriovenous fistulas, Paget disease or beriberi.

02Etiology and pathophysiology

Causes

• Coronary artery disease, the commonest cause in Europe, through infarction, scarring and hibernating myocardium.
• Hypertension, through hypertrophy and stiffening, the main cause of HFpEF.
• Cardiomyopathies: dilated (genetic, alcohol, chemotherapy, myocarditis, peripartum), hypertrophic, restrictive and infiltrative (amyloidosis).
• Valve disease: aortic stenosis, mitral and aortic regurgitation.
• Arrhythmias: persistent tachycardia, atrial fibrillation, complete heart block.
• Drugs and toxins: anthracyclines, trastuzumab, immune checkpoint inhibitors, alcohol, cocaine.
• Endocrine and metabolic disease: diabetes, thyroid disease, phaeochromocytoma, iron overload.
• Pericardial disease, congenital heart disease and pulmonary hypertension.

Often several act together, such as hypertension, coronary disease and diabetes in an older patient.

The failing heart and the body's response

1. 1

   The injury

   An infarction, a cardiomyopathy or a long pressure or volume load reduces the stroke volume, or stiffens the ventricle so that it fills only at a high pressure.
2. 2

   Compensation

   The fall in output is sensed by baroreceptors and the kidneys. The sympathetic system speeds and strengthens the heart and constricts the vessels; the renin-angiotensin-aldosterone system and vasopressin retain salt and water. The blood pressure and the filling are maintained, and by the Frank–Starling law the stretched ventricle ejects more.
3. 3

   The vicious circle

   Over months the same responses do harm. Vasoconstriction raises the afterload, retained salt and water cause congestion, and angiotensin II, aldosterone and noradrenaline directly damage the myocytes, causing fibrosis, hypertrophy and apoptosis. Catecholamines provoke arrhythmias.
4. 4

   Remodelling

   The ventricle dilates and becomes more spherical. By the law of Laplace, a larger radius raises the wall stress and the oxygen demand. The mitral annulus stretches and the valve leaks, adding a volume load, and the function declines further.

The natriuretic peptides oppose these responses. ANP from the atria and BNP from the ventricles are released when the walls are stretched; they cause natriuresis and vasodilatation and suppress renin and aldosterone. In heart failure they are overwhelmed, but they rise in proportion to the wall stress, which makes them the main diagnostic blood test. The enzyme neprilysin breaks them down, which is why inhibiting it helps.

Outside the heart, the kidneys retain sodium and, with venous congestion and low flow, lose function (the cardiorenal syndrome). Skeletal muscle wastes and its metabolism changes, which explains much of the fatigue; iron deficiency, anaemia, endothelial dysfunction and, in advanced disease, cardiac cachexia add to it. Treatments that block the neurohormonal responses, not those that simply stimulate the heart, are the ones that prolong life.

Preserved ejection fraction

In HFpEF the ventricle contracts normally but is stiff and relaxes slowly, from hypertrophy, fibrosis and changes in the giant protein titin. The filling pressure rises, especially on exercise, when the heart cannot fill faster. A systemic inflammatory state driven by obesity, diabetes, hypertension and kidney disease damages the small vessels of the heart. The left atrium dilates and fibrillates, the pulmonary pressure rises, and the heart rate fails to rise enough on exertion. HFpEF is a syndrome with several causes, and specific diseases such as amyloidosis and hypertrophic cardiomyopathy hide within it.

03Clinical features

Symptoms

• Breathlessness on exertion, then at rest; orthopnoea, breathlessness lying flat, measured by the number of pillows; and paroxysmal nocturnal dyspnoea, waking breathless at night.
• Fatigue and poor exercise tolerance.
• Swelling of the ankles and legs, weight gain, abdominal fullness, loss of appetite and nausea from congestion of the gut and liver.
• Night-time cough and wheeze, nocturia, breathlessness on bending forwards (bendopnoea).
• Confusion, low mood and, in advanced disease, weight loss and muscle wasting.

Signs

• A raised JVP and a positive hepatojugular reflux, the most specific signs of congestion.
• A third heart sound, a gallop rhythm, and a displaced apex beat in a dilated heart.
• Crackles at the lung bases and pleural effusions; often absent in chronic heart failure, because the lymphatics clear the fluid.
• Pitting oedema of the ankles, or of the sacrum in a patient in bed, an enlarged liver and ascites.
• Tachycardia, an irregular pulse in atrial fibrillation, pulsus alternans in severe failure, cool peripheries, and Cheyne–Stokes breathing.
• Murmurs of functional mitral or tricuspid regurgitation, or of the valve disease causing the failure.

No single symptom or sign is reliable. Breathlessness and oedema have many causes, and a raised JVP and a third sound are specific but often missed, which is why the diagnosis rests on tests.

04Diagnosis and management

Diagnosis

• Natriuretic peptides in everyone with suspected heart failure. A normal value makes it unlikely. European guidance uses age-adjusted NT-proBNP thresholds above which heart failure is likely: 125 pg/mL under 50, 250 pg/mL between 50 and 75, and 500 pg/mL over 75. Very high levels, over 2000 pg/mL, call for specialist assessment within 2 weeks. Atrial fibrillation, kidney disease, older age and pulmonary embolism raise the peptides; obesity lowers them.
• ECG: a normal ECG makes heart failure with reduced ejection fraction unlikely. It shows Q waves, hypertrophy, atrial fibrillation, bundle branch block (which matters for resynchronisation) and low voltage.
• Echocardiography, the key test: the ejection fraction, the size and wall thickness of the chambers, regional wall motion, the valves, and the pulmonary pressure. In HFpEF it shows the signs of a stiff ventricle and high filling pressure: a thick or heavy left ventricle, a left atrial volume above 34 mL per square metre in sinus rhythm, an E/e′ ratio above 9 and a tricuspid regurgitant velocity above 2.8 m/s.
• A chest X-ray for an enlarged heart, congestion, effusions and lung disease.
• Blood tests: full blood count, creatinine and electrolytes, liver tests, thyroid function, glucose and HbA1c, lipids, and iron studies (ferritin and transferrin saturation) in every patient, because iron deficiency is common and treatable.
• Tests for the cause: coronary angiography or CT, cardiac MRI for cardiomyopathies and scar, bone scintigraphy and tests for a monoclonal protein when amyloidosis is suspected, genetic testing, and occasionally a biopsy.
• When the diagnosis of HFpEF is uncertain, an exercise echocardiogram or right heart catheterisation shows the rise in filling pressure on exertion.

Management

Heart failure is managed by a multidisciplinary team, in hospital and in the community. The aims are to reduce deaths and admissions and to improve symptoms and quality of life:

• treating the cause: revascularisation, valve intervention, control of the heart rate and rhythm, stopping alcohol or a cardiotoxic drug;
• preventing progression from stage A and B: control of blood pressure, diabetes and lipids, and an ACE inhibitor and a beta-blocker for a reduced ejection fraction without symptoms;
• the foundational drugs, devices and other measures described in treatment of chronic heart failure;
• treating the other diseases that come with heart failure: atrial fibrillation, kidney disease, diabetes, anaemia and iron deficiency, sleep apnoea, depression and frailty;
• education, self-care and palliative care in advanced disease.

05Epidemiology

Heart failure affects about 1 to 3 per cent of adults, and more than 1 in 10 people over 70. Its incidence in Europe is about 2 to 13 per 1000 people a year; the age-adjusted incidence has fallen over three decades, but the number of patients is rising because people live longer and survive heart attacks. About half of patients have a preserved ejection fraction, a share that grows with age, and these patients are more often women. Heart failure is the commonest cause of hospital admission in people over 65.

06Prognosis

Heart failure has a poor outlook, worse than many cancers: fewer than 6 in 10 patients are alive 5 years after the diagnosis. In Danish data, about 15 per cent of patients under 65 and about 39 per cent of those aged 65 to 79 died within 5 years. Each admission marks a step down. Patients die of progressive pump failure, of sudden arrhythmic death (more common in milder heart failure with reduced ejection fraction), and, especially with preserved ejection fraction, of other diseases.

Older age, worse NYHA class, a lower ejection fraction, high natriuretic peptides, low sodium, poor kidney function, low blood pressure, cachexia and repeated admissions predict a worse outcome. Modern treatment has changed the outlook of heart failure with reduced ejection fraction more than of any other form: the full combination of drugs can add years of life, and some patients recover their ejection fraction.