P1832 T1 mapping and echo-global longitudinal strain are early markers of cardiac involvement in patients with fabry disease

Abstract OnBehalf Constantin Gatterer Introduction Fabry disease (FD) is one of the most common lysosomal storage diseases caused by deficiency of Alpha-Galactosidase A and accumulation of glycosphingolipids in all cells containing lysosomes. Cardiac involvement is characterized by left ventricular hypertrophy, conduction abnormalities and myocardial fibrosis with consecutive cardiomyopathy in late stages. Purpose As the detection of early signs of cardiac involvement is crucial for the initiation of enzyme replacement therapy (ERT) or Chaperon therapy, we intended to find early imaging markers. Methods Cardiac MRI (CMR) including Late Gadolinium Enhancement (LGE), representing fibrosis, and T1-mapping as well as echocardiography with measurement of global longitudinal strain (GLS) were done as part of the regular check-ups for patients with FD. Results The study cohort of 30 FD patients (20-69 years, 53% women) in different stages of disease showed low GLS values already at the time of baseline echocardiography (mean: -17,22%), correlating with the amount of LGE (r = 0,73; p = 0,003) and ejection fraction measured by CMR (CMR-EF; r=-0,74; p = 0,002). After an average follow-up of 39 months (STD 18), GLS values were significantly declined (-15,51 %; p = 0,009) and correlated with T1 times (r = 0,7; p = 0,04), while LGE and CMR-EF did not significantly change compared to baseline. Baseline T1 times correlated negatively with the reduction of GLS (r=-0,7; p = 0,003), while LGE and CMR-EF showed no correlation with the course of GLS. ERT appeared to have no influence on the extend of GLS reduction. Conclusion Low native CMR T1 times, indicating sphingolipid accumulation in the myocardium, seem to represent the beginning of cardiac involvement in FD and might predict the course of GLS. GLS is a sensitive parameter for early detection of cardiac manifestation and disease progression, while LGE and CMR-EF could not recognize slight deterioration of left ventricular function.

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Progression of electrocardiogram changes in an untreated fabry disease: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytab045 ◽

2021 ◽

Vol 5 (2) ◽

Author(s):

Isabel Mattig ◽

Sima Canaan-Kühl ◽

Christoph Tillmanns ◽

Fabian Knebel

Keyword(s):

Fabry Disease ◽

Global Longitudinal Strain ◽

Left Ventricular ◽

P Wave ◽

Multidisciplinary Teams ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Organ Manifestations ◽

Over Time ◽

T Waves

Abstract Background Fabry disease (FD) is a rare lysosomal storage disorder with multiorgan manifestation and associated with an increased morbidity and mortality. Fabry cardiomyopathy includes left ventricular ‘hypertrophy’ (LVH), cardiac arrhythmias, and heart failure. We report a case of an untreated FD with characteristic findings in electrocardiogram (ECG) over a follow-up period of 10 years. Case summary A 53-year-old man with FD presented to our outpatient department. He suffered from symptomatic ventricular extrasystoles. Echocardiography detected LVH and reduced global longitudinal strain. Twelve years ago, first examination was conducted due to ventricular arrhythmias. Electrocardiogram showed a short PQ minus P-wave (PendQ) interval and negative T-waves. Over time, the number of leads with negative T-waves increased. Moreover, the echocardiography revealed a thickened left ventricular wall. Without any further examinations at that time, the patient was treated for arterial hypertension with proteinuria. Ten years after first symptoms appeared, FD was diagnosed utilizing cardiac magnetic resonance imaging and genetic tests. Hence, enzyme replacement therapy was initiated. Discussion The ECG is a fast diagnostic method and it may — even without additional organ manifestations — provide preliminary suspicion of FD. In particular, as shown in our case, a short PendQ and QT interval indicate FD. Over time, disease progression can be detected through ECG changes. T-waves correlate with an increasing LVH and a reduction in longitudinal function in echocardiographic examinations. Unexplained LVH must be followed by differential diagnosis. In case of confirmed FD, patients should be treated by multidisciplinary teams in experienced centres.

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Sex difference in left ventricular global longitudinal strain in patients with systemic sclerosis: association with outcomes

European Heart Journal ◽

10.1093/ehjci/ehaa946.3165 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

T Gegenava ◽

N Leeuwen ◽

S Wijngaarden ◽

J Vries-Bouwstra ◽

D Cassani ◽

...

Keyword(s):

Systemic Sclerosis ◽

Longitudinal Strain ◽

Cardiac Involvement ◽

Global Longitudinal Strain ◽

Left Ventricular ◽

Chi Square ◽

Female Patients ◽

All Cause Mortality ◽

Echocardiographic Parameters ◽

Males And Females

Abstract Background Cardiac involvement is an important cause of hospitalization and mortality in patients with systemic sclerosis (SSc). Advanced echocardiographic measures such as global longitudinal strain (GLS) have already demonstrated to help identifying cardiac involvement and improve risk-stratification in these patients. However, possible sex differences in echocardiographic parameters including GLS have not been explored so far. Purpose To compare standard and advanced (GLS) echocardiographic parameters between male and female patients with SSc and evaluate their association with cardiovascular outcomes. Methods A total of 408 patients (345 females, 54±14 years old and 63 males 51±13 years old) were included in the study. The study endpoint was all-cause mortality combined with hospitalisations for heart failure, myocardial infarction, coronary interventions, device implantations, arrhythmias, cerebral infarction and peripheral ischemic disease. Results Males and females were comparable in terms of cardiovascular risk-factors and comorbidities but showed differences in terms of disease characteristics: greater modified rodnan skin score and higher creatine phosphokinase was observed in males as compared to females, although high NT-proBNP and deteriorated glomerular filtration rate was more prevalent in females. By standard echocardiography, male SSc patients were characterised by greater left ventricular (LV) volumes, but no difference was observed in LV ejection fraction. By advanced echocardiographic analysis, LV GLS was more preserved in female patients (−21% (IQR: −22% to −20%) as compared to males (−20% (IQR −21% to −19%), p<0.001. After median follow-up of 39 months (IQR: 22–66), the combined endpoint occurred in 84 patients, males were affected significantly more frequently as compared to females (20 (32%) vs. 64 (19%), p=0.017). Kaplan-Meier survival analysis showed that impaired LV GLS (based on median value −20%) was associated with higher cumulative rates of all-cause mortality both in males and females with SSc (females: Chi-Square = 80.307 Log Rank <0.001; males: Chi-Square = 4.493 Log Rank = 0.034) (Fig. 1). In univariate cox regression analyses, LV GLS was also significantly associated with the endpoint both in males and females (in males HR: 1.291, 95% CI: 1.033–1.612, p=0.025, in females HR: 1.386, 95% CI: 1.290–1.491, p<0.001). Conclusions Our study shows that among patients with SSc, LV GLS is more impaired in males as compared to females but in both groups is associated with higher prevalence of death and cardiovascular hospitalization. Funding Acknowledgement Type of funding source: None

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Rare presentation of Fabry disease as ‘burnt-out’ hypertrophic cardiomyopathy

BMJ Case Reports ◽

10.1136/bcr-2021-243604 ◽

2021 ◽

Vol 14 (9) ◽

pp. e243604

Author(s):

Sam Williams ◽

Ahmed El-Medany ◽

Angus Nightingale ◽

Yasmin Ismail

Keyword(s):

Heart Failure ◽

Hypertrophic Cardiomyopathy ◽

Fabry Disease ◽

Left Ventricular ◽

Diagnostic Tools ◽

Lysosomal Storage ◽

Rare Presentation ◽

Enzyme Replacement ◽

End Stage Heart Failure ◽

End Stage

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow-up, before presenting with end-stage heart failure. This was initially suspected as dilated cardiomyopathy and then ‘burnt-out phase’ of HCM but subsequently the underlying diagnosis was Fabry disease. Fabry disease is an uncommon lysosomal-storage disease due to reduced or absent activity of the alpha-galactosidase A enzyme. Cardiac involvement most frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabry can progress to a ‘burnt out’ phase, whereby initial hypertrophy undergoes eccentric remodelling to a dilated, severely impaired left ventricle.

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P340Inflammatory cardiomyopathy in Fabry disease

European Heart Journal ◽

10.1093/eurheartj/ehz747.0174 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

J A Bicho Augusto ◽

S Nordin ◽

R Kozor ◽

R Vijapurapu ◽

K Knott ◽

...

Keyword(s):

Fabry Disease ◽

T1 Mapping ◽

Troponin T ◽

T2 Mapping ◽

International Study ◽

High Sensitivity ◽

Left Ventricular ◽

Strong Positive Correlation ◽

Lysosomal Storage ◽

2D Strain

Abstract Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in α-galactosidase A. Cardiovascular magnetic resonance (CMR) has helped unveil the pathogenesis of Fabry cardiomyopathy: sphingolipid storage (low T1 mapping values), left ventricular hypertrophy (LVH) and myocardial fibrosis with late gadolinium enhancement (LGE) characteristically present in the basal inferolateral (BIFL) wall. Recent evidence has suggested that the LGE may be inflammation and oedema as part of this pathogenic process. Purpose To assess the presence of inflammation in patients with FD using T2 mapping (for oedema/inflammation) supported by blood troponin levels (showing myocyte death and by inference inflammation). Methods A multi-centre international study in gene positive FD patients using CMR and blood biomarkers. All participants underwent CMR at 1.5 T. Native T1 and T2 mapping were performed. The T1 mapping sequence was MOLLI with sampling scheme in seconds. LGE used a phase sensitive inversion recovery sequence. Global longitudinal 2D strain (GLS) values were obtained using feature tracking analysis. Blood high-sensitivity troponin T (hsTnT) was measured on the same day. Results 100 FD patients (age 43.8±1.3 years, 42% male) were included. 45% had LVH, 35% LGE. Low T1 mapping (normal <943ms) was found in 49% and 33% had high hsTnT values (normal <15ng/L). Mean T2 mapping values were 52.6±0.6ms in the BIFL wall and 49.5±0.3ms in the remote myocardium/septum (p<0.001, normal <53ms). T2 values in the BIFL wall were significantly higher among patients with LGE (58.2±6.1ms vs 49.2±3.1ms, p<0.001, Figure 1). In a per-segment analysis of 1600 segments, higher T2 values correlated positively with percentage of LGE per segment (r=0,262, p<0.001), T1 values (r=0,205, p<0.001), maximum wall thickness (r=0,253, p<0.001) and GLS values (r=0,212, p<0.001). HsTnT values were higher among patients with LGE (median of 31 vs 3ng/L in patients without LGE, p<0.001). There was a strong positive correlation between T2 values in the BIFL wall and ln(hsTnT) (r=0.776, p<0.001, Figure 2). The strongest predictor of increased hsTnT in multivariate analysis (age, sex, LVH, septum T1, T2 in the BIFL, GLS, LGE) was T2 in the BIFL wall (β=0.4, p=0.001). Conclusions Cardiac involvement in FD goes beyond storage (low T1 values). When LGE is present, this is almost always associated with a high T2 and troponin elevation supporting FD as a chronic inflammatory cardiomyopathy. Initial reports of LGE being fibrosis are too simplistic – LGE in FD appears to have a significant chronic inflammation/oedema component.

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Migalastat Treatment in a Kidney-Transplanted Patient with Fabry Disease and N215S Mutation: The First Case Report

Pharmaceuticals ◽

10.3390/ph14121304 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1304

Author(s):

Valeria Di Stefano ◽

Marta Mancarella ◽

Antonia Camporeale ◽

Anna Regalia ◽

Marta Ferraresi ◽

...

Keyword(s):

Fabry Disease ◽

Cardiac Involvement ◽

Late Onset ◽

Left Ventricular ◽

Lysosomal Storage ◽

Fabry Patient ◽

First Case ◽

Gla Gene ◽

Stage Renal Disease ◽

End Stage

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat.

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T1 mapping in patients with Fabry disease predicts functional and morphological abnormalities in cardiac MRI

European Heart Journal ◽

10.1093/ehjci/ehaa946.0268 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Gatterer ◽

G Mundigler ◽

S Graf ◽

D Beitzke ◽

G Sunder-Plassmann

Keyword(s):

Fabry Disease ◽

Feature Tracking ◽

T1 Mapping ◽

Tissue Characterization ◽

Global Longitudinal Strain ◽

Myocardial Strain ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction

Abstract Introduction About 50% of Fabry disease (FD) patients develop cardiac manifestation, also known as Fabry cardiomyopathy. Beside echocardiography, cardiac magnetic resonance imaging (CMR) is included in the regular assessment of these patients, allowing non-invasive tissue characterization via T1 Mapping but also evaluation of morphological and functional characteristics. Purpose Myocardial strain measured by feature-tracking CMR has been previously shown to be a sensitive indicator of mechanical dysfunction in different diseases. We therefore evaluated changes of these parameters over the time, potentially reflecting disease progression in patients with FD. Furthermore, we also assessed the association of T1 mapping with follow-up changes of myocardial strain. Thus, our data may provide novel insights about cardiac changes in the natural course of the disease and cardiac effects of specific therapies. Methods We used post processing software for CMR to analyze baseline and follow-up cardiac involvement in a cohort of FD patients who were enrolled in the KarMA study, which examines cardiac changes over time. We measured left ventricular mass (LVM), left ventricular end-systolic and end-diastolic volume (LVEDV, LVESV), left ventricular ejection fraction (LVEF), mean left ventricular T1 relaxation times (T1), global longitudinal strain (GLS), global regional strain (GRS) and global circumferential strain (GCS). Statistical analyses included T-test and Spearman's correlation. Results CMR Images of 33 Patients were analyzed (22 females; mean age 40.8±16.3 years; at baseline 17 were therapy naïve and 16 on ERT), of whom 31 underwent a second CMR. In 18 patients (10 females; 44.9±16.0 years) myocardial strain measurement by feature-tracking was possible in both examinations. T1, LVM, LVEDV and LVESV, LVEF as well as GLS, GRS and GCS showed no significant change during the mean follow-up period of 43 (±17) months in all patients. However, we found a significant correlation of baseline T1 (967±84.5ms) with follow up values of LVM (84.9±32.7 g/m2; p=0.02, ρ=−0.462), LVEDV (63.0±17.6 g/m2 p=0.049 ρ=−0.398) and GRS (70.2±14.2% p=0.011 ρ=−0.5). Baseline T1 also correlated with changes in LVM (p=0.036 ρ=−0.44) and changes of GCS (p=0.001 ρ=−0.858) from baseline to follow up. Differences in T1 from baseline to follow up correlated with follow-up values of GLS (−19.5±3.57 p=0.044, ρ=−0.414) and GRS (69.1±18.7 p=0.003, ρ=−0.588). Conclusion T1, reflecting glycosphingolipid accumulation might predict changes in LVM, LVEDV and strain. Moreover, changes in T1, reflecting myocardial remodeling, go in parallel with worse left ventricular function shown by more positive values of GLS, GCS and GRS. T1 mapping together with strain parameters are important markers for monitoring patients with FD. Funding Acknowledgement Type of funding source: None

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Cardiac involvement in critically ill patients with leptospirosis: A prospective study using myocardial deformation imaging

European Heart Journal Acute Cardiovascular Care ◽

10.1177/2048872618809319 ◽

2018 ◽

Vol 9 (8) ◽

pp. 975-983 ◽

Cited By ~ 1

Author(s):

Anoop Mathew ◽

Miriam Shanks ◽

Eapen Punnoose ◽

Louie Fischer ◽

George Koshy ◽

...

Keyword(s):

Longitudinal Strain ◽

Cardiac Involvement ◽

Left Ventricular Systolic Dysfunction ◽

Systolic Dysfunction ◽

Global Longitudinal Strain ◽

Sepsis Syndrome ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Systolic Dysfunction ◽

Ventricular Ejection Fraction

Background: Myocardial inflammation often complicates leptospirosis, a re-emerging global zoonosis. Leptospirosis associated myocardial dysfunction is equivocal and the pattern of cardiac involvement may not differ from that of sepsis associated myocarditis. Methods: We prospectively compared cardiac involvement in 113 intensive care unit patients with severe leptospirosis to 31 patients with sepsis syndrome using a comprehensive assessment comprising of clinical presentation, electrocardiography, two-dimensional echocardiography (with global longitudinal strain calculation), and cardiac biomarker evaluation. Binomial logistic regression was performed to identify independent predictors of left ventricular systolic dysfunction in leptospirosis. Results: Compared to sepsis syndrome, leptospirosis patients were younger, had higher body mass index measurements and were more likely to be smokers. Electrocardiography abnormalities were common and similar in both groups. Myocardial systolic dysfunction was common in both groups (leptospirosis: 55.86% vs sepsis syndrome: 51.61%, p=0.675) with subclinical left ventricular systolic dysfunction (characterized by abnormal global longitudinal strain and normal left ventricular ejection fraction) being most frequent followed by isolated right ventricular systolic dysfunction, isolated left ventricular systolic dysfunction, and bi-ventricular systolic dysfunction (leptospirosis: 31.43%, 18.42%, 13.16%, 10.53%, respectively; sepsis syndrome: 22.22%, 12.00%, 12.00%, 8.00%, respectively ( p>0.05 for each comparator)). Leptospirosis patients had a trend towards greater troponin-T elevation (61.0% vs 40.0%, p=0.057). ST-segment elevation and elevated troponin were independent predictors of reduced left ventricular ejection fraction in leptospirosis. Conclusions: Cardiac involvement in leptospirosis appears to be similar to that of sepsis syndrome, with myocardial systolic dysfunction being common. As such, clinical vigilance pertaining to cardiac status is paramount in these high-risk patients.

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Assessment of Cardiac Involvement in Fabry Disease (FD) with Native T1 Mapping

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/a-0836-2723 ◽

2019 ◽

Vol 191 (10) ◽

pp. 932-939

Author(s):

Fritz Christian Roller ◽

Sven Fuest ◽

Marco Meyer ◽

Sebastian Harth ◽

Dursun Gündüz ◽

...

Keyword(s):

Fabry Disease ◽

T1 Mapping ◽

Cardiac Involvement ◽

Morphological Changes ◽

Tissue Level ◽

Therapeutic Benefit ◽

Left Ventricular ◽

Imaging Biomarker ◽

Native T1 ◽

Native T1 Time

Purpose Fabry disease (FD) is an X-linked multi-organ disorder of lysosomal metabolism with cardiac disease being the leading cause of death. Identifying early FD-specific pathologies is important in the context of maximum therapeutic benefit in these stages. Therefore, the aim of this study was to investigate the value of quantitative cardiac T1 mapping as a potential disease-specific surrogate. Methods 16 consecutive FD patients (9 female, 7 male; median age: 54 years, IQR 17) and 16 control patients (9 female, 7 male; median age: 52 years, IQR 20) were investigated at 1.5 Tesla. Native T1 mapping was performed using a modified look locker inversion recovery sequence (MOLLI) and native T1 times were measured within the septal myocardium at the midventricular short-axis section. Also functional parameters, left ventricular morphology, presence of late-gadolinium enhancement, cTnI- and Lyso-Gb3-Levels were evaluated. Results The median native septal T1 time for FD was 889.0 ms and 950.6 ms for controls (p < 0.003). LGE and positive cTnI values (0.26 ± 0.21) were present in 5 FD patients (31.25 %), and left ventricular hypertrophy (LVH) was present in 4 FD patients (25.00 %). The 4 cTnI and 8 Lyso-Gb3 positive FD patients had significantly lower native T1 values (p < 0.05, respectively p < 0.01). Assuming a T1 cut-off value of 900 ms for the identification of increased cardiac lipid deposit, 9 patients with FD (56.25 %) had pathologic values (4 patients cTnI and 8 patients Lyso-Gb3 positive). Moreover, native septal T1 showed a good negative correlation to Lyso-Gb3 (r = – 0.582; p = 0.018). Conclusion A pathologic cardiac native T1 time obviously reflects cardiac involvement in the scope of FD at tissue level. In the future native T1 mapping as an imaging biomarker might allow identification of early stages of cardiac involvement in FD before morphological changes are obvious. Key Points: Citation Format

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Characterization of Fabry Disease cardiac involvement according to longitudinal strain, cardiometabolic exercise test, and T1 mapping

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-020-01823-7 ◽

2020 ◽

Vol 36 (7) ◽

pp. 1333-1342

Author(s):

Patricia Réant ◽

Emilie Testet ◽

Amélie Reynaud ◽

Catherine Bourque ◽

Matthieu Michaud ◽

...

Keyword(s):

Fabry Disease ◽

Exercise Test ◽

Longitudinal Strain ◽

T1 Mapping ◽

Cardiac Involvement

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A Case of a 50-Year-Old Woman with Typical Fabry Disease Who Showed Serial Electrocardiographic and Echocardiographic Changes over a 17-Year Period

Case Reports in Cardiology ◽

10.1155/2019/9385361 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Su Nam Lee ◽

Gee-Hee Kim ◽

Ki-Dong Yoo

Keyword(s):

Fabry Disease ◽

Ventricular Hypertrophy ◽

Cardiac Involvement ◽

Premature Death ◽

Vascular Wall ◽

Lag Time ◽

Left Ventricular ◽

The Body ◽

Lysosomal Storage ◽

Major Organ

Fabry disease (FD) is a progressive, X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A activity. Affected individuals accumulate globotriaosylceramide and glycosphingolipids in the lysosomes and cytoplasm of cells throughout the body, leading to major organ failure and premature death. Cardiac involvement includes left ventricular hypertrophy, arrhythmia, endothelial dysfunction at vascular wall, and cardiomyopathy. The diagnosis of FD can be difficult and there is often a long lag time between symptoms and diagnosis. Here, we present a case of a 50-year-old woman with typical Fabry disease who showed serial electrocardiographic and echocardiographic changes over 17 years prior to diagnosis with Fabry disease.

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