Second- or third-degree heart block, sick sinus syndrome (in the absence of a permanent pacemaker). Sinus bradycardia (<50 bpm). Initiation of a B -blocker \200 The common practice of addin g a B -blocker to a regime containing an ACE-I is based on the fact that the ACE-I trials w ere performed \201 rst, with the B -blocker trials done with the drugs used on top of the ACE-I. Two large trials however (CARMEN (Randomized Controlled Multicentre Trial), CIBIS I II (Cardiac Insuf \201 ciency Bisoprolol Study)), indicate that the two approaches, i.e. B -blocker \201 rst vs. ACE-I \201 rst, are comparable, thereby allowing clinicians to s elect the best approach for their patients with chronic HF. More importantly, the results o f these studies support a therapeutic strategy in which the institution of an early combina tion therapy should not be delayed. HF symptoms should be relatively stable prior to initiation. \200 Start with a low dose a nd up-titrate every 2 \200\2234 weeks. \200 Monitor the patient for symptoms and signs of deteriorating HF, hypotension, or excessive bradycardia. Aim for the evidence-based target dose or the maximum tolerated dose. BETA-BLOCKERS FOR HEART FAILURE 395 Practical considerations in treatment of heart failure with B -blockers Deteriorating sympt oms and/or signs of HF \200 Exclude co-existent pathology, i.e. increasing breathlessness secondary to bronchospasm in asthma. Remember that fatigue can be a direct side-effect of the B -blocker not related to the HF status. Increase the dose of diuretics (usually required temporarily). \200 If symptoms persist, consider reducing (or as a last resort stopping) the B -blocker dose and monitor the patient. Symptomatic hypotension \200 Asymptomatic hypotension does not require intervention. \200 May improve with time. \200 Consider reducing the dose of other hypotensive drugs ( particularly vasodilators). If symptoms persist consider reducing (or as a last resort stopping) the B -blocker dose and monitor the patient. Excessive bradycardia \200 Perform an ECG and/or ambulatory monitoring when necessary to exclude signi \201 cant heart block, pauses. If heart rate is <50 bpm and the patient is symptomatic, discontinue other contributing drugs (digoxin, amiodarone). If symptoms persist, consider reducing (or as a last resort stopping) the B -blocker dose, and monitor the patient. Sexual dysfunction \200 May be precipitated or exacerbated by B -blockers. \200 Conside r reducing the B -blocker dose. \200 Refer to a specialist. Doses of B -blockers used in heart failure See Table 7.9 . Table 7.9 Doses of B -blockers used in heart failure Licensed B -blocker Initiating dose (mg) Target dose (mg) Bisoprolol 1.25 once daily 10 once daily Carvedilol 3.125 twice daily 25 \200\22350 twice daily Metoprolol succinate a 12.5 once daily 200 once daily Nebivolol 1.25 once daily 10 once daily a Not available in the UK. 396 CHAPTER 7 Heart failure Advice to patients \200 Explain the expected bene \201 ts. \200 Emphasize that treatme nt is given as much to prevent worsening of HF as to improve symptoms; beta-blockers also increase survival. If symptomatic improvement occurs, this may develop slowly \200\224 over 3 \200\2236 months or longer. Temporary symptomatic deterioration may occur (estimated 20 \200\22330 % of cases) during initiation/up-titration phase. Advise the patient to report deterioration and that deterioration (tiredness, fatigue, breathlessness) can usually be easily managed by adjustment of their m edication; patients should be advised not to stop B-blocker therapy without consulting thei r physician. Patients should be encouraged to weigh themselves daily (after walking, before dressing, after voiding, before eating) and to consult their doctor if they have per sistent weight gain. This page intentionally left blank 398 CHAPTER 7 Heart failure Aldosterone receptor antagonists in heart failure \200 Aldosterone antagonists are indica ted in patients with left ventricular dysfunction (LVEF \211 35 % ) and severe symptomati c heart failure (NYHA class III or IV), despite treatment with optimal doses of ACE-I and B -blocker. Aldosterone inhibitors reduce both mortality and the number of hospital admissions secondar y to deteriorating HF symptoms. \200 The \201 rst-line aldosterone antagonist used in c linical practice is spironalactone (RALES (Randomized Aldactone Evaluation Study)). Eplerenone is indicated in a speci \201 c subgroup of post acute MI patients with LVEF \211 40 % and HF or diabetes (EPHESUS (Epelerenone Post- Acute Myocardial Infarction Heart Failure Ef \201 cacy and Su rvival Study)) or in those developing endocrine side-effects on spironalactone (10 % of mal es may develop breast tenderness or enlargement). Contraindications \200 Serum potassium > 5.0 mmol/L \200 Serum creatinine > 220 mol/L \200 Addition to a combination of ACE-I and ARB. Initiation of aldosterone antagonists \200 Check renal function and serum electrolytes. \200 Recheck renal function and serum electrolytes 1 and 4 weeks after starting treatment. Consider dose up-titration after 4 \200\2238 weeks. Do not increase the dose if there is wo rsening renal function or hyperkalaemia. Recheck renal function and serum electrolytes 1 an d 4 weeks after increasing the dose. Aim for the evidence-based target dose or maximum tolerated dose. \200 Recheck renal func tion and serum electrolytes 1, 2, 3, and 6 months after achieving the maintenance dose, and 6 monthly thereafter. Doses of aldosterone receptor antagonists used in heart failure See Table 7.10. Table 7.10 Doses of aldosterone receptor antagonists used in heart failure Licensed aldosterone antagonist Initiating dose (mg) Target dose (mg) Spironalactone 25 once daily 50 once daily Eplerenone 25 once daily 50 once daily ALDOSTERONE RECEPTOR ANTAGONISTS IN HEART FAILURE 399 Practical considerations in treatment of heart failure with aldosterone receptor antagonist s Deteriorating renal function \200 Check for other nephrotoxic drugs (NSAIDs). \200 If creatinine rises to > 210 mol/L, halve the dose of aldosterone antagonist and monitor biochemistry closely. If creatinine rises to \211 310 mol/L, stop the aldosterone antagonist and monitor biochemistry closely. Hyperkalaemia \200 Check for other drugs causing hyperkalaemia (potassium-sparing diuretics, supplements). If potassium rises to > 5.5 mmol/L, halve the dose of aldosterone antagonist and monitor biochemistry. If potassium rises to > 6.0 mmol/L, stop the aldosterone antagonist and monitor biochemistry. Speci \201 c treatment of hyperkalaemia may be needed. Symptomatic hypotension \200 Asym ptomatic hypotension does not require intervention. \200 It may improve with time. \200 Consider reducing the dose of other hypotensive drugs (particularly vasodilators). If symptoms persist, reduce the dose or stop the aldosterone antagonist and monitor the patient. Breast tenderness or enlargement \200 Switch from spironalactone to eplerenone. Advice to patients \200 Explain the expected bene \201 ts. \200 Treatment is given to improve symptoms, prevent worsening of HF, and increase survival. Symptom improvement occurs within a few weeks to a few months of starting treatment. Aviod NSAIDs not prescribed by a physician (self-purchased \200\230over-the - counter \200\231 treatment, e.g. ibuprofen). Temporarily stop sprionolactone if the patient has diarrhea and/or vomiting, and contact the physician. 400 CHAPTER 7 Heart failure Cardiac glycosides (digoxin) in heart failure \200 Digoxin is a useful aid to B -blockers for rate control of AF (when > 80 bpm at rest or > 110 \200\223120 bpm at exercise) in patients with HF, but its role is less well established in patients with sinus rhythm or rate- controlled AF. Two large digoxin-withdrawl trials (RADIANCE (Randomized Assessment of Digoxin on Inhibitor s of ACE) and PROVED (Prospective Randomized Study of Ventricular Failure and Ef \201 cacy of Digoxin)) demonstrated that patients from whom digoxin was withdrawn were more likely t o be admitted with worsening HF. \200 The DIG (Digitalis Investigation Group) trial enrol led 6800 patients with classes I to III HF with a mean EF of 28 % . This showed that there was no increase in mortality in the group given digoxin. There was a trend to a decrease in mortality due to pump failure, balanced by a slight increase in non-pump-failure-related cardiac deaths. Dig oxin reduced the number of hospitalizations for HF signi \201 cantly. Overall, the clinical trials support the use of digoxin in patients in sinus rhythm with mi ld to moderate HF. Trough levels should be maintained between 0.5 and 1.0 ng/mL. Digoxin has been shown to reduce morbidity, i.e. the number of hospitalizations, but not mortality in patients in sinus rhythm (DIG trial; performed prior to the use of B -blockers). Digoxin could be used prior to the initiation of a B -blocker in patients with decompensate d HF and should be considered where B -blockers are contraindicated. Digoxin should be considered in patients in sinus tachycardia, in addition to a B -blocker to control the heart rate (when > 80 bpm at rest or > 110 \200\223 120 bpm at exercise). Digoxin should be considered in symptomatic patients on optimal medical treatment, i.e. on ACE-I, B -blocker and aldosterone antagonist, irrespective of th e need for heart-rate control. Contraindications \200 Signi \201 cant bradycardia (<50 bpm) or 2nd- or 3rd-degree heart block without a permanent pacemaker Pre-excitation syndromes (Wolff \200\223Parkinson \200\223White). Initiation of digoxin \200 Unless there is a clinical emergency, oral treatment should su f \201 ce. \200 The therapeutic serum concentration should be maintained between 0.5 and 1.0 ng/mL. Certain drugs (amiodarone, diltiazem, verapamil, certain antibiotics) and renal impairment may increase plasma levels. Monitor potassium serum levels (hypokalaemia) and for signs of toxicity. VASODILATORS IN ACUTE HEART FAILURE 401 Hydralazine and isosorbide dinitrate in heart failure \200 In chronic HF, the combination of hydralazine and isosorbide dinitrate should be considered: \200 as an alternative to an ACE-I or ARB in patients who do not tolerate either of these drugs as an addition to patients on optimal medical therapy, i.e. ACE-I/ ARB, B -blocker, aldosterone antagonist, who remain symptomatic. Evidence regarding the use of hydralazine and isosorbide dinitrate is strongest in patients of African descent with the A-HeFT (African- American Heart Failure Trial), demonstrating reduced morbidity (relative risk ratio (RRR): 33 % ) and mortality (RRR: 43 % ) in African- American patients in NYHA III or IV. Isosorbide dinitrate is the only nitrate formulation that has been shown to increase exerci se tolerance, and, in combination with hydralazine, prolongs survival in patients with HF. The addition of hydralazine appears to attenuate nitrate tolerance. Contraindications \200 Symptomatic hypotension \200 Lupus syndrome \200 Severe renal impairment. Initiation of hydralazine and isosorbide dinitrate \200 Starting dose: hydralazine 25 mg three times daily \200 isosorbide dinitrate 20 mg three times daily Target dose: hydralazine 75 mg three times daily \200 isosorbide dinitrate 40 mg three times daily Monitor for drug-induced lupus (arthralgia, myalgia, rash, unexplained pyrexia, pericarditi s, pleurisy, increased antinuclear antibodies (ANA) titre). Vasodilators in acute heart failure \200 Vasodilators are useful in controlling HF sympto ms in acute decompensation in patients without symptomatic hypotension. Vasodilators should be avoided in patients with systolic blood pressure (BP)<90 mmHg, as they may reduce central organ perfusion. Intravenous nitrates (isosorbide mononitrate, isosorbide dinitrate), sodium nitroprusside, and nesiritide (not available in the UK) can all be used as infusions in the acute setting. Calcium antagonists are not recommended in the management of acute HF. 402 CHAPTER 7 Heart failure Other pharmacological treatments used in heart failure Positive inotropic support \200 In otropic agents should be considered in the acute setting in patients with low-output states and signs of hypoperfusion or congestion despite vasodilator and diuretic treatment. They should be used with caution in patients with tachycardia ( > 100 bpm) as they may exacerbate it or precipitate arrhythmias. \200 Stimulation of B -receptors may lead to vasoconstriction and elevated systemic vascular resistance. Dobutamine \200 Acts through stimulation of B 1 -receptors to produce a dose-dependent positive inotropic response. The elimination of the drug is rapid after the cessation of infusion. \200 Care should be exercised when weaning patients off dobutamine infusion, with gradual tapering and simultanous optimization of the oral treatment. Dopamine \200 Acts through stimulation of B -receptors to produce a positive inotropic response. At low doses ( \211 2 \200\2233 mcg/kg/min), dopamine stimulates dopaminergic receptors a nd may enhance the diuretic effect. Current trials have not provided any evidence of signi \201 cant morbidity or mortality bene \201 t with low-dose dopamine in normotensive patie nts. Noradrenaline (norepinephrine) \200 Not recommended as a \201 rst-line inotrope due to its vasopressor effect. \200 Only indicated in cardiogenic shock when the combination of a \202 uid challenge and alternative inotropic agents fails to restore adequate organ per fusion (systolic BP<90 mmHg) despite an improvement in cardiac output. It may also be used in septic patients with HF. \200 Exert extreme caution when used in c ombination with other inotropes, and in particular dopamine which already exerts a signi \201 cant vasopressor effect at high doses. Adrenaline (epinephrine) \200 Its use should be restricted to cardiac arrest only. Levosimendan \200 Is a unique inotropic agent with dual action: (1) a calcium sensitizer by binding in troponin-C in cardiac myocytes, resulting in improved cardiac contractility a nd cardiac output; and (2) opening of the ATP- sensitive potassium channels in the vascular smooth muscle, resulting in reduction in systemic and pulmonary vascular resistance. It is administered as an IV bolus followed by a 24-hour infusion, and the haemodynamic response may be maintained over several days. OTHER PHARMACOLOGICAL TREATMENTS USED IN HEART FAILURE 403 Current evidence from placebo-controlled trials suggest a favorable effect on symptoms (REV IVE (Randomized Multicenter Evaluation of Intravenous Levosimendan Ef \201 cacy)) and shor t-term survival (CASINO (Calcium Sensitizer or Inotropic Agent or None in Low Output Heart Failure)) in patients with acute, decompensated heart failure. Levosimendan treatment is associated with an increase in heart rate and reduction in blood pressure and should therefore be used with caution in patients with hypotension. Clinical trials with oral preparations are ongoing. Phosphodiesterase inhibitors \200 Type III phosphodiesterase inhibitors inhibit the break down of cyclic adenosine monophosphate (AMP) and have inotropic and peripheral vasodilating effects, resulting in: \200 increased cardiac output \200 reduced systemic and pulmona ry vascular resistance Their effects are maintained during concomitant B -blocker therapy. \200 They are usually administered as an IV bolus followed by infusion. \200 Caution should be exerted in pati ents with coronary artery disease, as they may increase medium-term mortality (OPTIME-CHF ( Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure). Antiplatelet agents and anticoagulants \200 Antiplatelet agents are indicated in patients with HF of ischaemic etiology (see b Chapter 4). There is no evidence to support the use of antiplatelet agents in HF of non-ischaemic etiol ogy. On the contrary, NSAIDs like aspirin should be avoided due to their \202 uid-retaini ng and renotoxic effects. Oral anticoagulants (warfarin) are recommended in patients with HF and: atrial \201 brillation \200 intracardiac thrombus \200 left ventricular aneurysm \200 prosthetic valves \200 other non-cardiac conditions (pulmonary embolism, recurrent deep vein thromboses (DVTs)). There is no evidence supporting the use of oral anticoagulation based on a poor EF alone. HMG-CoA reductase inhibitors (statins) \200 Statins are indicated in HF of ischaemic etio logy (CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure)). There is no indication for statins outside the context of ischaemia or primary cardiovascular prevention. 404 CHAPTER 7 Heart failure Device therapy for heart failure Implantable cardiac de \201 brillator (ICD) Secondary pre vention \200 Survivors of sudden cardiac death secondary to either ventricular tachycardia or ventricular \201 brillation Spontaneous sustained ventricular tachycardia causing syncope or signi \201 cant haemodynamic compromise Sustained ventricular tachycardia (VT) without signi \201 cant haemodynamic compromise in patients with a LVEF \211 35 % , who are no worse than NYHA fu nctional class III and have a reasonable expectation of survival for > 1 year. Primary prevention \200 Current data suggest that the etiology of HF may not justify a di fferent approach for primary prevention of sudden cardiac death. Data for patients in NYHA I are less robust. \200 Post-MI and all of the following: \200 at least 40 days post-MI \200 on optimal medical therapy \200 LVEF \211 35 % \200 NYHA functional class II or III \200 reasonable expectation of survival for > 1 year. (According to the National Institute for Health and Clinical Excellence (NICE) guidelines 2 003, documented non-sustained VT on Holter monitor or inducible VT on electrophysiological studies was also a prerequisite.) \200 Non-ischaemic cardiomyopathy and all of the follow ing: on optimal medical therapy \200 LVEF \211 35 % \200 NYHA functional class II or III \200 reasonable expectation of survival for > 1 year. Pacemakers \200 The conventional indications for the implantation of a permanent pacemaker apply to HF patients. Wherever possible, dual-chamber pacemakers should be implanted to maintain atrioventricular synchrony. In HF patients with signi \201 cant symptoms (NYHA II \200\223IV), dilated LV, or severely impaired LVEF ( \211 35 % ), right ventricular pacing may cause or increase interventric ular dys-synchrony and exacerbate symptoms. Cardiac resynchronization therapy (CRT) with pa cemaker function should therefore be considered. Cardiac resynchronization \200 Involves the implantation of a biventricular pacemaker, pa cing the right and the left ventricles simultaneously. Implantation can be challenging and should be performed by experienced operators. CRT improves quality of life and functional status (MIRACLE (Multicenter InSync Randomized Clinical Evaluation)), reduces DEVICE THERAPY FOR HEART FAILURE 405 HF-related hospitalizations (COMPANION (Comparison of Medical Therapy, Pacing and De \201 brillation in Heart Therapy)), and prolongs survival (CARE-HF (Cardiac Resynchronization in Heart Failure)). \200 Candidates for resynchronization therapy should satisfy all of the following criteria: \200 optimal medical treatment (or best treatment tolerated) \200 N YHA functional class III \200\223IV \200 LVEF \211 35 % \200 QRS duration \211 120 ms. Although biventricular pacemakers have been implanted in patients without ECG evidence of signi \201 cant electrical dyssynchrony (QRS<120 ms) based on echo cardiographic evidence of dys-synchrony, there are no studies supporting such a practice. O n the contrary, the PROSPECT (Predictors of Response to CRT) trial did not identify any ech ocardiographic measures of dys-synchrony that reliably predicted patients likely to respond to CRT. Resynchronization therapy may be combined with a de \201 brillator but the bene \201 t of CRT \200\223de \201 brillator versus CRT \200\223pacemaker only has not been adequately a ddressed. 406 CHAPTER 7 Heart failure Surgery for heart failure Valve surgery \200 Patients with primary valve disease should b e considered for valve repair/replacement surgery (see b Valvular heart disease, Chapter 3, p. 143). Selected patients with severe functional MR and depressed LV function, who remain symptomatic despite optimal medical therapy may be considered for surgery. Surgery for isolated functional tricuspid regurgitation is not recommended. Coronary artery bypass grafting (CABG) \200 CABG and percutaneous coronary intervention ( PCI) should be considered in selected patients with HF, after careful consideration of symptoms, objective evidence of myocardial ischaemia (stress-induced ischaemia or hibernating myocardium), co- morbidities, procedural risk, and coronary anatomy. Single-center, observational studies suggest that revascularization may improve symptoms an d cardiac function. Clinical trials are ongoing. Transplantation Cardiac transplantation is reserved for those patients with end-stage HF. I t is a major undertaking for the patient, who must be willing to undergo intensive treatmen t and be emotionally capable of withstanding the uncer- tainties that occur both before and after transplantation. There are a number of contraindications, some of which are shown be low. Contraindications for heart transplantation \200 Persistent alcohol/drug abuse \200 Tre ated cancer with remission and <5 years \200\231 follow-up \200 Systemic disease with mul ti-organ involvement \200 Infection \200 Fixed high pulmonary vascular resistance. Desp ite problems with rejection and complications of immunosuppressive therapy (infection, hype rtension, renal failure, malignancy), the 5-year survival is of the order of 70 \200\22380 % , with many patients returning to work. Assist devices Because of the lack of organ donors for cardiac transplantation, much intere st has been shown in the development of LV assist devices (LVADs) and mechanical hearts. LV ADs are automatic pumps that take over the work of the heart. They have been used as a brid ge to transplantation and also as a bridge to recovery in those with potentially reversible causes for their HF (e.g. post-viral). The next stage up from these large devices is the implantation of a permanent arti \201 ci al heart. An example is the Jarvik 2000 , which has been successfully implanted in a relat ively small number of patients. SURGERY FOR HEART FAILURE 407 Heart transplantation guidelines adapted from European Society of Cardiology (ESC)/AHA guid elines Indications Contraindications and cautions Current alcohol and/or drug abuse \200 Chronic mental illness, that cannot be Patients must be willing and able to withstand the physical and emotional demands of the procedure and its postopera tive sequelae adequately controlled Treated cancer with remission and <5 years \200\231 follow-up. Systemic disease with multi-organ Objective evidence of involvement Uncontrolled infection \200 Severe renal failure (creatinine clearance <50 mL/min) or cre atinine > 200 mol/L, although some centers accept patients on haemodialysis limitation, e.g. peak oxygen consumption less than 10 mL/min/kg on cardiopulmonary exercise test with evidence for anaerobic metabolism a \200 Patients who are dependent Fixed high pulmonary vascular resistance (6 \200\2238 Wood units and mean transpulmonary gradient > 15 mmHg and pulmonary artery sys tolic pressure > 60 mmHg) on IV inotropes and mechanical circulatory support Recent thromboembolic complication \200 Unhealed peptic ulcer \200 Evidence of signi \201 cant liver impairment \200 Other disease with a poor prognosis a Patients with signi \201 cant exercise limitation that have a peak oxygen consumption le ss than 55 % predicted or between 11 and 15 mL/min/kg also warrant consideration for cardia c transplantation if they have recurrent unstable myocardial ischaemia that is untreatable by other means, or recurrent episodes of congestive heart failure in spite of adherence to optimum medical therapy. 408 CHAPTER 7 Heart failure Heart failure with normal ejection fraction (HFNEF)/diastolic heart failure (DHF) \200 Th e terms diastolic heart failure, heart failure with normal ejection fraction, and heart fai lure with preserved ejection fraction are used interchangeably. Approximately 50 % of the HF population have a normal or near-normal LVEF. Diastolic dysfunction, however, is not unique to patients with diastolic HF, and often co-exists with systolic dysfunction. Compared with patients with heart failure with reduced ejection fraction (HFREF; systolic heart failure), individuals with HFNEF are typically older and mo re likely to be female. Pathophysiology \200 Impaired active ventricular relaxation \200 Impaired passive ventr icular \201 lling due to increased ventricular stiffness. The increased stiffness leads t o an increase of the LV end-diastolic pressure and pulmonary venous pressure, which in turn leads to increased dyspnoea during exercise and even pulmonary oedema Exercise intolerance is thought to be due to a combination of impaired LV \201 lling and inability to utilize the Frank \200\223Starling mechanism, resulting in failure to increase the cardiac output suf \201 ciently during exertion (see Fig. 7.5 ) In contrast to patients with HFREF, who typically exhibit LV dilatation and eccentric LV hy pertrophy, patients with HFNEF are characterized by non-dilated LV and concentric hypertrop hy (Fig. 7.5 ) Causes of HFNEF are similar to those of HFREF, with ischaemia and hypertension being top of the list. HFNEF is, however, associated with a higher prevalence of hypertension (up to 88 % ), obesity (up to 40 % ), renal failure, anemia, and AF. Systolic heart failure HFNEF LV morphology Fig. 7.5 Comparison of the characteristics of LV morphology and function in patients with H F and reduced LVEF and HFNEF. Reproduced with permission from Maeder MT et al (2009). J Am Coll Cardiol 53 : 905 \200\22318. HFNEF/DHF 409 Pressure- volume loop LV pressure LV pressure LV volume LV volume \206\221 Normal LV end- diastolic volume \206\221 \206\221 LV end- diastolic pressure LV mass Eccentric hypertrophy Concentric hypertrophy Left atrium Dilated Dilated \206\223 LVEF Normal (stiffness constant) \206\221 Normal \206\221 \206\221 E/E \206\221 \206\221 BNP/NT- proBNP Fig. 7.6 The pressure \200\223volume loops highlight that in patients with systolic heart f ailure, the slope of the end-systolic pressure \200\223volume relationship, which is obtain ed by recording pressure \200\223volume loops at different pre-load levels, is typically le ss steep (solid lines) than in individuals with normal hearts (dashed lines), and the loops are shifted toward larger volumes. In contrast, the end-systolic pressure \200\223 volume relationship is steeper or normal in HFNEF. However, HFNEF patients typically exhibit an en d-diastolic pressure \200\223volume relationship that is shifted upwards and to the left. L V = left ventricular; E/E = transmitral peak velocity during early relaxation to early dia stolic peak mitral annulus velocity; BNP = B-type natriuretic peptide; NT-proBNP = N-termin al pro-B-type natriuretic peptide. 410 CHAPTER 7 Heart failure Diagnosis and treatment of HFNEF A diagnosis of HFNEF requires (Fig. 7.7 ): \200 signs an d/or symptoms of HF (clinical symptoms and signs of HFNEF are similar to those of HFREF). normal or mildly reduced LV systolic function (LVEF > 50 % ). \200 evidence of diastolic dysfunction (although evidence of diastolic dysfunction can be obtained with invasive measurements, transthoracic echocardiography is t he investigation of choice in everyday clinical practice). every effort should be made to exclude other possible diagnoses that may present in a simil ar manner, as well as to exclude technical pitfalls on echocardiography (see Fig. 7.8 ). Treatment of HFNEF \200 Unlike HFREF, there is limited evidence-based treatment for HFNEF . \200 LV hypertrophy seems to be an important target for prevention of HF. \200 Aggres sive treatment of hypertension and diabetes is recommended. \200 Diuretics are used for r elief of \202 uid overload and symptom control. \200 Given the high prevalence of LVH a nd diabetes, there is a compelling argument for use of ACE-Is or ARBs. However, none of the randomized controlled t rials (CHARM-Preserved (Effects of Candesartan in Patients with Chronic Heart Failure and P reserved LVEF), I-Preserved (Irbesartan in Heart Failure with Preserved Ejection Fraction), PEP-CHF (Perindopril in Elderly People with Chronic Heart Failure) using cardesartan, irbe sartan, and perindopril respectively) to date have demonstrated any convincing mortality be ne \201 t. As with ACE-Is/ARBs, B -blockers are commonly used in HFNEF. However, once again, there are very limited data to support their use outside the context o f hypertension or rate control. Restoration of sinus rhythm in patients with AF, and coronary revascularization in patients with signi \201 cant reversible ischaemia are recommended. DIAGNOSIS AND TREATMENT OF HFNEF 411 Symptoms/signs of HF LVEF>50% and LVEDVI <97ml/m2 Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffn ess Invasive measurements \200 mPCWP >12 mmHg \200 LVEDP >16 mmHg \200 t >48 ms \200 b >0.27 Natriuretic peptides \200 NT-proBNP >220 pg/ml \200 BNP >200 pg/ml Echo TDI E/E \200 >15 8< E/E \200 <15 Natriuretic peptides \200 NT-proBNP >220 pg/ml \200 BNP >200 pg/ml E/A \206\223, DCT \206\221 \200 Abnormal pulmonary venous flow \200 Left atrial dilat ion \200 LVH \200 Atrial fibrillation TDI E/E \200 >8 HFNEF Fig. 7.7 Principles of the algorithm proposed for the diagnosis of HFNEF by the Working Gro up of the European Society of Cardiology. b = left ventricular passive stiffness; DCT = dec eleration time; E/A = ratio of early to late diastolic peak mitral in \202 ow velocities; LVEDVI = left ventricular end-diastolic volume index; LVH = left ventricular hypertrophy; m PCWP = mean pulmonary capillary wedge pressure; \204 = time constant of the isovolemic pre ssure decline; TDI = tissue Doppler imaging. Reproduced from Principles of the Algorithm Pr oposed for the Diagnosis of HFNEF by the Working Group of the European Society of Cardiolog y. Paulus WJ et al . Eur Heart J 2007; 28 :2539 \200\2232550. Shortness of breath and LVEF >50% Non-cardiac causes Cardiac causes HFNEF Lung disease Other cardiac entities Obesity Coronary artery disease \200 Valvular heart disease \200 HOCM \200 Restrictive CMP \200 Constrictive pericarditis \200 Intracardiac shunt Deconditioning Anemia Hyperventilation Thyrotoxicosis PAHT Extracardiac shunt Fig. 7.8 Scheme illustrating the differential diagnoses to the syndrome of HFNEF. HOCM = hy pertrophic obstructive cardiomyopathy. Reproduced with permission from Maeder MT et al (200 9). J Am Coll Cardiol 53 : 905 \200\22318. 412 CHAPTER 7 Heart failure Common co-morbidities in patients with heart failure Hypertension \200 Should be treated aggressively in all HF patients \200 Target BP should be <140/90 mmHg and <130/80 mmHg in high-risk groups (proteinuria, renal dysfunction, myocardial ischaemia). Diabetes mellitus \200 Tight glycaemic control is recommended. \200 Patients should be treated as per established guidelines. \200 Thiazolinediones have been associated with in creased \202 uid overload and symptomatic HF, and are therefore contraindicated in patien ts in NYHA functional class III \200\223IV and should be used with caution in less symptoma tic patients (NYHA I \200\223II). Given the close association of HF and renal dysfunction, renal function should be monitored in patients on metformin, which may require discontinuation in acute exacerbations associa ted with acute or chronic renal failure. Renal impairment \200 Common in HF; prevalence increase with increasing HF severity, age, diabetes mellitus, hypertension \200 Strongly linked to poorer prognosis \200 Always lo ok for potentially reversible causes. COPD \200 Common in HF (20 \200\22330 % ). \200 Associated with increased morbidity and mortality. \200 Although it may be dif \201 cult, attempt to quantify the relative contribution of each component to the symptoms of the patient, since it may affect optimal management. The majority of COPD patients will tolerate B -blockers well. Anemia \200 Anemia of chronic disease is common in HF, with reported prevalence varying widely (up to 70 % ). Anemia confers increased morbidity and mortality. \200 Correction of chronic anemia has n ot been established as routine treatment in HF, and blood transfusion is not recommended unless the patient is compromised . Erythropoietin treatment has been trialed but remains of unproven bene \201 t. Gout \200 Common in HF, given the use of loop diuretics and high prevalence of renal dysfunction. Hyperuricaemia is an independent risk factor of poor prognosis in HF. \200 Avoid NSAIDs/s teroids and treat acute attacks with colchicine. \200 Prophylactic treatment with allopur inol is recommended to prevent recurrence. This page intentionally left blank 414 CHAPTER 7 Heart failure Palliative care for heart failure \200 Patients with clinical features of advanced HF, wh o experience refractory symptoms despite optimal treatment, should be referred for a structured palliati ve care assessment. Symptoms and compromised quality of life, however, prevail throughout the course of HF and should therefore be speci \201 cally addressed with pallia tive care measures. Palliative care for HF should be integrated into comprehensive HF care to improve decision making and supportive care: \200 communication \200 education \200 psychological and spiritual needs \200 symptom management. Worsening heart failure When a patient is seen with worsening heart failure, it is importan t to try and ascertain the cause. The most frequent reasons for symptom deterio- ration are shown next. Causes of worsening heart failure Non-cardiac \200 Non-compliance (lifestyle changes, med ication) \200 Newly prescribed drugs \200 Renal dysfunction \200 Infection \200 Pul monary embolus \200 Anemia. Cardiac \200 Atrial \201 brillation \200 Other tachyarr yhthmias \200 Bradycardia/heart block \200 Worsening valve disease \200 Myocardial is chaemia (including infarction). WORSENING HEART FAILURE 415 Table 7.11 Summary of common side-effects of drugs used in heart failure Drugs Complications Diuretics Common : postural hypotension, gout, urinary urgency Serious : electrolyte imbalance (hypokalaemia, hypomagnesia, hyponatraernia), arrhythmia ACE-Is Common : cough, hypotension including postural Serious : worsening renal function, renal infarction in renal artery stenosis, angio-oedema B-blockers Common : tiredness, bradycardia, coldness Serious : asthmatic attack, exacerbation of heart failure, heart block Spironolactone Common : gynaecomastia, tiredness, rashes Serious : hyperkalaemia, hypotraemia Digoxin Common : nausea Serious : life-threatening arrhythmias Common : hypotension including postural Angiotensin-II receptor antagonists Serious : worsening renal function, renal infarction in renal artery stenosis Amiodarone Common : photosensitivity, nausea, thyroid dysfunction, sleep disturbance, corneal microdep osits Serious : thyrotoxic storm, pro-arrhythmia, pulmonary/hepatic \201 brosis Inotropes Common : nausea, palpitation Serious : arrhythmia, cardiotoxicity 416 CHAPTER 7 Heart failure High-output heart failure In high-output states, the only way that the oxygen demands of th e peripheral tissues can be met is by an increase in cardiac output. If there is underlying heart disease, the heart is unable to augment the cardiac output in the long term, and HF results. Causes of high-output states \200 Anemia \200 Acquired arteriovenous \201 stula \200 Haemangioma \200 Hereditary haemorrhagic Thyrotoxicosis \200 Beri-beri heart disease \200 Paget \200\231s disease of the bone \200 Fibrous dysplasia \200 Polycythaemia rubra vera \200 Carcinoid syndrome \200 Mu ltiple myeloma telangiectasia Hepatic haemangioendothelioma \200 Pregnancy \200 Acromegaly Anemia When the hemoglobin levels fall below 8 gm/dL, the anemia produces a high cardiac ou tput. However, even when severe, anemia rarely causes HF or angina in patients with normal hearts. Look for an underlying cardiac problem or valve disease. Try to determine the etiol ogy for the anemia. Patient should be on bed rest and transfused with packed red blood cell s accompanied with IV diuretics. Systemic arteriovenous \201 stulas The increase in cardiac output depends on the size of the \201 stula. The Branham sign consists of slowing of the heart rate after manual compr ession of the \201 stula. It also raises arterial blood pressure. Surgical repair or exci sion is the ideal treatment. Pregnancy (see b Heart disease in pregnancy, Chapter 15, p. 67 3) Thyrotoxicosis Raised levels of thyroxine produce increased heart rate and cardiac contrac- tility, reduction in systemic vascular resistance, and enhanced sympathetic activation. Th yrotoxicosis does not usually precipitate HF unless there is reduced cardiac reserve. Atria l \201 brillation occurs in about 10 % of patients, exacerbating the HF. Respiratory musc le weakness may contribute to the dyspnoea. Beri-beri (see b Beri-beri (thiamine deifciency ), p. 664) Paget \200\231s disease There is a linear relationship between the extent of bone involveme nt and rise in cardiac output. Involvement of about 15 % of the skeleton is required before the rise is seen, and patients may tolerate the early stages well for years. Concomitant v alvular disease or iachaemic heart disease results in decompensation. Successful treatment of Paget \200\231s disease with bisphospho- nates may reverse the rise in cardiac output ov er several months. 417 Chapter 8 Heart muscle diseases Classi \201 cation 418 Dilated cardiomyopathy 420 Dilated cardiomyopathy: treatment 422 Hy pertrophic cardiomyopathy 424 Hypertrophic cardiomyopathy: investigations 428 Hypertrophic cardiomyopathy: treatment 430 Restrictive cardiomyopathy 432 Cardiac amyloidosis 434 Cardia c amyloidosis: treatment 436 Fabry disease 438 Arrhythmogenic right ventricular cardiomyopa thy (ARVC) 440 ARVC: management 442 Left ventricular non-compaction 444 Ischaemic cardiomyo pathy 446 Valvular cardiomyopathy 446 Hypertensive cardiomyopathy 446 Alcoholic cardiomyopa thy 446 Metabolic cardiomyopathy 447 Takotsubo cardiomyopathy 447 Peripartum cardiomyopathy 447 Cardiomyopathy in systemic disease 448 Nutritional cardiomyopathy 448 Sensitivity or t oxic reactions 448 Neuromuscular disorders 448 Muscular dystrophies 450 Myocarditis 452 Vir al myocarditis 453 Rickettsial myocarditis 453 Bacterial myocarditis 454 Spirochetal myocar ditis 454 Protozoal myocarditis 455 Fungal myocarditis 455 Toxic and metabolic myocarditis 456 418 CHAPTER 8 Heart muscle diseases