Topic 4.1. Overview of the heart effects of Friedreich ataxia

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

Topic Contents

4.1 Overview of the heart effects of Friedreich ataxia
4.1.1 Cardiac effects of Friedreich ataxia
4.1.2 Literature review of the structural and functional cardiac effects of Friedreich ataxia
4.1.3 Arrhythmias in Friedreich ataxia
4.1.4 Heart failure in Friedreich ataxia

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These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
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4.1 Overview of the heart effects of Friedreich ataxia

Roger E. Peverill, Kimberly Y. Lin, Francoise Pousset, Aarti Patel and Konstantinos Savvatis

4.1.1 Cardiac effects of Friedreich ataxia

Friedreich ataxia (FRDA) is commonly accompanied by abnormalities of both cardiac structure and function, and cardiac disease is the main cause of death (1). Individuals with FRDA can experience arrhythmias, most commonly of atrial origin, and symptoms include palpitations, dizziness, dyspnea and chest discomfort. Individuals with FRDA can also develop heart failure (HF) with its associated symptoms, and the combination of HF and arrhythmia conveys a poorer prognosis (1). Deficiency of the protein frataxin is the fundamental abnormality which leads to expression of the cardiac phenotype of FRDA (2). As a result of mutations in both alleles of the FXN gene, most commonly due to a GAA repeat expansion, and the decreased levels of frataxin there is impaired assembly of iron–sulphur clusters that are critical to key enzyme functions in mitochondria and throughout the cell.

There has been no consistent definition or terminology used in published studies to describe the features of the cardiac involvement in FRDA (3-14), and this lack of consistency has made interpretation of, and comparison between, studies difficult. The most common description of the cardiac phenotype in FRDA has been “hypertrophic cardiomyopathy”, yet there are a number of reasons to question whether this is the best terminology in FRDA. One concern is that this can lead to confusion with the autosomal dominant conditions that are also termed hypertrophic cardiomyopathies. This is an important distinction as there are fundamental molecular and clinical differences between FRDA and these autosomal dominant conditions, which have implications for both outcomes and treatment. First, the mechanism which underlies the cardiac changes in FRDA is based on frataxin deficiency in the mitochondria, whereas in the autosomal dominant hypertrophic cardiomyopathies it is sarcomere abnormalities and myocardial fiber disarray (15). Second, the pattern of hypertrophy in FRDA is generally concentric, asymmetric septal involvement is not common, and there is rarely any outflow tract obstruction (6, 9). This is unlike the pattern seen in the autosomal dominant hypertrophic cardiomyopathies in which asymmetric septal hypertrophy is more frequent, and are more commonly associated with a resting or inducible dynamic outflow tract gradient (15). Furthermore, the term hypertrophic implies an increase in left ventricular mass index (LVMI), whereas the most common pattern of LV geometry in FRDA is an increase in relative wall thickness (RWT) (9, 16). Even in the absence of any definite increase in RWT or LVMI, abnormalities on the electrocardiogram can occur (17), suggesting that there is at least some degree of myocardial abnormality in the majority of FRDA individuals. Individuals with FRDA can also have a dilated left ventricle with reduced LV ejection fraction (LVEF), that is, a phenotype consistent with a dilated cardiomyopathy. LV dilatation and reduced LVEF are generally not seen in FRDA at first presentation (9, 10, 18), indicating that there is evolution of this cardiac phenotype later in the disease process (18, 19). On the basis of the issues discussed above, the heterogeneous and unique collection of cardiac abnormalities seen in FRDA might be better described as “FRDA cardiomyopathy”.

To determine the direct effects of frataxin deficiency on the heart in FRDA, possible cardiac effects from coexistent conditions which are more common in FRDA as well as other common unrelated conditions need to be considered. Diabetes mellitus occurs in approximately 10% of individuals with FRDA (20, 21) and is recognized to have effects on cardiac structure and function (22-24). Sleep apnea is also recognized to have effects on the heart (25-27), is more common in FRDA than in the non-FRDA population, and has been reported to occur in young adults with FRDA even in the absence of morbid obesity (28). Hypertension and ischemic heart disease both become more common with age in FRDA, as they do in the non-FRDA population. Hypertension can lead to, and in FRDA presumably contribute to, similar LV geometric patterns (concentric remodeling and concentric hypertrophy) as seen early in the course of FRDA in the absence of hypertension (29). On the other hand, ischemic heart disease can lead to regional and possibly global hypokinesis of the left ventricle and these cardiac abnormalities can also occur late in the disease course in FRDA. Other acquired heart disease is not common in the FRDA population but should also be kept in mind. For example, myocarditis is not common but can occur at any age. Because of the underlying FRDA related cardiac abnormality, individuals with FRDA could be more susceptible to the effects of myocarditis.

4.1.2 Literature review of the structural and functional cardiac effects of Friedreich ataxia

The literature in FRDA can be loosely divided into studies before and after 1996, the year when the mutation in the FXN gene was first described. Most studies published after 1996 have included subjects with genetic confirmation of the diagnosis of FRDA. The early studies still provide useful information about the cardiac phenotype in FRDA, but due to the lack of genetic confirmation it is very likely that these studies also included some subjects without FRDA (30, 31). Furthermore, individuals who were homozygous for GAA expansions in the FXN gene but with atypical neurological presentations would not have been included in studies prior to 1996 (32, 33). In addition, point mutations in the FXN gene are now recognized to occur in more than 2% of people with FRDA (34-36), and it likely that some of the individuals in the early studies will have had such point mutations. There may be systematic differences in the cardiac phenotype of individuals with FRDA due to a point mutation compared to homozygotes for GAA expansions.

Cardiac involvement in FRDA has been assessed by a number of non-invasive techniques, including electrocardiography (EKG), echocardiography and cardiac magnetic resonance (CMR). There is only limited data regarding the natural history of cardiac disease in FRDA both before and after 1996. Part of this limitation is because cardiac disease is not usually diagnosed until after FRDA diagnosis, which is dependent on an individual presenting with neurological symptoms. There is limited pathological and histological data from post mortems and almost no cardiac biopsy data or catheterization-based data from living people with FRDA.

Electrocardiographic findings

Most individuals with FRDA have evidence of cardiac involvement as determined by the presence of an abnormal EKG (3, 17, 37, 38). A recent study of 239 children and adults, 79% of whom had genetically confirmed FRDA, found EKG abnormalities in 90% (17). The most common findings were nonspecific ST-T wave changes (53%), right axis deviation (32%), left ventricular hypertrophy (19%), and right ventricular hypertrophy (17). Females and those with smaller GAA repeats in the shorter allele of FXN (GAA1) were less likely to have EKG abnormalities. Longitudinal follow-up data is still required to determine whether an EKG can assist in early diagnosis of FRDA-associated cardiomyopathy, aid in the assessment of prognosis, or help to define the underlying pathophysiological processes.

Echocardiography and cardiac magnetic resonance imaging

Structural abnormalities frequently described in echocardiographic studies in FRDA are increase in left ventricular wall thickness (12, 13, 16, 39-42) and increase in left ventricular mass index (LVMI) (13, 16, 42, 43). However, the most common abnormality in FRDA is an increase in RWT, with only a proportion of subjects with increased RWT also having an increase in LVMI (9, 16, 39, 42). RWT is a simple and useful measure for the assessment of LV structural change in FRDA, although it is greater in males than females sex (44-46) and different thresholds in adults and children are appropriate for the diagnosis of an abnormal RWT (9, 45). While an increase in RWT without accompanying increase in LVMI (concentric remodeling pattern) could just be an earlier stage of the hypertrophic process than an increase in both RWT and LVMI (concentric hypertrophy pattern), there are alternative explanations for the relative lack of increase in LVMI in FRDA. One important component of the relative lack of increase in LVMI compared to RWT is that the LV remodeling in FRDA is not just reflected in an increase in wall thickness but also by a decrease in LV end-diastolic cavity size (9, 16, 39, 40, 43), the latter change necessarily associated with a lower LVMI than if the cavity size had not decreased. Another important observation from several cross-sectional studies in adults is that LVMI is inversely correlated with age (9, 41, 43), and therefore additional possible explanations for the relative lack of LVMI increases in FRDA could be aging-related LV remodeling, premature mortality or morbidity in individuals with FRDA with a higher LVMI, or a combination of both.

A definition of hypertrophy based on Henry’s nomograms has been used in a number of studies in FRDA (10, 12, 13, 47). However, a diagnosis of the absence of cardiomyopathy based on a normal LV wall thickness using Henry’s nomograms not only has the intrinsic limitation of lacking consideration of the sex effects on LV mass index in healthy people and individuals with FRDA (9), but it has also been demonstrated in previous FRDA studies to fail in identifying an increase in RWT in a proportion of individuals. Thus, a RWT of 0.42±0.08 was found in a subgroup of 64/205 children and adults who were classified to be free of cardiomyopathy, indicating that a substantial proportion of the individuals in this subgroup would have had an abnormal RWT (i.e. 0.43 or above in adults) (12). Similarly, in another study in a subgroup of 56/133 individuals who were classified as not having LV hypertrophy, the RWT was 0.43±0.07 (10).

An additional accompaniment of the reduced LV end-diastolic volume in FRDA, in the absence of an increase in, rather than just preservation of LVEF, must be a reduction in stroke volume (39, 43). This would be predicted to lead to a decrease in the cardiac output even in the face of preserved LVEF. However, the cardiac output is at least partly preserved in FRDA despite the lower stroke volume because individuals with FRDA have a higher heart rate compared to controls (16, 39).

There is only limited data on the effects of FRDA on Doppler measures of left ventricular relaxation and filling, including transmitral E and A, their ratio (E/A) and isovolumic relaxation time (IVRT), in comparison with age- and sex-matched controls. Furthermore, the results have not been consistent (5, 16, 39, 40, 48). An issue not considered in previous studies is that E is negatively correlated with heart rate, A is positively correlated with heart rate, and therefore the E/A ratio is inversely correlated with heart rate (49). The higher heart rate in individuals with FRDA should have been, but was generally not, adjusted for in comparisons with controls.

While LVEF is generally preserved in FRDA, some of the markers used to assess LV systolic function are reduced. Both systolic (and early diastolic) myocardial velocity gradients of left ventricular short axis function (reflecting radial systolic and early diastolic strain) were reduced compared to controls in a group of individuals with FRDA who were free of cardiac symptoms (40). Tissue Doppler measurements of longitudinal function in individuals with FRDA with preserved LVEF showed reduced peak velocities of both systolic and early diastolic left ventricular motion when compared to controls (16). Global longitudinal strain and peak systolic twist are also reduced in individuals with FRDA with normal LVEF and LVMI, but RWT is increased (39).

Left atrial (LA) dilatation is a sign of chronic elevation of left atrial pressure (50) and left atrial size is thus of considerable interest in FRDA as it might also be expected to increase in the setting of a small thick left ventricle. However, while there is limited information about left atrial size in FRDA, available data suggests that it is not routinely increased in individuals with increased RWT and normal ejection fraction (16, 39). In turn, this raises the possibility that the ratio of E/e`, which is elevated in FRDA (39), and increases with LA pressure in other cardiac conditions (50), may not be an accurate reflection of left atrial pressure in FRDA.

A number of studies have reported an association between the number of GAA repeats in the GAA1 allele and LV structural changes in FRDA, but the findings have not been consistent. GAA1 has been noted to be higher in people with a “cardiomyopathy” (4, 51) and other reports include positive correlations of GAA1 with wall thickness (31, 47, 52), RWT (11), LV mass (31, 43), LVMI (12, 47) and an inverse correlation of GAA1 with LV end-diastolic dimension (53). On the other hand, there have also been recent moderate-sized studies which have not replicated previous findings (13, 42). Potential explanations for these differences in results between studies include differences in the cohort characteristics and the limited size of individual cohorts. There has also been heterogeneity between studies in the statistical methods, for example, whether adjustments were made for potential confounding factors such as sex, age or body size. Neither is it clear that an adjustment for age is possible when children and adults are included in the same study, due to the complex nature of the differences between children and adults with FRDA (45, 54, 55). Furthermore, any FRDA cohort will necessarily be missing those individuals who have died prematurely from heart disease. As mortality is more likely to affect adults than children with FRDA (1), and occurs earliest in those with the most severe cardiac involvement (1), absence of individuals due to early mortality is likely to confound any analysis which includes adults and children together.

To address some of these issues a recent study investigated the correlation of GAA1 with LV echocardiographic measures separately in 68 children and 148 adults with FRDA (9). Increases in RWT and age-normalized RWT were the most frequent LV structural abnormalities, sex and body size were important determinants of most other LV structural variables in both children and adults, and GAA1 was associated with a smaller left ventricle and increased LV wall thickness in adults, but not associated with either LV size or wall thickness in children.

With regard to LV function, GAA1 has not generally been correlated with LVEF or LV fractional shortening, but has been reported to be inversely correlated with both systolic and early diastolic radial strain (40). GAA1 has also been reported to be an inverse correlate of right ventricular s` and e`, whereas a negative correlation of the number of GAA repeats in the longer allele (GAA2) with LV regional s` (anterior and lateral walls) has also been reported (56). In other studies which have reported associations of GAA2 with cardiac variables, it has not been clear whether this association was independent of a positive correlation of GAA2 with GAA1 within the same study (10).

Using CMR spectroscopy, the cardiac phosphocreatine to ATP ratio was lower in individuals with FRDA with and without hypertrophy, implying that cardiac metabolic dysfunction in FRDA precedes hypertrophy and may play a role in its development (57, 58). In another CMR study, myocardial perfusion reserve index quantification revealed significantly lower endocardial-to-epicardial perfusion reserve in subjects with FRDA versus controls, whereas there was no difference in myocardial iron between the two groups using the CMR technique of T2* (11). The former finding suggests a greater potential for subendocardial ischemia in FRDA in situations where cardiac perfusion reserve is under stress (e.g., atrial fibrillation with a rapid ventricular response). The latter finding implies that the intra-mitochondrial iron particles in FRDA are relatively isolated compared with the large iron aggregates seen in transfusion-associated myocardial iron overload, making CMR measurement of iron content in the FRDA heart uninformative for guiding therapeutic interventions.

CMR has also been used to determine the presence of LV focal fibrosis using late gadolinium enhancement (LGE), and diffuse myocardial fibrosis using T1 mapping techniques. The proportion of people with LGE in studies in FRDA has been variable. Raman et al (11) reported the presence of LGE in 58% of adult subjects with a normal LVEF (age range 18-57 years). Weidemann et al (19) reported the presence of LGE in 66% of 32 subjects (age 33±13 years; number of children in the study not reported), 25% of whom had a LVEF <55%. All those with a reduced LVEF were positive for LGE, whereas 13/25 (52%) with a normal LVEF had LGE. That children with FRDA can develop LGE was also reported in 3 children with a normal LVEF by Mavrogeni et al (59). In contrast, Takazaki et al (60) reported only 15% LGE positivity in 27 subjects with a normal LVEF (age = 28±10 years). There is currently no explanation for the substantial variation in LGE positivity in the different studies. T1 mapping data has only been reported in one study in FRDA, and suggested the presence of diffuse myocardial fibrosis (60). However, there were a number of methodologic issues with this study, including the use of different CMR machines for the FRDA and control groups, and the lack of age matching.

Natural history studies and predictors of reduced left ventricular ejection fraction

Until recently there have only been limited natural history data regarding the cardiac manifestations of FRDA, with most studies performed before the identification of the FXN gene (61-63). However, several studies have been published since 1997. In a prospective echocardiographic study with a median 5-year follow-up of individuals with FRDA, most of whom (61/70) were taking idebenone, there were decreases in posterior wall thickness, LVMI and ejection fraction (12). In a retrospective analysis of LV structural and functional changes during follow-up in 23 children with FRDA there was a slow non-linear decline in LVEF, with more rapid decreases as age increased, but with maintenance of LVEF within the normal range until the age of 22 years (64). Of the 12 children with reduced LVEF and follow-up echocardiograms, 10 showed improvement to the normal LVEF range on at least one echocardiogram, and 5 remained normal through the last study. However, this cannot be concluded to reflect spontaneous improvement as LVEF is dependent on and therefore will vary with loading conditions. Furthermore, echocardiographic assessment of LVEF is recognized to have substantial variability. In a longitudinal study of 138 individuals with FRDA, with a mean follow-up of 10.5 (range 0.6-23.0) years, there was a decrease in LVEF accompanied by an increase in LV size and a reduction in LV wall thickness (10). In a study of 115 adults with FRDA and a baseline LVEF of 65±7%, LV systolic dysfunction with a LVEF<50 % occurred in 12 individuals after a mean follow-up of 13±6 years (18). Individuals with a GAA1 >800 were classified as high risk in this study.

Mortality studies and predictors of mortality

A number of mortality studies predate 1996. A study of 82 fatal cases of FRDA showed that over half died of HF while nearly three-quarters had evidence of cardiac dysfunction during life (38). In a population-based study of survival in FRDA in northwestern Italy, 58 individuals were identified and followed to death or to December 31, 1984 (whichever came first) to determine the patterns of survival (65). The 10-, 20-, and 30-year survival rates were 96%, 80%, and 61%, respectively. Survival for males was poorer than for females even after adjustment for expected survival. Somewhat unexpectedly, age of onset of FRDA was not a significant prognostic factor. In a follow-up study of 61 individuals with FRDA, cardiac failure was evident in 5% and was the most common cause of death (61).

There have also been mortality studies after 1996. A retrospective study of individuals with FRDA was performed to determine cause of death followed by a case-control analysis comparing characteristics of deceased individuals with living, age- and sex-matched FRDA controls (1). Causes of death were cardiac dysfunction (59%), probable cardiac dysfunction (3.3%), a non-cardiac cause (27.9%) or unknown (9.8%). Compared to non-cardiac deaths, cardiac deaths occurred earlier in the disease course (median 29 vs. 17 years duration of FRDA). Congestive HF and arrhythmia were common causes of cardiac-related death. Compared to living matched FRDA controls, deceased individuals had longer GAA1, higher rates of an arrhythmia and reduced LVEF. The presence of the diagnosis of a “hypertrophic cardiomyopathy” did not differ between the deceased and living groups.

In a study of 138 adults with FRDA with a mean follow-up of 10 years, the 10-year survival rate was 88.5% (10). In 80% (12/15) of individuals with FRDA who died during the study period, death was due to a cardiac cause, and predictors of mortality were a longer GAA1, a reduced LVEF and an increased LVMI. A longitudinal study from the same group, of 140 individuals with FRDA, showed LVEF to be an independent predictor of mortality, whereas global longitudinal strain (measured from apical 4 chamber view only) was not an independent predictor of mortality after adjusting for LVEF (66).

Post mortem and biopsy studies

There have been a number of post mortem studies in FRDA (3, 67-71), but only a few of these postdated genetic confirmation techniques (69-71). In a post mortem study of 16 hearts from people with FRDA, including three complete hearts (67), all hearts showed extensive interstitial fibrosis with considerable focal degeneration of muscle fibers. One heart showed extensive active muscle necrosis. Antemortem cardiac thrombus and thromboembolism were common findings. The main coronary arteries showed no gross disease. In a clinical study of 75 individuals with FRDA in which two died, post mortem revealed a minimally dilated but flabby left ventricle in both (3). Post mortem cardiac findings from 3 individuals with FRDA who died of congestive HF and had atrial arrhythmias showed pleomorphic nuclei and focal fibrosis and degeneration throughout each heart, including in the conduction system (68). There were distinctive abnormalities of both large and small coronary arteries, and focal degeneration of nerves and ganglia.

In 18 post mortem specimens of individuals with genetically confirmed FRDA, histological sections revealed abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue (69). Scattered muscle fibers displayed perinuclear collections of minute iron-positive granules in rows between myofibrils, but total iron in the left ventricular wall of individuals with FRDA was not significantly higher than normal. In a further study from the same group, regions of significantly increased iron were irregularly distributed throughout the working myocardium (71). These observations are at odds with the concept of selective iron toxicity only in cardiac mitochondria, and the role of iron in mediating the cardiomyopathy of FRDA remains unclear.

There is minimal data available from cardiac biopsy in FRDA (69) and thus little information about the cardiac histology in individuals with early stages of the cardiac disease process. Based on post mortem data from individuals with more advanced cardiac disease, it might be assumed that there is a combination of myocyte loss, myocyte hypertrophy and interstitial fibrosis in the left ventricular wall of an individual with FRDA and increased RWT or LVMI. However, the age at which these individual components develop, whether they occur simultaneously or in some sequence, and the temporal progression of these changes is unknown.

Late onset Friedreich ataxia

Late onset FRDA, defined as the onset of neurologic symptoms after age 25, is generally found in people with very short GAA1, and may not be, or at least is less likely to be, associated with cardiac abnormalities (7, 72-74). Whether this means that cardiac screening is not necessary in late onset FRDA is not yet clear as there are only a small number of cases described in the literature. Until greater natural history data has accumulated, a conservative recommendation is to perform cardiac screening in all individuals with a diagnosis of FRDA.

4.1.3 Arrhythmias in Friedreich ataxia

Atrial tachyarrhythmias

Atrial tachyarrhythmias occur frequently in FRDA, particularly in the later stages of the course of cardiac disease, and cause morbidity, and may also contribute to mortality (1, 38). In a longitudinal study of 138 individuals with FRDA, 6 had a previous history of atrial fibrillation (AF) at baseline, and over 0.6 to 23 years of follow-up, supraventricular arrhythmias were reported to occur in 16.5%, although the type of supraventricular arrhythmia was not reported (10). Intermittent palpitations have also been described in FRDA and the cause of these has not always been determined (37). AF is the most common reported tachyarrhythmia and may be paroxysmal or persistent (12, 38), but atrial flutter also occurs (37, 75). The combination of palpitations and angina has been reported in young people with FRDA (38), and it is feasible that individuals with a very thick walled left ventricle and a strain pattern on the resting EKG could develop angina due to subendocardial ischemia in the setting of a tachycardia and the absence of epicardial coronary artery disease.

Tsou and colleagues reported that arrhythmias were present or associated in approximately 16% of the deaths in FRDA (1). Although arrhythmia was listed either as the cause of death, or at least of playing a significant role in the death, there was insufficient detail from the records to determine the type of arrhythmia. Thus, the nature of the relationship of atrial arrhythmias with mortality in FRDA remains unclear.

Ventricular arrhythmias and death

Ventricular tachycardia (VT) and ventricular fibrillation (VF) have rarely been described in FRDA and there are few reports of sudden unexpected death or syncope due to arrhythmia. Current evidence suggests that such events are not likely to be common in FRDA cardiomyopathy, particularly in the absence of LV dilatation and a reduction in ejection fraction. On the other hand, it cannot yet be concluded that these arrhythmias occur rarely in FRDA as natural history studies are lacking. Furthermore, a single episode of either type of ventricular arrhythmia could result in sudden death in FRDA and yet not be documented. There is a single case report of syncope due to a ventricular arrhythmia in an individual with FRDA which was managed with the insertion of an internal cardioverter-defibrillator (76). Cases of sudden death have been reported (70, 77, 78), but the cause of death has not been certain. Further information is required about the nature and frequency of ventricular arrhythmias in FRDA. There should be a low threshold for investigation with Holter monitoring and/or Loop monitoring in individuals with FRDA and palpitations, dizziness or syncope.

4.1.4 Heart failure in Friedreich ataxia

The symptoms of HF may be recognized late in FRDA because dyspnea and/or fatigue with exertion may be less prominent clinical features in an individual who is wheelchair bound. The spontaneous development of HF symptoms or signs in individuals with FRDA and normal ejection fraction is rare, even if there is a severe increase in RWT or LVMI. The presence of HF symptoms and signs therefore generally suggests the presence of a reduced LVEF. In a retrospective review, Tsou and colleagues (1) identified a history of HF in approximately 65% of people dying from FRDA.

Classification of heart failure in Friedreich ataxia

The New York Heart Association (NYHA) HF classification scheme is commonly used to assess the severity of functional limitations (ability to exercise) and there is a correlation of this classification with outcomes (Table 4.1) (79). However, the NYHA classification scheme has limitations for the assessment of individuals with neuromuscular disorders due to the inability of some individuals to perform exercise. NYHA Stage I is when there are no symptoms related to the heart even during exercise, such as climbing two flights of stairs. This stage may be easy to determine in a person newly diagnosed with FRDA, but becomes more difficult to assess as the neurologic features of FRDA advance and lead to limitations of mobility. Stages II and III are difficult to assess in FRDA because loss of ability to exercise is common in advanced neurologic disease. Thus, it could be difficult to tell if HF is advancing using this classification. Stage IV is easier to assess as cardiac symptoms with rest or minimal activity and particularly orthopnea and paroxysmal nocturnal dyspnea are more specific for cardiac disease.

Table 4.1 New York Heart Association stages of heart failure (79)

I No limitations with normal physical activity
II Slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitations, dyspnea or angina pectoris.
III Marked limitation of physical activity. Less than ordinary activity results in symptoms.
IV Unable to carry out any physical activity without discomfort. Symptoms are present at rest.

Kimberly Y. Lin, MD
Associate Professor, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Aarti Patel, MD
Associate Professor of Medicine, University of South Florida, Tampa, Florida, USA

Roger E. Peverill, MBBS, PhD
Cardiologist, MonashHeart, Monash Health, Clayton, Victoria, Australia

Francoise Pousset, MD
Sorbonne Université, Cardiology Department, AP-HP, Pitié-Salpêtrière University Hospital, Paris, France

Konstantinos Savvatis, MD, PhD
Consultant Cardiologist, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.