Heart failure

Abstract

Congestive heart failure is a complex clinical syndrome characterized by impaired ventricular performance, exercise intolerance, a high incidence of ventricular arrhythmias and shortened life expectancy. Congestive heart failure is common and is estimated to affect five million people in the US, 300 000 of whom die per year.34Hunt SA Baker DW Chin MH et al.ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.Circulation. 2001; 104: 2996-3007Crossref PubMed Scopus (1175) Google Scholar Hospitalizations and mortality from heart failure have increased steadily since 1968, despite the overall improvement in mortality from cardiovascular disease. Among adults over 65 yr of age, heart failure is the commonest reason for admission to a hospital.11Berry C Murdoch DR McMurray JJ. Economics of chronic heart failure.Eur J Heart Fail. 2001; 3: 283-291Crossref PubMed Scopus (322) Google Scholar Heart failure may occur suddenly or develop gradually and is the final common pathway of a variety of primary cardiovascular disease entities. Coronary artery disease and hypertension are the two major risk factors for the development of heart failure in the elderly. Other common aetiologies include diabetes mellitus, valvular heart disease, especially aortic stenosis and mitral regurgitation, and non-ischaemic myopathies.8Aronow WS Ahn C Kronzon I Koenigsberg M. Congestive heart failure, coronary events and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy.Am J Cardiol. 1991; 67: 295-299Abstract Full Text PDF PubMed Scopus (141) Google Scholar It is often multifactorial, but specific independent risk factors are male gender, hypertension, coronary artery disease, diabetes mellitus and age.7Aronow WS Ahn C Kronzon I. Comparison of incidences of congestive heart failure in older African‐Americans, Hispanics and whites.Am J Cardiol. 1999; 84 (A9): 611-612Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar At present, the only cure for end-stage congestive heart failure is cardiac transplantation. Heart failure can be broadly subdivided into two distinct forms (although other classification schemes exist) and distinguishing between the two forms is often difficult. The first form is termed diastolic dysfunction or diastolic heart failure and is due to inadequate ventricular relaxation preventing adequate end-diastolic filling. This type of heart failure affects the left ventricle. The second is the more common systolic dysfunction or systolic heart failure due to inadequate force generation to eject blood normally. This type of heart failure can affect either ventricle but failure of the left heart is more common. The principle problems associated with the aging and failing heart are changes in shape, associated with chamber enlargement, and ventricle wall thickness and stiffness. As humans age they progressively lose cardiac myocytes. Their maximal heart rate and cardiac output decrease, while systemic vascular resistance and left ventricular (LV) stiffness, systolic arterial pressure and LV wall thickness increase.4Aronow W. Effects of aging on the heart.in: Tallis R Fillit H Broccklehurst J Brocklehurst's Textbook of Geriatric Medicine and Gerontology. Churchill Livingstone, Edinburgh1998: 255-262Google Scholar Myocellular hypertrophy and increased myocellular mass result from increased wall stress and reduction of contractility; this in turn leads to chamber enlargement due to cell slippage and sarcomere growth.5Aronow WS. Epidemiology, pathophysiology, prognosis and treatment of systolic and diastolic heart failure in elderly patients.Heart Dis. 2003; 5: 279-294Crossref PubMed Scopus (35) Google Scholar Increased interstitial fibrosis and cross-linking of collagen in the heart are also associated with aging and this contributes to increased LV stiffness.54Olivetti G Melissari M Capasso JM Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy.Circ Res. 1991; 68: 1560-1568Crossref PubMed Scopus (593) Google Scholar In addition, prolongation of isovolaemic relaxation time and slowing of the rate at which calcium is sequestered by the sarcoplasmic reticulum after myocardial relaxation result in poor LV relaxation. The compliance and early diastolic filling of the left ventricle is decreased and, because LV relaxation is impaired, a significantly greater percentage of LV filling is due to atrial contraction.4Aronow W. Effects of aging on the heart.in: Tallis R Fillit H Broccklehurst J Brocklehurst's Textbook of Geriatric Medicine and Gerontology. Churchill Livingstone, Edinburgh1998: 255-262Google Scholar In addition to the decreased early diastolic filling, increased LV stiffness and prolonged relaxation time cause raised LV pressures at rest and during exercise.53Ogawa T Spina RJ Martin 3rd, WH et al.Effects of aging, sex and physical training on cardiovascular responses to exercise.Circulation. 1992; 86: 494-503Crossref PubMed Scopus (492) Google Scholar The major neurohumoral systems activated in response to a reduction in cardiac output are the sympathetic nervous system and renin–angiotensin–aldosterone (RAA) system. In addition, modifications to endothelin receptors, natriuretic peptides and tumour necrosis factor receptors are now recognized to be involved in the secondary response.5Aronow WS. Epidemiology, pathophysiology, prognosis and treatment of systolic and diastolic heart failure in elderly patients.Heart Dis. 2003; 5: 279-294Crossref PubMed Scopus (35) Google Scholar Stimulation of the sympathetic nervous system causes peripheral vasoconstriction and retention of sodium and water by the kidney.22Cohn JN Levine TB Olivari MT et al.Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.N Engl J Med. 1984; 311: 819-823Crossref PubMed Scopus (2775) Google Scholar Plasma norepinephrine levels correlate directly with prognosis in congestive heart failure patients.22Cohn JN Levine TB Olivari MT et al.Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.N Engl J Med. 1984; 311: 819-823Crossref PubMed Scopus (2775) Google Scholar Sympathetic activity also activates the RAA. While these responses have an initial benefit to the patient, they also compound the injury to the heart so that in heart failure the reflex activation of the neurohumoral systems eventually contributes to detrimental effects instead of maintaining arterial pressure and cardiac output. LV remodelling and LV systolic dysfunction occur as a consequence of activation of neurohumoral activation. These deleterious effects are related to alterations in afterload, preload, stretch, increased wall tension, interstitial collagen deposits and through direct toxic effects. Increased wall tension and myocardial oxygen consumption, together with reduced subendocardial perfusion, combine to reduce myocyte shortening and with remodelling, the LV dilates and becomes more spherical. The signs and symptoms of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary oedema and cardiomegaly. There are a number of precipitating factors for acute-on-chronic organ failure. Examples include inadequate compliance with medication, hot weather, uncontrolled hypertension, anaemia, infection with fever, hypoxia, alcohol intake, myocardial infarction (MI), pulmonary embolism, renal insufficiency and thyroid abnormalities.5Aronow WS. Epidemiology, pathophysiology, prognosis and treatment of systolic and diastolic heart failure in elderly patients.Heart Dis. 2003; 5: 279-294Crossref PubMed Scopus (35) Google Scholar One of the most common precipitating factors is the development of an arrhythmia, especially an atrial arrhythmia. The prevalence of atrial fibrillation increases with age from 5% at age 60 yr to about 22% by the age of 90 yr.6Aronow WS Ahn C Gutstein H. Prevalence of atrial fibrillation and association of atrial fibrillation with prior and new thromboembolic stroke in older patients.J Am Geriatr Soc. 1996; 44: 521-523Crossref PubMed Scopus (82) Google Scholar Atrial fibrillation may suddenly worsen heart failure by reducing cardiac output because of a shortened diastolic filling time and a loss of the atrial kick that was contributing to late diastolic filling. The single most useful diagnostic test in the evaluation of patients with heart failure is echocardiography, particularly transoesophageal echocardiography (TOE) coupled with Doppler flow studies. These tests determine whether the primary abnormality is pericardial, myocardial or valvular, and if myocardial, whether the dysfunction is primarily systolic or diastolic. The functional information gained from the echocardiogram is the measurement of LV ejection fraction; patients with an ejection fraction less than 40% are generally considered to have systolic dysfunction. In addition, the echocardiogram allows for the quantitative assessment of the dimensions, geometry, thickness and regional motion of the right and left ventricles and the qualitative evaluation of the atria, pericardium, valves and vascular structures. Such a comprehensive evaluation is important, since it is not uncommon for patients to have more than one cardiac abnormality that can cause or contribute to the development of heart failure. LV size is assessed by measuring the inside diameter at the junction of the basal and mid third at end diastole. This value should be less than 5.5 cm with a wall thickness of 1.2 cm or less at end diastole. Systolic LV global function can be assessed quantitatively or qualitatively. Fractional area change (FAC) is a two-dimensional TOE equivalent of ejection fraction. It is obtained by measuring the LV chamber cross-sectional area at the transgastric mid short axis view at end-systole and end-diastole to get the end-diastolic area (EDA) and end-systolic area (ESA). FAC=EDA–ESA/EDA and is normally greater than 0.5. This method is not as accurate when regional wall motion abnormalities are present. A qualitative assessment is done by examination of all areas of the ventricle and estimation of ejection fraction as normal (>55%), mildly decreased, moderately decreased, moderately severely decreased or severely decreased (<25%). This method in experienced hands correlates well with other non-echocardiographic methods of ejection fraction measurement such as ventriculography. Diastolic LV function can be assessed using pulse wave Doppler echocardiography. The transmitral inflow velocity profile during diastole in the normal patient has an ‘E’ wave corresponding to early passive filling of the ventricle, followed by an ‘A’ wave corresponding to atrial contraction (Fig. 1). Impaired relaxation patterns with decreased peak E-to-A velocity ratio and prolonged E wave deceleration time signify mild diastolic dysfunction. A restrictive pattern, with raised filling pressures and severe diastolic dysfunction, is associated with an increased peak E-to-A velocity ratio and decreased E wave deceleration time. A period where the mitral inflow pattern appears normal may occur as diastolic dysfunction progresses from mild to severe. The pulmonary venous inflow velocity profile may help to distinguish between these two. No cure exists for most people with heart failure but much can be done to make physical activity more comfortable and improve the quality and duration of life. The American College of Cardiology and American Heart Association have described four stages of heart failure (Table 1).34Hunt SA Baker DW Chin MH et al.ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.Circulation. 2001; 104: 2996-3007Crossref PubMed Scopus (1175) Google Scholar Patients in stage A have a known risk factor. Those in stage B are known to have LV dysfunction but have not developed heart failure. Those in stage C have current or previous evidence of heart failure with known LV dysfunction and the stage D patients have refractory end-stage heart failure. Although this is a useful classification to differentiate between various management strategies, it is also obvious that the symptomatic and pathological development of heart failure is on a continuum.Table 1The four stages of heart failure (A–D) as defined by the Joint Task Force of the American College of Cardiology and American Heart Association.35 HF, heart failure; LV, left ventricularStageDescriptionExamplesImplicationsAPatients at high risk of developing HF because of the presence of conditions that are strongly associated with the development of HF. These patients should have no identified structural or functional abnormalities of the pericardium, myocardium or cardiac valves and have never shown signs or symptoms of HFSystemic hypertensionCoronary artery diseaseDiabetes mellitusRisk of anaesthesia/surgery is related to underlying conditionBPatients who have developed structural heart disease that is strongly associated with the development of HF but who have never shown signs or symptoms of HFLV hypertrophy or fibrosisLV dilatation or hypocontractilityAsymptomatic valvular heart diseasePrevious myocardial infarctionRisk of anaesthesia/surgery related to underlying condition; optimizing therapy before surgery is most importantCPatients who have current or prior symptoms of underlying HF associated with underlying structural heart diseaseDyspnoea or fatigue due to LV systolic dysfunctionAsymptomatic patients who have undergone treatment for prior symptoms of HFHigh risk of decompensation and adverse cardiac outcomeDPatients with advanced structural heart disease and marked symptoms of HF at rest despite maximal medical therapy and who require specialized interventionsPatients who are frequently hospitalized for HF and cannot be safely discharged from the hospitalPatients in the hospital awaiting heart transplantationPatients at home receiving continuous i.v. support for symptom relief or being supported with a mechanical circulatory assist devicePatients in a hospice setting for the management of HFExtreme risk for anaesthesia; patient will usually present in an intensive care setting or specialist unit Open table in a new tab The three approaches to therapy are intended to: (i) treat the underlying cause; (ii) remove contributing factors that can worsen heart failure, and (iii) treat the heart failure itself. Surgical interventions include heart surgery for valvular or coronary artery disease. Medical treatment to remove contributing factors might include treatment of infection and intervention for an overactive thyroid. Patients with stage-A heart failure without contraindications, who have exercise-limiting angina pectoris or frequent angina at rest should have angiography with a view to revascularization. A few patients with ischaemia of effort present not with chest pain but with shortness of breath. These patients also warrant investigation and possible angiography. Patients with stage-B heart failure and haemodynamically significant valvular regurgitation or stenosis are candidates for valve replacement or repair. Anaesthetic considerations for stage-A patients undergoing cardiac or major non-cardiac surgery mainly centre around the therapy they are receiving. The majority will be being treated for hypertension (diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta blockers), diabetes, or both.34Hunt SA Baker DW Chin MH et al.ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.Circulation. 2001; 104: 2996-3007Crossref PubMed Scopus (1175) Google Scholar For stage B-heart failure, all measures used for stage A are recommended. If ACE inhibitors and beta blockers have not already been started their addition to the patient's medication should be considered. Patients are usually anticoagulated with oral anticoagulants to an international normalized ratio of 2–3. Medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and all antiarrhythmic drugs other than beta blockers, digoxin and amiodarone should be stopped as they aggravate heart failure.34Hunt SA Baker DW Chin MH et al.ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America.Circulation. 2001; 104: 2996-3007Crossref PubMed Scopus (1175) Google Scholar If the patient does present for surgery that is unrelated to their heart failure, the two principal cardiovascular events to control during anaesthesia are myocardial depression and peripheral vasodilatation. Any changes in either of these variables should be minimized. Historically drugs such as etomidate and ketamine have been suggested as useful in this regard. However, there is a lack of evidence to support these in the patient whose cardiac condition has been optimized with currently advocated preoperative pharmacological interventions. The majority of patients with impaired LV function are dependent on their preload to maintain ventricular filling and many patients with heart failure also rely on increased sympathetic tone to maintain tissue perfusion and cardiac output. Patients with severe impairment of LV function are therefore extremely sensitive to changes in the fine balance in which they exist. Moreover, the underlying cardiomyopathy leading to heart failure has different aetiology and thus different problems of management. Cardiomyopathy is associated with a high incidence of heart failure and may be restrictive, dilated or hypertrophic. Restrictive cardiomyopathy is the most difficult to deal with and is characterized by stiff ventricles that impair ventricular filling; pronounced right heart failure is a frequent problem. If the technique of general anaesthesia produces myocardial depression, vasodilatation and reduced venous return allied to increased intrathoracic pressure from IPPV, then this may lead to circulatory arrest. Spontaneous ventilation is therefore preferred while maintaining an elevated right heart pressure by administration of fluid. Dilated cardiomyopathy manifests as a large, poorly contractile heart, with stroke volume preserved by dilatation and increased LV end-diastolic volume. Functional mitral and tricuspid incompetence is common due to the dilatation of the annulus of the valve, and exacerbates the problem. Arrhythmias are frequent and may be life-threatening. Amiodarone is the drug of choice to treat these arrhythmias as it has the least myocardial depressant effect.14Bovill J. Anesthesia for patients with impaired ventricular function.Semin Cardiothorac Vasc Anesth. 2003; 7: 49-54Crossref Scopus (3) Google Scholar Inhalational anaesthetics reduce myocardial contractility in a dose-dependent manner, but effects differ between the different agents. Isoflurane is a popular anaesthetic for patients undergoing coronary revascularization and appears to have certain cardioprotective properties. Sevoflurane, unlike isoflurane and desflurane, does not induce a tachycardia. Recent human studies have also suggested that isoflurane and sevoflurane have cardioprotective effects similar to those induced by ischaemic preconditioning.24De Hert SG ten Broecke PW Mertens E et al.Sevoflurane but not propofol preserves myocardial function in coronary surgery patients.Anesthesiology. 2002; 97: 42-49Crossref PubMed Scopus (295) Google Scholar 70Zaugg M Lucchinetti E Garcia C et al.Anaesthetics and cardiac preconditioning. Part II. Clinical implications.Br J Anaesth. 2003; 91: 566-576Crossref PubMed Scopus (110) Google Scholar 71Zaugg M Lucchinetti E Uecker M Pasch T Schaub MC. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms.Br J Anaesth. 2003; 91: 551-565Crossref PubMed Scopus (217) Google Scholar Because of the extreme sensitivity to negative inotropic agents, these patients frequently require inotropic support.14Bovill J. Anesthesia for patients with impaired ventricular function.Semin Cardiothorac Vasc Anesth. 2003; 7: 49-54Crossref Scopus (3) Google Scholar Hypertrophic cardiomyopathy is characterized by outflow tract obstruction produced by septal hypertrophy. Impaired diastolic function is an important feature, and diastolic filling of the ventricles may rely on atrial systole (‘atrial kick’) for up to 75% of end-diastolic volume (Fig. 1), therefore sinus rhythm is very important. Tachycardia may also be a problem, as it reduces diastolic filling time of both the coronaries and the ventricle. Inotropic support may worsen outflow obstruction and increase myocardial oxygen demand at the same time as lessening oxygen supply by increasing ventricular wall tension.14Bovill J. Anesthesia for patients with impaired ventricular function.Semin Cardiothorac Vasc Anesth. 2003; 7: 49-54Crossref Scopus (3) Google Scholar In general, vasodilators that do not induce a tachycardia should be useful here. These patients are most likely to present to the anaesthetist in intensive care rather than for elective surgery, as mortality following anaesthesia and surgical interventions in this group is extremely high. The cardiac glycosides have been the mainstay of treatment for those with chronic heart failure.14Bovill J. Anesthesia for patients with impaired ventricular function.Semin Cardiothorac Vasc Anesth. 2003; 7: 49-54Crossref Scopus (3) Google Scholar Their mechanisms of action leading to subjective reduction in symptoms in heart failure are multiple.42Lonn E McKelvie R. Drug treatment in heart failure.BMJ. 2000; 320: 1188-1192Crossref PubMed Google Scholar In addition to effects on ion exchange channels, it is hypothesized that digoxin also provides a reduction in the sympathetic hyperactivity associated with congestive heart failure.27Ferguson D. Sympathetic mechanisms in heart failure.Circulation. 1993; 87: 68-75Google Scholar Diuretics should be given for patients with evidence of fluid retention, and spirinolactone is often used in patients with recurrent symptoms and preserved renal function. Patients should also be treated with neurohormonal blockade with an ACE inhibitor (or angiotensin receptor blocker in patients with persistent cough or angioedema) and a beta blocker. Calcium channel blockers (except amlodipine) and NSAIDs should not be given. The basis of added therapy in advanced heart failure is interventions to increase inotropy and reduce preload. The fundamental mechanism to improve inotropy is to increase myocyte intracellular cyclic AMP. Figure 2 shows the various pathways that can be used to achieve this effect. In the acute setting the usual inotropic support is from catecholamines acting through the beta adrenoceptor. I.V. dobutamine has been used for short-term support in severe heart failure and LV dysfunction, but older patients treated with dobutamine commonly develop arrhythmias,60Rich MW Woods WL Davila‐Roman VG et al.A randomized comparison of intravenous amrinone versus dobutamine in older patients with decompensated congestive heart failure.J Am Geriatr Soc. 1995; 43: 271-274Crossref PubMed Scopus (30) Google Scholar and there is evidence that an increased rate of ventricular arrhythmias and subsequent mortality are associated with use of dobutamine. The FIRST study showed that long-term use of dobutamine in heart failure patients was an independent predictor of mortality, and did not improve quality of life.52O’Connor CM Gattis WA Uretsky BF et al.Continuous intravenous dobutamine is associated with an increased risk of death in patients with advanced heart failure: insights from the Flolan International Randomized Survival Trial (FIRST).Am Heart J. 1999; 138: 78-86Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar Phosphodiesterase inhibitors (PDI) have become another mainstay of treatment but recent trials have shown an increased mortality in patients with congestive heart failure,55Packer M Carver JR Rodeheffer RJ et al.Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.N Engl J Med. 1991; 325: 1468-1475Crossref PubMed Scopus (1951) Google Scholar and patients with heart failure and abnormal LV ejection fraction;21Cohn JN Goldstein SO Greenberg BH et al.A dose‐dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.N Engl J Med. 1998; 339: 1810-1816Crossref PubMed Scopus (575) Google Scholar 55Packer M Carver JR Rodeheffer RJ et al.Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.N Engl J Med. 1991; 325: 1468-1475Crossref PubMed Scopus (1951) Google Scholar 68Uretsky BF Jessup M Konstam MA et al.Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group.Circulation. 1990; 82: 774-780Crossref PubMed Scopus (284) Google Scholar however, they remain in use for acute heart failure. The principal problem with these agents is that with prolonged i.v. administration the associated peripheral arterial dilatation leading to hypotension may be difficult to control. Recently there has been a resurgence of interest in the use of nutritional and metabolic support in heart failure. Nutritional supplements (such as coenzyme Q10, carnitine, taurine and antioxidants) have been the subject of small-scale studies. The administration of glucose-insulin-potassium (GIK) may be of benefit. First suggested as an intervention for improving ventricular function and reducing infarct size in the 1970s,44Mantle JA Rogers WJ Smith LR et al.Clinical effects of glucose‐insulin‐potassium on left ventricular function in acute myocardial infarction: results from a randomized clinical trial.Am Heart J. 1981; 102: 313-324Abstract Full Text PDF PubMed Scopus (45) Google Scholar 57Rackley CE Russell Jr, RO Rogers WJ et al.Clinical experience with glucose‐insulin‐potassium therapy in acute myocardial infarction.Am Heart J. 1981; 102: 1038-1049Abstract Full Text PDF PubMed Scopus (69) Google Scholar GIK's popularity waned because of concerns about various safety issues.50Neely JR Grotyohann LW. Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts.Circ Res. 1984; 55: 816-824Crossref PubMed Scopus (535) Google Scholar However in 1987, a study advocated the use of GIK following coronary thrombolysis with streptokinase, stating that its use improved ejection fraction and reduced segmental wall motion abnormalities.63Satler LF Green CE Kent KM et al.Metabolic support during coronary reperfusion.Am Heart J. 1987; 114: 54-58Abstract Full Text PDF PubMed Scopus (33) Google Scholar A further approach to improving carbohydrate utilization is to cause the myocyte to metabolize carbohydrate as its principal substrate in preference to fatty acids. One approach to increase glucose oxidation is to inhibit fatty acid oxidation; three agents that work in this manner are trimetazidine, etomoxir and ranolizine. Trimetazidine is widely available for clinical use.43Lopaschuk G Manzilli M. Mode of action of trimetazidine and other metabolic agents in the treatment of ischaemic heart disease.Semin Cardiothorac Vasc Anesth. 2003; 7: 91-96Crossref Scopus (5) Google Scholar It optimizes cardiac metabolism by inhibition of fatty acid oxidation through inhibition of mitochondrial palmitoylcarnitine oxidation, while only partially inhibiting pyruvate oxidation and preserving mitochondrial oxidation.26Fantini E Demaison L Sentex E Grynberg A Athias P. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation.J Mol Cell Cardiol. 1994; 26: 949-958Abstract Full Text PDF PubMed Scopus (168) Google Scholar 37Kantor PF Lucien A Kozak R Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long‐chain 3‐ketoacyl coenzyme A thiolase.Circ Res. 2000; 86: 580-588Crossref PubMed Scopus (718) Google Scholar A European collaborative working group on trimetazidine has undertaken a number of trials. These have