Abolition of left ventricular out \202 ow obstruction Left ventricular out \202 ow obstru ction is treated pharmacologically, surgically, or by alcohol-induced trancoronary septal a blation. \200 Drugs : the drugs of choice include B -blockers or verapamil. Disopyramide, a negatively inotropic agent may be added in those with large symptomatic pre ssure gradients. Surgical myomectomy : surgical septal myotomy \200\223myectomy (Morrow procedure) directly debulks the proximal septum. It has been shown to relieve obstruction i n 90 % of cases and symptoms in 70 % over 5 years. The procedure is complicated by a risk o f high-degree AV block, requiring permanent pacing, and long-term complications include aor tic regurgitation. \200 Transcoronary septal ablation : alcohol septal ablation involves chemical infarction of the proximal portion of the interventricular septum by injection of alcohol into the \201 rst or second septal perforator artery. Initially, results have bee n promising; however, a signi \201 cant number of patients (10 \200\22325 % ) are rendered with complete heart block, necessitating permanent pacing. Unfortunately, there remain con cerns HYPERTROPHIC CARDIOMYOPATHY: TREATMENT 431 about the procedure in terms of the long-term impact of MI, notably adverse LV remodeling o f potentially sinister arrhythmias. Cardiac pacing : dual-chamber pacing with short AV delay has been shown to improve symptoms and abolish gradients in a small proportion of patients. In previous trials, most patients were asymptomatic for only short periods and therefore the procedure is only reserved for patients with severe symptomatic obstruction who are unsuitable for surgery or transcoronar y septal ablation. Sudden cardiac death The only effective therapy to prevent SCD is an ICD. De \201 nitive ( secondary) indications for an ICD include previous aborted SCD or haemodynamically unstable VT. Risk strati \201 cation in patients who are relatively asymptomatic and do not fall into t his category is less straightforward. There are currently several established risk factors; however, all have a relatively low sensitivity or speci \201 city to predict SCD in isola tion. The box below lists established risk factors for SCD. Each risk factor has a positive predi ctive accuracy of 20 \200\22325 % ; however, the negative predicitive accuracy of these ris k factors exceeds 90 % ; therefore the absence of any of these risks allows reassurance in most patients. Due to the relatively Iow positive predictive accuracy of any one of the fac tors in isolation, current practice indicates that at least two or more of these risk facto rs should be present to warrant ICD implantation for the purposes of primary prevention. Markers of risk for SCD in hypertrophic cardiomyopathy \200 Markers of risk for SCD in HC M \200 Unheralded syncope \200 Family history of SCD from HCM \200 Severe LVH ( > 30 mm) \200 Severe left ventricular out \202 ow obstruction ( > 60 mmHg) \200 Non-sustain ed VT on ambulatory ECG monitoring \200 Abnormal ( \202 at or decreasing) blood pressure response to exercise. 432 CHAPTER 8 Heart muscle diseases Restrictive cardiomyopathy Restrictive cardiomyopathy is a rare condition characterized by impaired diastolic function due to reduced ventricular compliance. It is very impor- tant t o distinguish restrictive cardiomyopathy from constrictive pericar- ditis, as the latter ca n be treated surgically by stripping the pericardium from the myocardium. Etiology The etiology of truly idiopathic cases remains obscure. A few cases are familial a nd tend to be associated with skeletal muscle disease. Other cases are associated with syst emic diseases, in \201 ltration, or endomyocardial \201 brosis. Symptoms Patients often have severely limited exercise tolerance due to an inability to inc rease cardiac output, as their stroke volume is relatively \201 xed. They are also limite d by breathlessness and have evidence of right heart failure (peripheral oedema). Diagnosis Physical examination In addition to signs of CCF, a loud S 3 , S 4 , or both may be present. There also may be prominent x and y descents of the JVP, and venous pres- sure may increase on inspiration (Kussmaul sign). The apex beat will be palpable, in contrast to constrictive pericarditis. Investigations \200 ECG may show P mitrale or P pulmonale, reduced precordial QRS voltages, and atrial arrhythmias. Echocardiography may be normal, or at least demonstrate normal systolic function. Alternati vely, systolic function may be reduced in advanced cases. In \201 ltration may be evident by hypertrophied ventricles, and thickened intra-atrial septum, and the myocardium may appe ar speckled. Bi-atrial enlargement may also be present. A restrictive mitral in \202 ow pa ttern is seen on Doppler tracing. Laboratory test are aimed at determining causes of in \201 ltration. Left and right heart catheterization may be necessary to help to exclude constrictive pericarditis (a difference in left (LVEDP) and right (RVEDP) end-diastolic pressures > 7 mmHg at end-expiration makes constriction unlikely). Computed tomography (CT) and MRI scanning are useful to look at pericardial disease. Treatment Treatment is aimed at the symptoms of CCF and the underlying condi- tion. Rate co ntrol in AF is important, as reducing ventricular \201 lling times will have signi \201 cant impact. Patients with amyloid are very sensitive to digoxin. RESTRICTIVE CARDIOMYOPATHY 433 Causes of restrictive cardiomyopathy Myocardial \200 Non-in \201 ltrative \200 Idiopat hic \200 Scleroderma \200 In \201 ltrative \200 Amyloid \200 Sarcoid \200 Storag e diseases \200 Lysosomal storage disease (Gaucher \200\231s, Hurler \200\231s, Fabry) \200 Glycogen storage disease \200 Haemochromatosis. Endomyocardial \200 Endomyocardia l \201 brosis \200 Hypereosinophilic syndrome \200 Metastatic malignancies \200 Car cinoid \200 Iatrogenic (radiation anthracyclines). 434 CHAPTER 8 Heart muscle diseases Cardiac amyloidosis Amyloidosis is a clinical disorder characterized by extracellular depos ition of insoluble \201 bril proteins. Amyloid deposition can occur in connective tissue or blood vessels, and in a variety of organs including the heart, kidney, liver, and nervou s system. Cardiac amyloidosis is de \201 ned clinically by signs of myocardial or conducti on system dysfunction, due to involvement of the heart by amyloid deposition either as part of systemic amyloidosis or as a localized process. Classi \201 cation Systemic AL amyloidosis is the commonest form of clinical amyloid disea se. AL \201 brils consist of monoclonal immunoglobulin light chains and can be derived fr om any B-cell dyscrasia (e.g. myeloma, lymphoma), though benign monoclonal gammopathies are commonest. The disorder occurs equally in males and females over the age of 50 years, and usually in \201 ltrates multiple organs. Cardiac involvement occurs in up to 90 % of patie nts with AL amyloidosis, with approximately 50 % suffering diastolic heart failure. Systemic AA amyloidosis is a consequence of any chronic in \202 ammatory condition that fe atures a sustained acute phase response causing elevated production of serum amyloid A prot ein. Cardiac involvement is rare, but renal disease is the predominant \201 nding, with p roteinuria and renal failure. ATTR cardiac amyloidosis is a form of hereditary systemic amyloidosis with autosomal domina nt inheritance due to a mutation in the transthy- retin molecule (ATTR). The most common AT TR amyloid cardiomyop- athy is due to the Val122Ile mutation (substitution of isoleucine fo r valine at position 122) and is more prevalent in African-Carribean individuals, causing l ate-onset cardiomyopathy and progressive severe heart failure. Senile systemic amyloidosis is a slowly progressive in \201 ltrative cardiomy- opathy. The re is a male preponderance, with a prevalence of 25 \200\22336 % in males aged over 80 year s. It is rare in individuals under 60 years, and has a slower progression than AL amyloidos is, despite there being greater cardiac in \201 ltration. Pathophysiology In \201 ltration of the ventricular myocardium with amyloid \201 brils i s associated with reduced compliance and impaired myocardial relaxation. Left and right atr ial pressures become progressively elevated, resulting in pulmonary oedema and peripheral v olume overload. Endocardial involvement results in mitral and tricuspid regurgitation, caus ing a further increase in atrial pres- sures. Amyloid \201 brils within the myocardium pr omote in \202 ammation and \201 brosis, and increase the propensity to fatal re-entrant arrhythmias. Atrial dilatation predisposes to AF. Direct involvement of the cardiac conduc- tion tissue is associated with heart block and sudden death. Deposition of amyloid within coronary arteries is recognized, and may be associated with angina or sudden death. Pericar dial involvement is characterized by small effusions, which are usually of little clinical signi \201 cance. CARDIAC AMYLOIDOSIS 435 Clinical features Isolated cardiac involvement is seen in <4 % of individuals with amyloido sis. The clinical presentation is dominated by right-sided heart failure, with left-sided h eart failure becoming evident in later stages of the disease. Angina is rare, and due to am yloid deposition in the intramyocardial coro- nary arteries. Dizziness and syncope are due to several factors, including postural hypotension secondary to autonomic neuropathy, over- diuresis, and tachy- and bradyarrhythmias. Clinical signs: raised JVP, hepatomegaly, lower- limb oedema, and ascites are common. In advanced cases, LV involvement is associated with h ypo- tension and pulmonary oedema. Precordial examination characteristically reveals a loud third heart sound, due to rapid and abrupt \201 lling of the ventricles in early diastol e. Diagnosis Cardiac amyloidosis should be suspected in any patient with unexplained heart failure, particularly if there is echocardiographic evidence of LVH with a normal cavity di mension. ECG: Is non-speci \201 c; however, diminished voltages (QRS <0.5 mV in limb leads and <1 mV in precordial leads) and pseudoinfarct patterns with pathological Q waves and T- wave inversion are observed in up to 50 % of cases. Atrial \201 brillation and \202 utt er are the commonest arrhythmias, followed by varying degrees of heart block. Echocardiogra phy: Thickening of the LV walls with normal cavity dimen- sions and diastolic dysfunction a re early features. The myocardium exhibits a characteristic \200\230speckled \200\231 appe arance. Thickened endocardial surfaces, regur- gitation of the AV valves, bi-atrial enlarge ment, a bright interatrial septum, and small pericardial effusions are also recognized. In advanced stages of the disease process, there is worsening ventricular compliance, resultin g in restrictive \201 lling and a marked increase in left and right atrial pressures. Sys tolic dysfunction is more prevalent in late stages of disease progression. Cardiac MRI: Is now an established investigation, which shows a character- istic global subendocardial enha ncement with late gadolinium enhancement. Nuclear maging: Using radio-labeled technetium ca n detect the distri- bution of serum amyloid protein but is rarely utilized in practice, du e to technical dif \201 culties with hollow and moving organs. Tissue biopsy: Of the endom yocardium is the gold-standard investigation and is diagnostic when tissue sections are sta ined with Congo red. Sections demonstrate an \200\230apple-green \200\231 colouration when visualized under polarized light. Tissue diagnosis is rarely necessary in the presence of characteristic myocardial appearances on the echocardiogram and cardiac MRI. Biochemistry: The cardiac biomarkers troponin I, troponin T and N-terminal pro-B-type natriuretic hormone (NT-proBNP) are elevated in cardiac amy- loidosis. Raised troponins are due to amyloid dep osition causing myocytes necrosis and small-vessel ischaemia. BNP levels are raised seconda ry to diastolic dysfunction and often precede the onset of clinical heart failure. Immunology: Serum immunoelectrophoresis and urinalysis for light chains is essential to exc lude an underlying paraproteinaemia. 436 CHAPTER 8 Heart muscle diseases Cardiac amyloidosis: treatment Treatment for cardiac amyloidosis is generally supportive, t hough there are chemotherapeutic and anti-in \202 ammatory treatments aimed at suppressing the expression of serum amyloid A protein and serum immunoglobulins. Symptomatic treatment of heart failure with diuretics and aldosterone antagonists is the mainstay of treatment. There is no evidence that ACE-Is are bene \201 cial in cardiac amyloidosis. Indeed, the ve nodilatation associated with ACE-Is may potentially reduce ventricular \201 lling and dim inish cardiac output. Beta-blockers may also be potentially detrimental in individuals requ iring an adequate chonotropic response to maintain cardiac output in the presence of severe impairment of myocardial relaxation. Digoxin and calcium-channel blockers are contraindicated in cardiac amyloidosis, as they se lectively bind to amyloid \201 brils causing cardiac toxicity. Anticoagulation must be co nsidered, due to an increased risk of intracardiac thrombus and also due to AF and LV systo lic dysfunction. Cardiac pacing is necessary in patients with heart block. The role of ICDs is contentious w hen one considers that most patients with symptomatic cardiac amyloidosis survive less than one year. The role of biventricular pacing is not established. Results of cardiac transpla ntation followed by high- dose chemotherapy or autologous stem cell transplantation are awa ited. This page intentionally left blank 438 CHAPTER 8 Heart muscle diseases Fabry disease Fabry disease is a rare X-linked recessive lysosomal storage disorder caused by mutations encoding the enzyme A -galactosidase A. This enzy- matic defect leads to accum ulation of globotriaosylceramide in several organs including the skin, nervous system, kidn ey, eyes, and heart. The disorder has a prevalence of 1 in 40 000. Despite the X-linked pat tern, women may also exhibit the Fabry disease phenotype, albeit mildly. Extra-cardiac manifestations Fabry disease is a multisystem disorder with a progressive cli nical course. Clinical manifestations are usually evident by 10 years of age, with cuta- ne ous angiokeratomata (affecting the hips, groins, and umbilical region) and painful neuropat hy affecting the hands and feet (acroparaesthesia) being predominant features. Hypohidrosis , heat intolerance, and gastro-intestinal disturbance also occur. In the second decade, pro teinuria, corneal opaci- ties, retinopathy, and vestibular and hearing de \201 cits can oc cur. By the third decade, renal failure, cerebrovascular disease, and cardiomyopathy may be evident, causing signi \201 cant morbidity and mortality in affected patients. Cardiac manifestations Cardiac involvement in Fabry disease may take two forms. There can b e multi-organ disease, in which cardiac involvement is a feature, but also an atypical vari ant in which cardiac manifestations occur in isola- tion. Hypertension, LVH, conduction def ects, coronary artery disease, aortic and mitral incompetence, and aortic root dilatation c an all occur. Accordingly, affected individuals may present with angina, dyspnoea, and palp itations. Investigations ECG: Findings include LVH most commonly. Short PR interval and con- duction disorders of th e AV node, His bundle, or its branches can all occur. Echocardiography: Abnormalities include the presence of LVH, which can be the earliest and only \201 nding. Atrial enlargement, aortic root dilatation, and valvular thickening (aor tic and mitral valves) can also be a feature. The increased ventricular wall thickness is d ue to deposition of globotria- osylceramide within cardiac myocytes. The increased wall thi ckness may mimic HCM, but thickening is generally symmetric. Systolic and diastolic functio n are often preserved. Cardiac MRI may be useful in differentiating other forms of cardiomy opathy, particularly when LVH is the predomi- nant echocardiographic feature (distribution of hypertrophy, large papil- lary muscles and trabeculae, RV hypertrophy, posterior wall ga d). Coronary angiography: Is performed due to a combination of anginal symptoms and an ischaemi c-looking ECG. In the majority of cases, cor- onary angiography is normal, with the ischaem ic manifestations due to endothelial dysfunction induced by globotriaosylceramide depositio n within coronary arteries. FABRY DISEASE 439 24-hour Holter monitoring: AF is the commonest arrhythmia, followed by VT. Due to lipid dep osition throughout the cardiac conduction tissue, any form of heart block can occur and may require permanent pacemaker implantation. Endocardial biopsy: The diagnosis may be ascertained by endomyocardial biopsy. Sarcoplasmic vacuolization is the classic \201 nding on light microscopy of haematoxylin and eosin-st ained tissue. Management There is no de \201 nitive cure for Fabry disease, but enzyme-replacement thera py has been demonstrated to cause greater clearance of micro- vascular endothelial deposits of globotriaosylceramide in the heart and kidneys. It has also been shown to reduce LVH an d enhance regional myocardial function. Given this potential for effective therapy, screeni ng for Fabry disease by measurement of plasma A -galactosidase A in patients with unexplain ed concentric LVH is prudent. Screening should be con- sidered in all \201 rst-degree rel atives of individuals diagnosed with Fabry disease, and in patients diagnosed with hypertro phic cardiomyopathy, particularly if LVH is symmetrical, and there is no family history of hyper- trophic cardiomyopathy. 440 CHAPTER 8 Heart muscle diseases Arrhythmogenic right ventricular cardiomyopathy (ARVC) Arrhythmogenic right ventricular car diomyopathy (ARVC) is a hereditary cardiac disorder characterized by \201 bro-fatty repla cement of the right ventricular myocardium, and a predilection to potentially fatal ventric ular arrhythmias. The disorder may progress to right ventricular dilatation and failure. In some advanced cases, the left ventricle is also involved, although there is a clinical var iant with isolated LV disease. The prevalence is reported as between 1 in 2000 and 1 in 500 0. Etiology Between 40% and 50 % of cases are familial with an autosomal dominant pattern of i nheritance. Several loci have been mapped to chromosomes 1, 2, 3, 10, and 14, causing mutat ions in genes encoding desmosomal proteins (e.g. plakoglobin, desmoplakin, plakophilin, and desmoglein). An autosomal recessive variant associated with palmoplantar keratosis, wooly hair, and a more malignant clinical course (Naxos disease) has been mapped to the plakoglob in gene on chromosome 17. Pathophysiology Macroscopically, the typical structural changes in ARVC include RV dila- ta tion with associated RV myocardial thinning and \201 bro-fatty in \201 ltration. Particu lar sites involved include the RV apex, in \202 ow tract, and out \202 ow tract. With dis ease progression, further involvement of the RV free wall leads to aneurysms and RV cavity dilatation. Left ventricular involve- ment can be a late feature, and is associated with a higher incidence of arrhythmia and heart failure. Histology demonstrates a segmental trans- mural \201 bro-fatty replacement of myocardium with areas of focal myocar- ditis and in \202 ammatory in \201 ltration. The focal \201 bro-fatty deposits are the arrhythmogeni c substrate that is a hallmark of ARVC. Symptoms Patients are often asymptomatic but symptoms of palpitations, pre-syncope and sync ope can occur and may be precipitated by exercise. ARVC can present at any age in either se x, and the \201 rst presentation in healthy young individuals may be exercise-related SCD . Overt signs of right heart failure are rare. Other patients present in later life with sy mptoms of CCF with or without ventricular arrhythmias, and advanced cases may be misdiag- n osed as having DCM. The natural history of ARVC may be separated into a number of distinct phases with progressive development of symptoms and structural abnormalities: \200 concea led phase : a subclinical asymptomatic phase with little or no structural RV abnormality. Sudden CD may still occur in this stage of disease overt electrical disorder : typically with symptomatic ventricular arrhythmias of RV origin. Arrhythmia may vary from premature ventricular beats to non-susta ined ventricular tachycardia to ventricular \201 brillation. Structurally, there is clear evidence of RV wall involvement ARVC 441 RV failure : progressive loss of RV myocardium due to \201 bro-fatty replacement impairs RV function and may result in severe pump failure. Gross dilatation of the RV occurs biventricular failure : an advanced stage with involvement of the interventricular septum and LV causing CCF and imitating DCM. Diagnosis Diagnosis of affected individuals can be very dif \201 cult, especially during f amily screening, as standard non-invasive investigations have poor sen- sitivity. Diagnosis relies on symptoms, a family history of ARVC, ECG abnormalities, and structural changes of the RV on imaging studies. A diagnosis is based on the presence of two \200\230major \200 \231; one \200\230major \200\231, and two \200\230minor \200\231; or four \200\230minor \200\231 criteria from differing categories. Investigations \200 12-lead and signal-averaged ECG : 12-lead ECG may be normal in 7 40 % of affected individuals. T-wave inversion in the right ventricular precordial leads (V 1 \200\223V 3 ) is the predominant abnormality. There may also be QRS prolongation with late potentials, known as Epsilon waves, again in leads V 1 \200\223V 3 , suggesting dela yed ventricular depolarization. Signal-averaged ECG demonstrates late potentials in 50 \200 \22380 % of individuals with ARVC. Echocardiogram ( cardiac MRI scan): echocardiography may be normal, particularly in the \200\230concealed \200\231 phase of ARVC. Findings can vary from mild focal RV hypokinesia to severe RV dilatation with aneurysm formation and reduced function. LV involvement and b iventricular failure are late features. Cardiac MRI (CMR) is more sensitive in identifying RV pathology in ARVC, and is now increasingly available. It can assess ventricular volumes, and global and regional ventricular function, as well as myocardial fat and late gadoliniu m enhancement. 24-hour ambulatory ECG monitoring : frequent ventricular ectopy ( > 1000/24 hours) and non- sustained or sustained ventricular tachycardia with a LBBB morphology (indicating origin in the RV) are recognized features of ARVC. Exercise testing : may provoke frequent ventricular ectopy and ventricular tachycardia in patients with ARVC. Invasive procedures : CMR has superseded RV angiography. Electrophysiological studies are useful in differentiating an RV out \202 ow ectopic focus from ARVC. Electro-anatomical mapping is being utilized to identify scar tissue. Tissue di agnosis is problematic, as a transmural sample is necessary. Furthermore, the disease usual ly affects the thinnest parts of the RV, increasing the risk of RV perforation. The disease is patchy; therefore, a negative biopsy does not exclude pathology. 442 CHAPTER 8 Heart muscle diseases ARVC: management Treatment There are no established best treatment options for patients wit h ARVC, and, as the disease is progressive, antiarrhythmic options are used for symptomatic bene \201 t in patients with haemodynamically well-tolerated ventricular arrhythmias. Giv en the association between exercise and SCD in ARVC, excessive training or participation in sport must be avoided. Patients who have developed RV LV dysfunction can be managed wit h standard treatments for CCF, and in severe cases transplantation may be an option. Antiarrhythmics B -blockers alone or in combination with class I and III antiarrhythmics ar e the most effective in reducing symptomatic but well-tolerated ventricular arrhythmias. So talol and amiodarone have been shown to be most effective. Radiofrequency ablation A small subset of patients with drug-refractory arrhythmias who are felt to have fairly localized disease may be amenable to electrophysiologic mapping and ra diofrequency ablation. However, it must be remembered that ARVC is a progressive disease, a nd such procedures cannot be regarded as a permanent cure for future arrhythmias. Implantable cardioverter de \201 brillators In patients with life-threatening or drug-refr actory ventricular arrhythmias and widespread disease, ICDs probably offer the best protect ive measure against SCD. Risk strati \201 cation There are no established or proven speci \201 c risk factors for SCD, but markers of increased risk include young age at presentation, malignant family hist ory, unheralded syncope, right ventricular dysfunction, left ven- tricular involvement, pre sence of VT on ambulatory monitoring, QRS dispersion of > 40 ms, and certain genetic mutati ons (in particular Naxos disease). Further reading The task force criteria for diagnosis of ARVC are available: Marcus FI, McK enna WJ, Sherrill D, et al ( 2010 ). Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modi \201 cation of the task force criteria . Circulati on 121 ( 13 ): 1533 \200\223 41 . Also available to download from http://eurheartj.oxfordj ournals.org/content/ early/2010/02/16/eurheartj.ehq025.full.pdf. This page intentionally left blank 444 CHAPTER 8 Heart muscle diseases Left ventricular non-compaction Left ventricular non-compaction (LVNC) is a rare cardiomyop athy char- acterized by marked trabeculations and deep intertrabecular recesses in the left ventricular wall. The disorder is also characterized by systolic and diastolic dysfunction , predilection to arrhythmias, and systemic thromboem- bolism. The prevalence of LVNC is un known and there is still debate over speci \201 c diagnostic criteria. The nomenclature of the condition is misleading, as both the right and left ventricle are commonly involved. Etiology Although the mechanism leading to LVNC is unclear, it is believed to be a disorder of retarded endomyocardial morphogenesis. In normal circum- stances, trabeculations in the fetal myocardial primordium occur at day 32 of embryonic development, before inverting ( \200\230compacting \200\231) by day 70. LVNC represents an arrest of this normal compaction process in utero , resulting in a layer of non-compacted myocardium lying adjacent to a co mpacted layer of endocardium. A genetic basis for LVNC has been demonstrated by a higher prevalence of the condition in \201 rst-degree relatives. The inheritance pattern, however, is variable, with autosomal d ominant, X-linked and even mitochondrial transmission being identi \201 ed. Mutations of G 4.5 , which encodes taffazins expressed in heart and skeletal muscle cells, were initially identi \201 ed in Barth syndrome. Other mutations encoding structural proteins, such as A- dystrobrevin, Cipher/ZASP and FKBP12, have also been associated with LVNC. Clinical features The major clinical manifestations of LVNC are of systolic and diastolic d ysfunction and congestive cardiac failure. There is a high prevalence of atrial and ventric ular arrhythmias, with WPW common amongst children with the condition. Sudden death due to ventricular tachyarrhythmia has been reported. Systemic emboli due to stagnation of blood i n the deep intertrabecular recesses can occur as a presentation or a complication of LVNC. LVNC is occasionally associated with other congenital cardiac conditions, including Ebstein \200\231s anomaly, bicuspid aortic valve, and congenital right or left ventricular out \202 ow tract abnormalities such as pulmonary atresia. It is also associated with certain n euromuscular disorders including Charcot \200\223 Marie \200\223Tooth disease and Melnick \200\223Needles syndrome. Diagnosis Based on relatively limited data from a small number of centers, the 12-lead ECG is abnormal in up to 95 % of cases but changes are non-speci \201 c. Features include bive ntricular hypertrophy, T-wave inversions, and con- duction abnormalities including complete heart block. The mainstay of investigation for LVNC is through imaging, particularly echoc ardiography. LEFT VENTRICULAR NON-COMPACTION 445 Echocardiography Some controversy surrounds speci \201 c diagnostic criteria for LVNC, but there are three separate criteria, which include: \200 the presence of multiple trabecul ations particularly at the apex and left ventricular free wall multiple deep intertrabecular recesses communicating with the left ventricular cavity, demo nstrable particularly with color Doppler imaging a two-layered structure to the endomyocardium with a non-compacted to compacted thickness r atio of greater than 2.0 in adults at end-systole in the parasternal short-axis view. Other \201 ndings may include reduced left ventricular systolic function, diastolic dysfu nction, left ventricular thrombi, and abnormal papillary muscle structure. Cardiac magnetic resonance imaging CMR is of particular use when satisfactory echocardiogra phic images are unattainable. It has also superseded the use of cardiac computed tomog- rap hy and left ventriculogram in assessing for LVNC in dif \201 cult cases. The best distingu ishing feature for LVNC using CMR was a maximum ratio in diastole of non-compacted to compa cted myocardial thickness of greater than 2.3 as assessed in three long-axis views. Genetic analysis Muscle biopsies, metabolic studies, and genetic testing may be helpful whe n LVNC is considered as part of a genetic or metabolic syndrome. Management There is no speci \201 c therapy for LVNC. Medical management varies with the c linical manifestations, and centers on treatment of heart failure using standard medication s. Anticoagulation is usually recommended in patients with AF and/or a LVEF of <40 % , to p revent systemic thromboembolism. Monitoring with 24-hour Holter analysis should be consider ed annually to detect asymptomatic arrhythmias. ICD therapy is recommended in patients with LVNC who have signi \201 cant left ventricular systolic impairment and non-sustained vent ricular tachycardia. Prognosis Initial studies on small groups of severely affected individuals suggested that L VNC was associated with a signi \201 cantly poorer prognosis than other forms of cardiomyo pathy, with higher rates of mortality and mor- bidity. However, with increasing awareness o f LVNC, more subtle forms in mildly symptomatic patients or severe forms in asymptomatic pa tients have been detected. 446 CHAPTER 8 Heart muscle diseases Ischaemic cardiomyopathy This is a condition de \201 ned as signi \201 cantly impaired le ft ventricular func- tion (EF<35 % ) in which CAD causes a picture that is often indistingu ish- able from DCM with or without a preceding history of angina or MI. Often the degree of dysfunction is inconsistent with the extent of CAD. There are two main pathological proces ses, which can be distinguished by the possibility for corrective therapy. Firstly, there i s irreversible loss of myo- cardium from previous MI and subsequent ventricular remodeling. There is no scope for recovery of myocardial function, as the infarcted tissue is no longe r viable. Secondly, there are those patients with hibernating viable myocardium who will be ne \201 t from revascularization. Once a diagnosis has been established, assessment for vi able myocardium can be done using stress echocardiography; however, coronary angiography angioplasty is the mainstay of diagnostic and therapeutic interventions. Valvular cardiomyopathy Patients with valvular heart disease will develop a cardiomyopathy that is dependent on the predominant valvular lesion. Signi \201 cant improvement in cardi ac function can often be seen after correction of the valve disease. Hypertensive cardiomyopathy Hypertension causes LVH in response to increased afterload, whi ch is compensatory and protective to a point. However, there are ultimately det- rimental e ffects on systolic and diastolic ventricular function. Hypertension also leads to accelerat ed atherosclerosis and ischaemic heart disease. Hypertensive cardiomyopathy is the commones t form of CCF outside the western world. Alcoholic cardiomyopathy Chronic alcohol excess is the commonest 2 cause of DCM in the w estern world. Proposed mechanisms include (1) a direct toxic effect of ethanol causing apop tosis and myocyte loss and acetyldehyde causing depressed myocardial contraction; (2) conco mitant nutritional de \201 ciencies (especially thiamine); and (3) rarely, toxic effects o f additives (cobalt). Progression to alcoholic cardiomyopathy is related to the mean daily alcohol intake and total duration of drinking (approximately 1 L of wine every day for 5 ye ars). Clinical presentation, diagnosis, and treatment are similar to DCM. However, unlike o ther forms of DCM, abstinence from alcohol early in the disease process may stop progressio n, or even result in signi \201 cant improvement in cardiac function. PERIPARTUM CARDIOMYOPATHY 447 Metabolic cardiomyopathy Various abnormalities in metabolism can result in cardiomyopathy. As already mentioned, lysosomal and glycogen storage diseases can cause a form of restricti ve cardiomyopathy. Haemochromatosis also causes restrictive cardiomyopathy by unknown mecha nisms. Acquired errors of metabolism such as acromegaly result in biventricular hypertrophy . Diabetes mellitus can cause cardiomyopathy with systolic and/or diastolic dysfunction, ev en in the absence of signi \201 cant epicardial CAD. Takotsubo cardiomyopathy Takotsubo cardiomyopathy, also known as stress-induced cardiomyop- athy, or transient apical ballooning syndrome, is a rare but increasingly recognized cardi ac syndrome. It is characterized by transient systolic dysfunction of the apical and/or mid segments of the left ventricle, with a compensatory hyperkinesis of the basal walls produc ing ballooning of the apex during systole. The condition is more prevalent in postmeno- pau sal women and is often triggered by intense emotional or physical stress (e.g. bereavement, domestic abuse, natural disasters). The clinical presentation of takotsubo cardiomyopathy is similar to acute MI, with retroste rnal chest pain, ST segment elevation and raised cardiac biomarkers. Other features may inc lude tachy- and bradyarrhythmias, signs of left ventricular failure, transient LVOT obstruc tion, and even cardiogenic shock. Coronary angiography, by de \201 nition, reveals no evid ence of signi \201 cant coronary stenosis. The diagnosis is reached by left ventriculograp hy or transthoracic echocardiography (TTE), which identi \201 es the characteristic apical ballooning with associated reduced left ventricular systolic function. The pathogenesis of takotsubo cardiomyopathy remains poorly understood; however, postulated mechanisms include catecholamine excess causing coronary artery spasm and microvascular dysfunction, or by di rect catecholamine-mediated myocardial toxicity. Management of this condition is essentially supportive, with IV hydration, treatment of com plications, and attempts to alleviate any causative emotional or physical stress. The progn osis, in small studies, is good in those individuals surviving the acute episode, with reco very of normal left ventricular function within 4 \200\2236 weeks. Peripartum cardiomyopathy Peripartum cardiomyopathy is a form of DCM. Symptoms occur in the third trimester and the diagnosis is made in the peripartal period. Approximately half wil l show complete or near-complete resolution over the \201 rst 6 months post-partum. Of th e remainder, some will continue to deteriorate and result in death or transplantation, whil e others continue to experience chronic CCF. Its diagnosis is established by excluding othe r causes of DCM, and the cause is unknown (also see b Chapter 15, Heart disease in pregnanc y, p. 673). 448 CHAPTER 8 Heart muscle diseases Cardiomyopathy in systemic disease Systemic lupus erythematosus (SLE) can cause heart disea se in many ways. Approximately 10 % of patients with SLE have evidence of myocar- ditis. Pa tients with associated antiphospholipid antibody syndrome have increased risk of valvular a bnormalities and DCM due to thrombotic occlusions of the microcirculation without vasculiti s. They also have increased atherogenesis. Pulmonary hypertension due to pulmonary vasculitis is an uncommon cause of cardiomyopathy i n patients with rheumatoid arthritis (see also b p. 618). Nutritional cardiomyopathy Thiamine is an important coenzyme in the hexose monophophate shu nt. Infants who are breast-fed in areas with diets de \201 cient in thiamine develop mainl y right ventricular failure between 1 and 4 months of age. Prompt correction of the vitamin de \201 ciency results in rapid improvement in the cardiac abnormalities without long-ter m consequence. Protein \200\223calorie malnutrition (marasmus, kwashiorkor) results in thinning and atroph y of muscle \201 bres and ultimately DCM. Careful treatment may result in marked improvem ent over several months, provided the patient survives the initial period (see also b Chapt er 14, Cardiovascular disease in less-developed countries, p. 653). Sensitivity or toxic reactions A large number of non-infectious agents can damage the myoca rdium. The damage can be acute, with evidence of an in \202 ammatory reaction, or there ma y be no in \202 ammation and necrosis as in hypersensitivity reac- tions. Other agents lea d to chronic changes, with progressive \201 brosis and an ultimate picture similar to DCM . Numerous chemical and industrial agents, radiation, and excessive heat can all cause myoc ardial damage. Neuromuscular disorders Cardiac involvement in Friedreich \200\231s ataxia is relatively co mmon, although usually asymptomatic. Friedreich \200\231s ataxia is an autosomal recessive trait with loss of function of the frataxin gene. Clinical manifestations include progressi ve ataxia of all four limbs, diabetes mellitus, and cardiac disease. It is most commonly as sociated with HCM on electrocardiography and echocardiography but is distinct from the gene tic variety by lack of myo \201 - brillar disarray on histology. Serious ventricular arrhy thmias and complica- tions related to cardiomyopathy are the most frequent cause of morbidi ty. Rarely, it is associated with DCM. This page intentionally left blank 450 CHAPTER 8 Heart muscle diseases Muscular dystrophies Muscular dystrophies (MDs) are a group of hereditary muscle disorders characterized by progressive skeletal muscle weakness. Over 100 condi- tions are associated with a muscular dystrophy, although the best charac- terized include Duchenne \200\231s an d Becker \200\231s, limb-girdle, facioscapulohumeral, myotonic, oculo-pharyngeal, distal, a nd Emery \200\223Dreifuss. A signi \201 cant number of types of muscular dystrophy are multisystem disorders, with ef fects on smooth muscle and cardiac muscle as well as skeletal muscle. The MDs can be inheri ted with an autosomal dominant, autosomal recessive, or X-linked pattern of inheritance. Th ey affect the myocardium and conduction tissue predominantly, causing varying degrees of he art block, tachyarrhythmias, and heart failure.