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phenotype.248,1005,1027–1029,1005,1027–1030,1030 Mitochondrial iron storage is the pathologic hallmark of the disease.1031

7.6.3.3 Clinical course, management, and risk stratification

Supraventricular arrhythmias, particularly AF, are commonly detected.1027 Despite the lack of long-term follow-up longitudinal studies, the risk of ventricular arrhythmias and SCD seems low compared with sarcomeric HCM.1027,1032,1033 The Mitochondrial Protection with Idebenone in Cardiac or Neurological Outcome (MICONOS) study group1034 has proposed a staging of cardiac involvement based on LVEF and end-diastolic wall thickness. The extent of TWI at ECG, LVEF, LV end-diastolic posterior wall thickness, fibrosis on CMR, and hs-TnT have been proposed as negative prognostic factors.1035

7.6.3.4 Management

No specific treatment is currently available for Friedreich ataxia. Treatment with idebenone, a coenzyme Q10 analogue, showed the potential to improve LV mass and cardiac outcomes in open-label studies;1036 nevertheless, four RCTs1037–1040 showed no significant benefit on cardiac or neurologic outcomes.

7.6.4 Glycogen storage disorders

7.6.4.1. Definition Glycogen storage disorders (GSDs) represent a heterogeneous group of metabolic diseases, including infantile-onset Pompe disease (GSD, type IIa), Danon disease (GSD, type IIb), and PRKAG2 disease.272

7.6.4.2 Diagnosis, clinical work-up, and differential diagnosis

Despite wide clinical heterogeneity, a presentation within the first few months of life, hypotonia, failure to thrive, generalized muscle weakness, and severe non-obstructive HCM with concentric pattern followed by hypokinetic end-stage cardiomyopathy, usually within the first year of life, are typical of GSD IIa.259,268,1041,1042 Short PR interval and increased ECG voltages may represent useful diagnostic clues for GSDs.1042,1043 PRKAG2 syndrome should be suspected in the setting of autosomal dominant transmission and association with conduction system disease including ventricular pre-excitation, sick sinus syndrome, AF, AV block, intraventricular conduction delays or sinoatrial blocks.1043–1047 An X-linked pattern of inheritance is typical of Danon disease (GSD IIb). Skeletal myopathy, in association with learning disability, retinal involvement and ventricular pre-excitation, has been detected in males affected by Danon disease, while the cardiac phenotype can be isolated in affected females.1048–1052

7.6.4.3 Clinical course, management, and risk stratification

In the absence of therapeutic intervention, Pompe disease has a poor prognosis, mainly due to end-stage heart failure.268,1041 Recently, data from a large multicentre European registry have shown that Danon disease runs a malignant phenotype, but there are insufficient data to identify candidate risk factors for sudden death.1049 Sudden cardiac death occurs in almost 10% of patients with PRKAG2 syndrome, mainly as a consequence of advanced AV block, supraventricular tachycardia degenerated to VF, or massive hypertrophy.1044,1053,1054

7.6.4.4 Management

Enzyme replacement therapy is recommended in patients with GSD IIa.269,274,275,1055,1056 To date, there are no approved aetiological therapies for PRKAG2 syndrome and Danon disease. Heart failure therapy, antiarrhythmic therapy, and indications for the implantation of devices are included in Section 6.10.

7.7 Amyloidosis

It is beyond the scope of this document to provide specific recommendations for the assessment and management of cardiac amyloidosis. Instead, the Task Force refers the reader to the 2021 position statement of the ESC Working Group on Myocardial and Pericardial Diseases on Diagnosis and Treatment of Cardiac Amyloidosis.375 This section highlights only the key diagnostic and management issues.

7.7.1 Definition

Cardiac amyloidosis is characterized by the extracellular deposition of misfolded proteins in the ventricular myocardium with the pathognomonic histological property of green birefringence when viewed under cross-polarized light after staining with Congo Red.375 Although once considered a rare disease, data obtained in the last decade suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes such as HFpEF, aortic stenosis, or unexplained LVH, particularly in the elderly.1057–1059 Although nine different types of cardiac amyloidosis have been described, most cases correspond to monoclonal immunoglobulin light chain amyloidosis (AL) or transthyretin amyloidosis (ATTR), either in its hereditary (ATTRv) or acquired (ATTRwt) form.375 The ATTRwt form, which is associated with ageing, is currently considered the most frequent form of cardiac amyloidosis worldwide.

7.7.2 Diagnosis, clinical work-up, and differential

diagnosis Cardiac amyloidosis should be suspected in patients with increased LV wall thickness in the presence of cardiac or extracardiac red flags and/or in specific clinical situations, as detailed in Figure 21, particularly in patients >65 years of age.375 Cardiac amyloidosis can be diagnosed using both invasive and noninvasive diagnostic criteria.375 Invasive diagnostic criteria apply to all forms of cardiac amyloidosis, whereas non-invasive criteria are accepted only for ATTR. Invasive criteria include demonstration of amyloid fibrils within cardiac tissue or, alternatively, demonstration of amyloid deposits in an extracardiac biopsy accompanied either by characteristic features of cardiac amyloidosis on echocardiography or CMR.375 Non-invasive criteria include typical echocardiographic/CMR findings combined with planar and single-photon emission computed tomography (SPECT) grade 2 or 3 myocardial radiotracer uptake in 99mtechnetium-pyrophosphate (99mTc-PYP) or 3,3-diphosphono-1,2propanodicarboxylic acid (DPD) or hydroxymethylene diphosphonate (HMDP) scintigraphy and exclusion of a clonal dyscrasia by all the following tests: serum free light chain assay, serum and urine protein electrophoresis with immunofixation.168 Tomographic scintigraphy should be considered in order to reduce the number of misclassifications.1060 False negative scans may rarely occur in certain ATTRv genotypes; false positives may be due to AL, recent myocardial infarction, or long-term chloroquine use.370 Therefore, planar and SPECT scintigraphy coupled with assessment for monoclonal proteins followed by CMR and/or cardiac/extracardiac biopsy if necessary allows appropriate diagnosis in patients with suggestive signs/symptoms, as described in Figure 22.375 However, the DPD/PYP/HMDP scan cannot distinguish between wildtype and mutated ATTR, and therefore TTR genetic testing is required. Of note, TTR genetic testing is recommended in all transthyretin amyloid cardiomyopathy (ATTR-CM) patients regardless of age, as 5% of

ESC Guidelines                                                                                                                                                                                          3579

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