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Investigation and Treatment of Heart Failure
MYOCARDIAL DISEASE
Chronic heart failure
Investigation and Treatment of Heart Failure
Clinical features The classical clinical symptoms of heart failure are exertional breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea and fatigue. More subtle symptoms include weight loss and nocturia. On examination, patients may have fluid retention (pitting oedema, raised jugular venous pressure), a displaced apex beat and a third heart sound. However, it is important to recognize that there are many causes of each of these symptoms and signs, and that many patients with heart failure may have none of them. Some form of diagnostic imaging is crucial.
Andrew L Clark John G F Cleland
Investigations have several aims in heart failure: • to help establish the diagnosis • to find a treatable underlying cause • to estimate the severity and give prognostic information • to guide treatment (and monitor for potential adverse effects of treatment).
Investigations Chest radiography helps exclude pulmonary causes of symptoms. The lung fields should be clear in patients with well-treated heart failure (Figure 1). Up to 50% of patients with chronic heart failure have a normal-sized heart on chest radiography, which is not a useful test for excluding left ventricular (LV) dysfunction.
Acute pulmonary oedema Pulmonary oedema is an acute medical emergency. The patient usually presents with acute, severe breathlessness, often with an obvious precipitant such as acute myocardial infarction or arrhythmia. Pulmonary crackles and wheezes are usually present. The most important investigation is chest radiography, which may show cardiomegaly (not universal) and interstitial or alveolar oedema. Other helpful investigations are measurement of transcutaneous oxygen saturation and blood gases. Patients are generally hypoxic. When there is diagnostic doubt (and, in selected cases, to help guide treatment), pulmonary artery catheterization to establish the pulmonary capillary wedge pressure can be helpful. The medical history, the presence of an obvious precipitating factor and chest radiography usually enable differentiation of respiratory infection and asthma from pulmonary oedema. Peak expiratory flow is usually more than 200 litres/ minute in patients with cardiac ‘asthma’. As the clinical emergency settles, further investigations are undertaken as for chronic heart failure.
ECG: 12-lead ECG is almost never normal in heart failure. However, an abnormal ECG does not help make the diagnosis. The ECG contains other important diagnostic information (e.g. previous infarction, LV hypertrophy) that helps identify the cause of heart failure. Echocardiography (Figures 2 and 3) is the standard imaging modality in heart failure. It is safe, non-invasive, quick and painless for the patient. It gives many different kinds of information, but is limited in many patients by obesity, chest wall deformity and lung pathology (particularly chronic pulmonary disease). Training in echocardiography and in interpreting the results is demanding, and modern equipment is expensive. LV systolic function may be normal or globally depressed. Echocardiography may show wall motion abnormalities or ventricular dyssynchrony.
Andrew L Clark is a Senior Lecturer at the University of Hull, UK. He qualified from the University of Cambridge and the Westminster Hospital, London, and trained in cardiology at the Royal Brompton Hospital, London and Western Infirmary, Glasgow. His research interests include the pathophysiology of cardiac heart failure and cachexia. John G F Cleland is Professor of Cardiology at the University of Hull, UK. He qualified from the University of Glasgow, and trained in Glasgow and at St Mary’s Hospital, London and the Hammersmith Hospital, London. His research interests include heart failure, and primary, secondary and tertiary prevention in cardiovascular disease.
MEDICINE
1 Chest radiograph in a patient with chronic heart failure. The left ventricular ejection fraction was 22%. The cardiac silhouette is slightly enlarged, but the lung fields are clear.
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MYOCARDIAL DISEASE
Diastolic function – the prevalence and importance of ‘diastolic heart failure’ are controversial. LV diastolic function can be assessed by examination of the mitral diastolic inflow pattern using Doppler echocardiography, but ventricular hypertrophy and atrial dilatation are probably better markers of diastolic dysfunction. Stress echocardiography – ventricular impairment can result from irreversible myocardial necrosis and scarring. There may be areas of viable but non-contractile myocardium (known as ‘hibernating myocardium’) that can recover contractile function if revascularized. On dobutamine echocardiography, areas of hibernating tissue appear akinetic, but begin to function as dobutamine is infused. At higher doses, function may again be lost as the tissue becomes more ischaemic. This biphasic response is highly predictive of recovery after revascularization. Newer modalities – faster image acquisition is allowing the development of three-dimensional echocardiography, which enables more accurate assessment of LV volumes. Tissue velocity imaging concentrates on tissue movement rather than blood movement through the heart. Contrast agents may better define anatomy and physiology.
2 Transoesophageal echocardiography in a 78-year-old woman with heart failure. She had a large left atrial myxoma and normal left ventricular function.
Nuclear imaging: radionuclide ventriculography gives the ejection fraction and information on regional function. It involves a significant radiation dose to the patient, but provides prognostic information and is usually more accurate and reproducible than echocardiography. Myocardial perfusion imaging can assess ischaemia and hibernation. Cardiac catheterization: left ventriculography gives information on LV function at the same time as it provides haemodynamic information (Figure 4). Coronary angiography is performed simultaneously to exclude coronary artery disease. Right ventricular biopsy can be helpful in selected cases (Figure 5). MRI: cardiac MRI is not widely available. Technical problems initially hampered the applicability of MRI to the heart (a moving target inside a moving thorax), but advances have improved the quality of images. MRI allows accurate and repeatable measurements of LV volume and myocardial mass.
3 Transthoracic echocardiography. The left ventricle is dilated. The colour jet between the left ventricle and the left atrium is mitral regurgitation, in this case secondary to left ventricular impairment.
‘Routine’ blood tests: all patients being investigated for heart failure should undergo a full blood count (primarily to exclude anaemia), and determination of urea and electrolytes (primarily to exclude renal failure) and serum protein (primarily to exclude hypoalbuminaemia as a cause of oedema). Liver function is often deranged in heart failure as a result of liver congestion. A screen for treatable causes of heart failure should include thyroid function (particularly to exclude thyrotoxicosis in patients with atrial fibrillation), ferritin (haemochromatosis) and serum protein electrophoresis (amyloid). Urinary catecholamine levels provide a method for detecting phaeochromocytoma as a rare cause of dilated cardiomyopathy.
Myocardial wall may be thickened as a result of hypertrophy or thinned from scar. Chamber dimensions – ventricular dilatation indicates either systolic dysfunction or volume overload caused by, for example, valve regurgitation. Atrial dilatation is a key marker of diastolic LV dysfunction. Valvular function – echocardiography allows accurate diagnosis of valvular heart disease. Older patients with heart failure often have unsuspected aortic stenosis. Mitral regurgitation is common, though it can be difficult to distinguish between mitral regurgitation secondary to LV dilatation, and heart failure caused primarily by mitral regurgitation (Figure 3). The velocity of any tricuspid regurgitation gives an estimate of pulmonary artery pressure.
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Other investigations: the following investigations are either new and therefore incompletely validated, or have not been
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MYOCARDIAL DISEASE
Haemodynamic tracing from a patient with aortic stenosis
Pressure (mm Hg)
200
100
On the left, the catheter is in the body of the left ventricle, at a pressure of 200 mm Hg. The catheter is withdrawn into the aorta, where the pressure is 120 mm Hg, giving a gradient of 80 mm Hg. 4
ing, but is now recognized to be safe. Coupled with metabolic gas exchange measurements, exercise testing gives valuable information. It is useful diagnostically (heart rate response, induction of ischaemia or arrhythmia, symptom limitation, to distinguish exercise limitation as a result of heart failure from other causes) and as an objective assessment of the severity of exercise limitation. Symptom-limited incremental tests are usually used to derive peak oxygen consumption as an index of exercise capacity, and the relationship between ventilation and carbon dioxide production gives an index of the ventilatory response to exercise. Endurance-limited tests such as the 6-minute walk test (which measures the distance covered in 6 minutes at the patient’s own speed) more closely resemble daily activity than maximal tests, and may be more sensitive to changes in response to therapy.
5 Myocardial biopsy specimen in amyloidosis. Apple-green birefringence is seen under polarized light.
Prognostic information: a wide variety of different variables have been shown to convey prognostic information in heart failure. Many are esoteric and not routinely available (e.g. tumour necrosis factor receptors). They may be broadly divided into indices of: • LV function (e.g. ejection fraction) • exercise capacity (e.g. peak oxygen consumption) • metabolic derangement (e.g. serum sodium or creatinine). Data from each of these domains should be collected from each patient to give prognostic information.
shown to be of value as part of the routine investigation of heart failure: Natriuretic peptides are released by the heart in response to cardiac chamber enlargement and are a sensitive (but not specific) indicator of heart failure. A normal plasma concentration effectively excludes heart failure and may be used as a biochemical screening test to identify patients who do not require echocardiography. Holter – ambulatory ECG commonly detects arrhythmias even in patients with no symptoms. Atrial flutter and fibrillation are common. Ventricular ectopic beats are almost universal, and non-sustained ventricular tachycardia is often seen. Sustained ventricular tachycardia is not uncommon (Figure 6). Guidelines on implantable defibrillators suggest that ambulatory patients with heart failure caused by coronary disease should routinely undergo electrophysiological investigation. Exercise testing – chronic heart failure has traditionally been thought to be a relative contraindication to exercise test-
MEDICINE
Management The aims of treatment in heart failure include relief of symptoms, reduced hospitalization and improved prognosis. Large randomized clinical trials have established several treatments as beneficial, and active treatment can now approximately double life expectancy. Nevertheless, angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists
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Holter recording from a 65-year-old man with dilated cardiomyopathy
The upper tracing shows non-sustained ventricular tachycardia; the lower shows sustained atrial flutter. The patient was asymptomatic throughout. 6
Henlé. They have a ‘high ceiling’; that is, increasing doses result in increasing diuresis over a large dose range. Frusemide (furosemide) and bumetanide are most widely used, and induce a brisk diuresis (which some patients find distressing). They cause hypokalaemia, an increase in serum lipids and impairment in glucose tolerance, and precipitate gout when used in high doses. Bumetanide and torasemide have a more reliable bioavailability and less metabolic effect than frusemide. A once-daily or twice-daily dosing schedule controls fluid retention. When oedema remains a problem, or when more than 80 mg of frusemide twice daily (or its equivalent) is needed, the combination of a loop diuretic and a thiazide can be particularly powerful. It is important to monitor urea and electrolytes closely – hypokalaemia is particularly common, and dehydration can occur rapidly.
(β-blockers) are underused, and are often not titrated up to the target doses shown to be beneficial in trials. It should be emphasized that clinical trials have concentrated on heart failure caused by systolic LV dysfunction. Less is known about the treatment of heart failure with preserved systolic function (‘diastolic heart failure’), though trials to address this issue are in progress. Non-drug treatment: management of heart failure should include advice, education and support. The role of the heart failure nurse specialist is increasingly recognized as important in helping patients learn about their condition and manage their therapy, thereby reducing hospital admissions and perhaps improving outcome. The traditional advice to rest with heart failure is incorrect. Many trials have shown that exercise training is beneficial in selected patients, and patients should be encouraged to keep active. There is little evidence to support dietary salt restriction, but it is conventional to tell patients not to add salt to their food and to avoid salty snacks. Fluid restriction (to about 1–1.5 litres/day) is helpful in patients with severe heart failure who are having problems controlling oedema.
Target doses for angiotensin-converting enzyme inhibitors in chronic heart failure
• • • • •
Diuretics remain the first-line treatment for fluid retention. Most patients need a loop diuretic. These drugs are excreted into the lumen of the renal tubules and block the sodium/ potassium/chloride pump in the thick ascending loop of
Captopril Enalapril Ramipril Trandolapril Lisinopril
Total daily dose 150–300 mg 20–40 mg 10 mg 4 mg 30–35 mg
Regimen t.d.s. b.d. b.d. o.d. o.d.
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β-blocker trials in chronic heart failure Study
Drug
• US Carvedilol
Carvedilol
• CIBIS-II
Bisoprolol
Patients IHD 48%
N
Follow-up
Placebo β-blocker
(months)
Placebo
β-blocker
change (%)
398
696
6.5
31
22
–65
0.00011
(7.8)
(3.2)
1320
1327
16
228
156
–32
< 0.0001
(17)
(12)
217
145
–35
0.0062
(10.8)
(7.3) –35
0.00014
II 54%, III 44% IHD 50%2 III 83%, IV 17% • MERIT-HF
Metoprolol
IHD 65%
2001
1990
12
II 41%, III 56% • COPERNICUS
Carvedilol
AII III and IV
1133
1156
15–45
Deaths (%)
190
130
(8.8)
(11.2)
Risk
P
The mortalities quoted are the crude data for the trials, not annualized mortality rates. IHD, ischaemic heart disease. 1
Not designed as a mortality study In 40% of patients in CIBIS-II, the underlying cause of heart failure was not known
2
8
dose of diuretic (frusemide, > 80 mg or equivalent per day) should be observed for hypotension for 2 hours. The dose should then be titrated up over the next month, and urea and electrolytes checked weekly. The most common side-effect is a dry cough. It is important to distinguish this from a cough related to heart failure. Angio-oedema can occur. Some decline in renal function is almost universal on starting an ACE inhibitor and is not an indication for stopping treatment. Renal failure can be precipitated in patients with bilateral renal artery stenosis. It is important to check renal function within 1 week of initiating or increasing the dose of an ACE inhibitor. Angiotensin receptor blockers (ARBs) are also being studied in heart failure. They have a better side-effect profile than ACE inhibitors, but have not been shown to be clinically superior. The role of ARBs as add-on therapy remains controversial.
In severe fluid retention, intravenous diuretics should be used to bypass the potentially oedematous gut wall. Dose for dose, intravenous infusions are more potent than bolus injections. ACE inhibitors have revolutionized the treatment of chronic heart failure. The first evidence of their benefits was seen in the CONSENSUS study, which demonstrated a 40% reduction in mortality in patients with severe heart failure treated with enalapril over 6 months. Long-term follow-up data suggest that enalapril increases survival time by 50%. Benefit has also been demonstrated in patients with mild-to-moderate heart failure and in those with asymptomatic LV dysfunction. Vasodilator agents (e.g. nitrates, hydralazine) generally do not reduce mortality in heart failure. All patients with significant LV systolic dysfunction, with or without symptoms, should receive an ACE inhibitor. The duration of treatment required is not certain, but is assumed to be life-long. There is firm mortality evidence to support the use of captopril, enalapril, trandolapril, lisinopril and ramipril at the target doses shown in Figure 7. Treatment with low doses should not be accepted unless the patient is intolerant of higher doses. On the day of initiation, diuretic should be omitted and a low dose of the ACE inhibitor given (e.g. enalapril, 2.5 mg). Patients with low blood pressure or who are taking a high
β-adrenoceptor antagonists: sympathetic activation causes vasoconstriction, and thus an increase in afterload, and increases heart rate. High levels of catecholamines are arrhythmogenic and cause cardiac myocyte necrosis. Catecholamines also facilitate the actions of other vasoconstrictor agents (e.g. angiotensin II). β-blockers may protect cardiac myocytes from direct catecholamine toxicity and slow the heart, reducing myocardial oxygen demand. β-blockers have anti-ischaemic and anti-
Dose schedules for β-blockers Drug • Carvedilol • Bisoprolol • Metoprolol
Starting dose 3.125 mg b.d. 1.25 mg o.d. 12.5 mg o.d.
Increment Doubling Doubling Doubling
Titration interval 2–4 weeks 2–4 weeks 2–4 weeks
Target 25 mg b.d.1 10 mg o.d. 200 mg o.d.2
1
50 mg b.d. if > 85 kg body weight Metoprolol is not licensed for treatment of heart failure in the UK; the preparation used in the MERIT-HF trial (metoprolol CR/XL) is not available in the UK
2
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arrhythmic effects and reduce the risk of recurrent myocardial infarction. With chronic use, LV ejection fraction improves. Both the CIBIS-II (bisoprolol) and the MERIT-HF (metoprolol) studies of mild-to-moderate heart failure were stopped early as a result of the pronounced beneficial effects of βblockade. More recently, the COPERNICUS study of severe heart failure was also stopped early (Packer et al.); in the most severely affected patients, there was a 50% reduction in the risk of death. Fewer patients withdrew from β-blockers than from placebo in the mortality trials (Figure 8). The initial dose must be low, and is increased gradually towards the target dose (Figure 9). Patients must be monitored closely, and may initially deteriorate on treatment or an increase in dose. Specialist supervision is required.
Unwanted treatment: many elderly patients with heart failure are given a large number of different drugs, many of which may be unnecessary or even dangerous. Non-steroidal antiinflammatory drugs should not be prescribed. Aspirin should be stopped if heart failure is difficult to control (its use in heart failure, even if coronary artery disease is present, remains controversial). Cholesterol reduction has not been shown to be useful in heart failure and is not recommended. Potassium supplements are unnecessary with ACE inhibitor and spironolactone. Other therapy: biventricular pacing (using the coronary sinus to gain access to the left ventricle) re-establishes coordinated ventricular contraction in patients with a broad QRS complex. Implantable defibrillators are the treatment of choice in symptomatic ventricular tachycardia, to prevent death from ventricular fibrillation. LV-assist devices and artificial heart technology continue to advance. These may become more widely used as the availability of organs for transplantation remains severely limited. For the first time, the role of conventional revascularization in patients with heart failure secondary to ischaemia is being subjected to a clinical trial.
Spironolactone: aldosterone is activated in heart failure, causing salt and water retention and additional growth factor effects (e.g. cardiac fibrosis). Spironolactone is an aldosterone antagonist. In the RALES trial (Pitt et al.), it was found to reduce the risk of death by 30% during a mean of 2 years’ followup. The dose was 25 mg once daily (a few patients received 50 mg), which is likely to have minimal diuretic effect. Spironolactone should be used in patients with moderateto-severe heart failure. It is well tolerated, but hyperkalaemia is an important potential side-effect. It is vital to measure potassium within 48 hours and 1 week after starting treatment. Other treatments: cardiac glycosides have been used in heart failure for thousands of years. Digoxin is helpful for symptomatic relief in the absence of other treatments, but its role in modern therapy is less certain. In patients in sinus rhythm, digoxin has no effect on outcome, but it can help those with intractable symptoms. In atrial fibrillation, digoxin has a role in controlling the ventricular rate. A combination of digoxin and β-blocker is usually required for optimal ventricular rate control. Warfarin should be used routinely in patients with atrial fibrillation, to reduce the risk of thromboembolism. Whether warfarin should also be given routinely to patients in sinus rhythm is under study. There is no place for the routine use of calcium antagonists. Amlodipine is probably safe in heart failure patients with limiting angina despite β-blockade.
REFERENCES CONSENSUS Trial Study Group. Effects of Enalapril on Mortality in Severe Congestive Heart Failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429–35. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A Randomised Trial. Lancet 1999; 353: 9–13. MERIT-HF Study Group. Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–7. Packer M, Coats A J, Fowler M B et al. Effect of Carvedilol on Survival in Severe Chronic Heart Failure. N Engl J Med 2001; 344: 1651–8. Pitt B, Zannad F, Remme W J et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999; 341: 709–17.
New developments: new treatment strategies targeted at neurohormonal activation are under development. Neutral endopeptidase (NEP) inhibitors prevent the breakdown of natriuretic peptides and promote diuresis. The combined ACE inhibitor/NEP inhibitor agent omapatrilat is closest to clinical use. Other strategies include endothelin antagonists such as bosentan. Arginine vasopressin antagonists cause potent aquaresis (increase in water excretion without natriuresis) and may be helpful in patients with resistant oedema. The role of allopurinol as an antioxidant therapy is being explored. Erythropoietin may be useful for treating chronic anaemia associated with heart failure. Levosimendan is a calcium sensitizer and exerts its inotropic effect only during systole. Unlike other inotropic agents, it appears to reduce morbidity and mortality.
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FURTHER READING Clark A L, McMurray J J V. Heart Failure: Diagnosis and Management. London: Martin Dunitz, 2001. Cleland J G F. Understanding Heart Failure. Banbury: Family Doctor, 2001. European Society of Cardiology. Guidelines for the Diagnosis and Treatment of Chronic Heart Failure. Eur Heart J 2001; 22: 1527–60. McMurray J J V, Cleland J G F. Heart Failure in Clinical Practice. 2nd ed. London: Martin Dunitz, 2001.
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Chronic heart failure
Investigation and Treatment of Heart Failure
Clinical features The classical clinical symptoms of heart failure are exertional breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea and fatigue. More subtle symptoms include weight loss and nocturia. On examination, patients may have fluid retention (pitting oedema, raised jugular venous pressure), a displaced apex beat and a third heart sound. However, it is important to recognize that there are many causes of each of these symptoms and signs, and that many patients with heart failure may have none of them. Some form of diagnostic imaging is crucial.
Andrew L Clark John G F Cleland
Investigations have several aims in heart failure: • to help establish the diagnosis • to find a treatable underlying cause • to estimate the severity and give prognostic information • to guide treatment (and monitor for potential adverse effects of treatment).
Investigations Chest radiography helps exclude pulmonary causes of symptoms. The lung fields should be clear in patients with well-treated heart failure (Figure 1). Up to 50% of patients with chronic heart failure have a normal-sized heart on chest radiography, which is not a useful test for excluding left ventricular (LV) dysfunction.
Acute pulmonary oedema Pulmonary oedema is an acute medical emergency. The patient usually presents with acute, severe breathlessness, often with an obvious precipitant such as acute myocardial infarction or arrhythmia. Pulmonary crackles and wheezes are usually present. The most important investigation is chest radiography, which may show cardiomegaly (not universal) and interstitial or alveolar oedema. Other helpful investigations are measurement of transcutaneous oxygen saturation and blood gases. Patients are generally hypoxic. When there is diagnostic doubt (and, in selected cases, to help guide treatment), pulmonary artery catheterization to establish the pulmonary capillary wedge pressure can be helpful. The medical history, the presence of an obvious precipitating factor and chest radiography usually enable differentiation of respiratory infection and asthma from pulmonary oedema. Peak expiratory flow is usually more than 200 litres/ minute in patients with cardiac ‘asthma’. As the clinical emergency settles, further investigations are undertaken as for chronic heart failure.
ECG: 12-lead ECG is almost never normal in heart failure. However, an abnormal ECG does not help make the diagnosis. The ECG contains other important diagnostic information (e.g. previous infarction, LV hypertrophy) that helps identify the cause of heart failure. Echocardiography (Figures 2 and 3) is the standard imaging modality in heart failure. It is safe, non-invasive, quick and painless for the patient. It gives many different kinds of information, but is limited in many patients by obesity, chest wall deformity and lung pathology (particularly chronic pulmonary disease). Training in echocardiography and in interpreting the results is demanding, and modern equipment is expensive. LV systolic function may be normal or globally depressed. Echocardiography may show wall motion abnormalities or ventricular dyssynchrony.
Andrew L Clark is a Senior Lecturer at the University of Hull, UK. He qualified from the University of Cambridge and the Westminster Hospital, London, and trained in cardiology at the Royal Brompton Hospital, London and Western Infirmary, Glasgow. His research interests include the pathophysiology of cardiac heart failure and cachexia. John G F Cleland is Professor of Cardiology at the University of Hull, UK. He qualified from the University of Glasgow, and trained in Glasgow and at St Mary’s Hospital, London and the Hammersmith Hospital, London. His research interests include heart failure, and primary, secondary and tertiary prevention in cardiovascular disease.
MEDICINE
1 Chest radiograph in a patient with chronic heart failure. The left ventricular ejection fraction was 22%. The cardiac silhouette is slightly enlarged, but the lung fields are clear.
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MYOCARDIAL DISEASE
Diastolic function – the prevalence and importance of ‘diastolic heart failure’ are controversial. LV diastolic function can be assessed by examination of the mitral diastolic inflow pattern using Doppler echocardiography, but ventricular hypertrophy and atrial dilatation are probably better markers of diastolic dysfunction. Stress echocardiography – ventricular impairment can result from irreversible myocardial necrosis and scarring. There may be areas of viable but non-contractile myocardium (known as ‘hibernating myocardium’) that can recover contractile function if revascularized. On dobutamine echocardiography, areas of hibernating tissue appear akinetic, but begin to function as dobutamine is infused. At higher doses, function may again be lost as the tissue becomes more ischaemic. This biphasic response is highly predictive of recovery after revascularization. Newer modalities – faster image acquisition is allowing the development of three-dimensional echocardiography, which enables more accurate assessment of LV volumes. Tissue velocity imaging concentrates on tissue movement rather than blood movement through the heart. Contrast agents may better define anatomy and physiology.
2 Transoesophageal echocardiography in a 78-year-old woman with heart failure. She had a large left atrial myxoma and normal left ventricular function.
Nuclear imaging: radionuclide ventriculography gives the ejection fraction and information on regional function. It involves a significant radiation dose to the patient, but provides prognostic information and is usually more accurate and reproducible than echocardiography. Myocardial perfusion imaging can assess ischaemia and hibernation. Cardiac catheterization: left ventriculography gives information on LV function at the same time as it provides haemodynamic information (Figure 4). Coronary angiography is performed simultaneously to exclude coronary artery disease. Right ventricular biopsy can be helpful in selected cases (Figure 5). MRI: cardiac MRI is not widely available. Technical problems initially hampered the applicability of MRI to the heart (a moving target inside a moving thorax), but advances have improved the quality of images. MRI allows accurate and repeatable measurements of LV volume and myocardial mass.
3 Transthoracic echocardiography. The left ventricle is dilated. The colour jet between the left ventricle and the left atrium is mitral regurgitation, in this case secondary to left ventricular impairment.
‘Routine’ blood tests: all patients being investigated for heart failure should undergo a full blood count (primarily to exclude anaemia), and determination of urea and electrolytes (primarily to exclude renal failure) and serum protein (primarily to exclude hypoalbuminaemia as a cause of oedema). Liver function is often deranged in heart failure as a result of liver congestion. A screen for treatable causes of heart failure should include thyroid function (particularly to exclude thyrotoxicosis in patients with atrial fibrillation), ferritin (haemochromatosis) and serum protein electrophoresis (amyloid). Urinary catecholamine levels provide a method for detecting phaeochromocytoma as a rare cause of dilated cardiomyopathy.
Myocardial wall may be thickened as a result of hypertrophy or thinned from scar. Chamber dimensions – ventricular dilatation indicates either systolic dysfunction or volume overload caused by, for example, valve regurgitation. Atrial dilatation is a key marker of diastolic LV dysfunction. Valvular function – echocardiography allows accurate diagnosis of valvular heart disease. Older patients with heart failure often have unsuspected aortic stenosis. Mitral regurgitation is common, though it can be difficult to distinguish between mitral regurgitation secondary to LV dilatation, and heart failure caused primarily by mitral regurgitation (Figure 3). The velocity of any tricuspid regurgitation gives an estimate of pulmonary artery pressure.
MEDICINE
Other investigations: the following investigations are either new and therefore incompletely validated, or have not been
99
© 2002 The Medicine Publishing Company Ltd
MYOCARDIAL DISEASE
Haemodynamic tracing from a patient with aortic stenosis
Pressure (mm Hg)
200
100
On the left, the catheter is in the body of the left ventricle, at a pressure of 200 mm Hg. The catheter is withdrawn into the aorta, where the pressure is 120 mm Hg, giving a gradient of 80 mm Hg. 4
ing, but is now recognized to be safe. Coupled with metabolic gas exchange measurements, exercise testing gives valuable information. It is useful diagnostically (heart rate response, induction of ischaemia or arrhythmia, symptom limitation, to distinguish exercise limitation as a result of heart failure from other causes) and as an objective assessment of the severity of exercise limitation. Symptom-limited incremental tests are usually used to derive peak oxygen consumption as an index of exercise capacity, and the relationship between ventilation and carbon dioxide production gives an index of the ventilatory response to exercise. Endurance-limited tests such as the 6-minute walk test (which measures the distance covered in 6 minutes at the patient’s own speed) more closely resemble daily activity than maximal tests, and may be more sensitive to changes in response to therapy.
5 Myocardial biopsy specimen in amyloidosis. Apple-green birefringence is seen under polarized light.
Prognostic information: a wide variety of different variables have been shown to convey prognostic information in heart failure. Many are esoteric and not routinely available (e.g. tumour necrosis factor receptors). They may be broadly divided into indices of: • LV function (e.g. ejection fraction) • exercise capacity (e.g. peak oxygen consumption) • metabolic derangement (e.g. serum sodium or creatinine). Data from each of these domains should be collected from each patient to give prognostic information.
shown to be of value as part of the routine investigation of heart failure: Natriuretic peptides are released by the heart in response to cardiac chamber enlargement and are a sensitive (but not specific) indicator of heart failure. A normal plasma concentration effectively excludes heart failure and may be used as a biochemical screening test to identify patients who do not require echocardiography. Holter – ambulatory ECG commonly detects arrhythmias even in patients with no symptoms. Atrial flutter and fibrillation are common. Ventricular ectopic beats are almost universal, and non-sustained ventricular tachycardia is often seen. Sustained ventricular tachycardia is not uncommon (Figure 6). Guidelines on implantable defibrillators suggest that ambulatory patients with heart failure caused by coronary disease should routinely undergo electrophysiological investigation. Exercise testing – chronic heart failure has traditionally been thought to be a relative contraindication to exercise test-
MEDICINE
Management The aims of treatment in heart failure include relief of symptoms, reduced hospitalization and improved prognosis. Large randomized clinical trials have established several treatments as beneficial, and active treatment can now approximately double life expectancy. Nevertheless, angiotensin-converting enzyme (ACE) inhibitors and β-adrenoceptor antagonists
100
© 2002 The Medicine Publishing Company Ltd
MYOCARDIAL DISEASE
Holter recording from a 65-year-old man with dilated cardiomyopathy
The upper tracing shows non-sustained ventricular tachycardia; the lower shows sustained atrial flutter. The patient was asymptomatic throughout. 6
Henlé. They have a ‘high ceiling’; that is, increasing doses result in increasing diuresis over a large dose range. Frusemide (furosemide) and bumetanide are most widely used, and induce a brisk diuresis (which some patients find distressing). They cause hypokalaemia, an increase in serum lipids and impairment in glucose tolerance, and precipitate gout when used in high doses. Bumetanide and torasemide have a more reliable bioavailability and less metabolic effect than frusemide. A once-daily or twice-daily dosing schedule controls fluid retention. When oedema remains a problem, or when more than 80 mg of frusemide twice daily (or its equivalent) is needed, the combination of a loop diuretic and a thiazide can be particularly powerful. It is important to monitor urea and electrolytes closely – hypokalaemia is particularly common, and dehydration can occur rapidly.
(β-blockers) are underused, and are often not titrated up to the target doses shown to be beneficial in trials. It should be emphasized that clinical trials have concentrated on heart failure caused by systolic LV dysfunction. Less is known about the treatment of heart failure with preserved systolic function (‘diastolic heart failure’), though trials to address this issue are in progress. Non-drug treatment: management of heart failure should include advice, education and support. The role of the heart failure nurse specialist is increasingly recognized as important in helping patients learn about their condition and manage their therapy, thereby reducing hospital admissions and perhaps improving outcome. The traditional advice to rest with heart failure is incorrect. Many trials have shown that exercise training is beneficial in selected patients, and patients should be encouraged to keep active. There is little evidence to support dietary salt restriction, but it is conventional to tell patients not to add salt to their food and to avoid salty snacks. Fluid restriction (to about 1–1.5 litres/day) is helpful in patients with severe heart failure who are having problems controlling oedema.
Target doses for angiotensin-converting enzyme inhibitors in chronic heart failure
• • • • •
Diuretics remain the first-line treatment for fluid retention. Most patients need a loop diuretic. These drugs are excreted into the lumen of the renal tubules and block the sodium/ potassium/chloride pump in the thick ascending loop of
Captopril Enalapril Ramipril Trandolapril Lisinopril
Total daily dose 150–300 mg 20–40 mg 10 mg 4 mg 30–35 mg
Regimen t.d.s. b.d. b.d. o.d. o.d.
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β-blocker trials in chronic heart failure Study
Drug
• US Carvedilol
Carvedilol
• CIBIS-II
Bisoprolol
Patients IHD 48%
N
Follow-up
Placebo β-blocker
(months)
Placebo
β-blocker
change (%)
398
696
6.5
31
22
–65
0.00011
(7.8)
(3.2)
1320
1327
16
228
156
–32
< 0.0001
(17)
(12)
217
145
–35
0.0062
(10.8)
(7.3) –35
0.00014
II 54%, III 44% IHD 50%2 III 83%, IV 17% • MERIT-HF
Metoprolol
IHD 65%
2001
1990
12
II 41%, III 56% • COPERNICUS
Carvedilol
AII III and IV
1133
1156
15–45
Deaths (%)
190
130
(8.8)
(11.2)
Risk
P
The mortalities quoted are the crude data for the trials, not annualized mortality rates. IHD, ischaemic heart disease. 1
Not designed as a mortality study In 40% of patients in CIBIS-II, the underlying cause of heart failure was not known
2
8
dose of diuretic (frusemide, > 80 mg or equivalent per day) should be observed for hypotension for 2 hours. The dose should then be titrated up over the next month, and urea and electrolytes checked weekly. The most common side-effect is a dry cough. It is important to distinguish this from a cough related to heart failure. Angio-oedema can occur. Some decline in renal function is almost universal on starting an ACE inhibitor and is not an indication for stopping treatment. Renal failure can be precipitated in patients with bilateral renal artery stenosis. It is important to check renal function within 1 week of initiating or increasing the dose of an ACE inhibitor. Angiotensin receptor blockers (ARBs) are also being studied in heart failure. They have a better side-effect profile than ACE inhibitors, but have not been shown to be clinically superior. The role of ARBs as add-on therapy remains controversial.
In severe fluid retention, intravenous diuretics should be used to bypass the potentially oedematous gut wall. Dose for dose, intravenous infusions are more potent than bolus injections. ACE inhibitors have revolutionized the treatment of chronic heart failure. The first evidence of their benefits was seen in the CONSENSUS study, which demonstrated a 40% reduction in mortality in patients with severe heart failure treated with enalapril over 6 months. Long-term follow-up data suggest that enalapril increases survival time by 50%. Benefit has also been demonstrated in patients with mild-to-moderate heart failure and in those with asymptomatic LV dysfunction. Vasodilator agents (e.g. nitrates, hydralazine) generally do not reduce mortality in heart failure. All patients with significant LV systolic dysfunction, with or without symptoms, should receive an ACE inhibitor. The duration of treatment required is not certain, but is assumed to be life-long. There is firm mortality evidence to support the use of captopril, enalapril, trandolapril, lisinopril and ramipril at the target doses shown in Figure 7. Treatment with low doses should not be accepted unless the patient is intolerant of higher doses. On the day of initiation, diuretic should be omitted and a low dose of the ACE inhibitor given (e.g. enalapril, 2.5 mg). Patients with low blood pressure or who are taking a high
β-adrenoceptor antagonists: sympathetic activation causes vasoconstriction, and thus an increase in afterload, and increases heart rate. High levels of catecholamines are arrhythmogenic and cause cardiac myocyte necrosis. Catecholamines also facilitate the actions of other vasoconstrictor agents (e.g. angiotensin II). β-blockers may protect cardiac myocytes from direct catecholamine toxicity and slow the heart, reducing myocardial oxygen demand. β-blockers have anti-ischaemic and anti-
Dose schedules for β-blockers Drug • Carvedilol • Bisoprolol • Metoprolol
Starting dose 3.125 mg b.d. 1.25 mg o.d. 12.5 mg o.d.
Increment Doubling Doubling Doubling
Titration interval 2–4 weeks 2–4 weeks 2–4 weeks
Target 25 mg b.d.1 10 mg o.d. 200 mg o.d.2
1
50 mg b.d. if > 85 kg body weight Metoprolol is not licensed for treatment of heart failure in the UK; the preparation used in the MERIT-HF trial (metoprolol CR/XL) is not available in the UK
2
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arrhythmic effects and reduce the risk of recurrent myocardial infarction. With chronic use, LV ejection fraction improves. Both the CIBIS-II (bisoprolol) and the MERIT-HF (metoprolol) studies of mild-to-moderate heart failure were stopped early as a result of the pronounced beneficial effects of βblockade. More recently, the COPERNICUS study of severe heart failure was also stopped early (Packer et al.); in the most severely affected patients, there was a 50% reduction in the risk of death. Fewer patients withdrew from β-blockers than from placebo in the mortality trials (Figure 8). The initial dose must be low, and is increased gradually towards the target dose (Figure 9). Patients must be monitored closely, and may initially deteriorate on treatment or an increase in dose. Specialist supervision is required.
Unwanted treatment: many elderly patients with heart failure are given a large number of different drugs, many of which may be unnecessary or even dangerous. Non-steroidal antiinflammatory drugs should not be prescribed. Aspirin should be stopped if heart failure is difficult to control (its use in heart failure, even if coronary artery disease is present, remains controversial). Cholesterol reduction has not been shown to be useful in heart failure and is not recommended. Potassium supplements are unnecessary with ACE inhibitor and spironolactone. Other therapy: biventricular pacing (using the coronary sinus to gain access to the left ventricle) re-establishes coordinated ventricular contraction in patients with a broad QRS complex. Implantable defibrillators are the treatment of choice in symptomatic ventricular tachycardia, to prevent death from ventricular fibrillation. LV-assist devices and artificial heart technology continue to advance. These may become more widely used as the availability of organs for transplantation remains severely limited. For the first time, the role of conventional revascularization in patients with heart failure secondary to ischaemia is being subjected to a clinical trial.
Spironolactone: aldosterone is activated in heart failure, causing salt and water retention and additional growth factor effects (e.g. cardiac fibrosis). Spironolactone is an aldosterone antagonist. In the RALES trial (Pitt et al.), it was found to reduce the risk of death by 30% during a mean of 2 years’ followup. The dose was 25 mg once daily (a few patients received 50 mg), which is likely to have minimal diuretic effect. Spironolactone should be used in patients with moderateto-severe heart failure. It is well tolerated, but hyperkalaemia is an important potential side-effect. It is vital to measure potassium within 48 hours and 1 week after starting treatment. Other treatments: cardiac glycosides have been used in heart failure for thousands of years. Digoxin is helpful for symptomatic relief in the absence of other treatments, but its role in modern therapy is less certain. In patients in sinus rhythm, digoxin has no effect on outcome, but it can help those with intractable symptoms. In atrial fibrillation, digoxin has a role in controlling the ventricular rate. A combination of digoxin and β-blocker is usually required for optimal ventricular rate control. Warfarin should be used routinely in patients with atrial fibrillation, to reduce the risk of thromboembolism. Whether warfarin should also be given routinely to patients in sinus rhythm is under study. There is no place for the routine use of calcium antagonists. Amlodipine is probably safe in heart failure patients with limiting angina despite β-blockade.
REFERENCES CONSENSUS Trial Study Group. Effects of Enalapril on Mortality in Severe Congestive Heart Failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429–35. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A Randomised Trial. Lancet 1999; 353: 9–13. MERIT-HF Study Group. Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–7. Packer M, Coats A J, Fowler M B et al. Effect of Carvedilol on Survival in Severe Chronic Heart Failure. N Engl J Med 2001; 344: 1651–8. Pitt B, Zannad F, Remme W J et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. N Engl J Med 1999; 341: 709–17.
New developments: new treatment strategies targeted at neurohormonal activation are under development. Neutral endopeptidase (NEP) inhibitors prevent the breakdown of natriuretic peptides and promote diuresis. The combined ACE inhibitor/NEP inhibitor agent omapatrilat is closest to clinical use. Other strategies include endothelin antagonists such as bosentan. Arginine vasopressin antagonists cause potent aquaresis (increase in water excretion without natriuresis) and may be helpful in patients with resistant oedema. The role of allopurinol as an antioxidant therapy is being explored. Erythropoietin may be useful for treating chronic anaemia associated with heart failure. Levosimendan is a calcium sensitizer and exerts its inotropic effect only during systole. Unlike other inotropic agents, it appears to reduce morbidity and mortality.
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FURTHER READING Clark A L, McMurray J J V. Heart Failure: Diagnosis and Management. London: Martin Dunitz, 2001. Cleland J G F. Understanding Heart Failure. Banbury: Family Doctor, 2001. European Society of Cardiology. Guidelines for the Diagnosis and Treatment of Chronic Heart Failure. Eur Heart J 2001; 22: 1527–60. McMurray J J V, Cleland J G F. Heart Failure in Clinical Practice. 2nd ed. London: Martin Dunitz, 2001.
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