Tim Salinger

α-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease

Background— Hypertrophic cardiomyopathy is the most common type of cardiomyopathy, but many patients lack sarcomeric/myofilament mutations. We studied whether cardio-specific &agr;-galactosidase A gene variants are misinterpreted as hypertrophic cardiomyopathy because of the lack of extracardiac organ involvement. Methods and Results— All subjects who tested positive for the N215S genotype (n=26, 13 females, mean age 49±17 [range, 14–74] years) were characterized in this prospective monocentric longitudinal cohort study to determine genotype-specific clinical characteristics of the N215S (c.644A>G [p.Asn215Ser]) &agr;-galactosidase A gene variant. All subjects were initially referred with suspicion of genetically determined hypertrophic cardiomyopathy. Cardiac hypertrophy (interventricular septum, 12±4 [7–23] mm; left ventricular posterior wall, 11±4 [7–21] mm; left ventricular mass, 86±41 [46–195] g/m2) was progressive, systolic function mainly preserved (cardiac index 2.8±0.6 [1.9–3.9] L/min per m2), and diastolic function mildly abnormal. Cardiac magnetic resonance imaging revealed replacement fibrosis in loco typico (18/26, 69%), particularly in subjects >50 years. Elderly subjects had advanced heart failure, and 6 (23%) were suggested for implantable cardioverter-defibrillator therapy. Leukocyte &agr;-galactosidase A enzyme activity was mildly reduced in 19 subjects and lyso-globotriaosylceramide slightly elevated (median, 4.9; interquartile range, 1.3–9.1 ng/mL). Neurological and renal impairments (serum creatinine, 0.87±0.20; median, 0.80; interquartile range, 0.70–1.01 mg/dL; glomerular filtration rate, 102±23; median, 106; interquartile range, 84–113 mL/min) were discreet. Only 2 subjects developed clinically relevant proteinuria. Conclusions— &agr;-Galactosidase A genotype N215S does not lead to the development of a classical Fabry phenotype but induces a specific cardiac variant of Fabry disease mimicking nonobstructive hypertrophic cardiomyopathy. The lack of prominent noncardiac impairment leads to a significant delay in diagnosis and Fabry-specific therapy.

Value of the CHA2DS2-VASc score and Fabry-specific score for predicting new-onset or recurrent stroke/TIA in Fabry disease patients without atrial fibrillation

ObjectivesTo evaluate potential risk factors for stroke or transient ischemic attacks (TIA) and to test the feasibility and efficacy of a Fabry-specific stroke risk score in Fabry disease (FD) patients without atrial fibrillation (AF).BackgroundFD patients often experience cerebrovascular events (stroke/TIA) at young age.Methods159 genetically confirmed FD patients without AF (aged 40u2009±u200914 years, 42.1% male) were included, and risk factors for stroke/TIA events were determined. All patients were followed up over a median period of 60 (quartiles 35–90) months. The pre-defined primary outcomes included new-onset or recurrent stroke/TIA and all-cause death.ResultsPrior stroke/TIA (HR 19.97, Pu2009<u2009.001), angiokeratoma (HR 4.06, Pu2009=u2009.010), elevated creatinine (HR 3.74, Pu2009=u2009.011), significant left ventricular hypertrophy (HR 4.07, Pu2009=u2009.017), and reduced global systolic strain (GLS, HR 5.19, Pu2009=u2009.002) remained as independent risk predictors of new-onset or recurrent stroke/TIA in FD patients without AF. A Fabry-specific score was established based on above defined risk factors, proving somehow superior to the CHA2DS2-VASc score in predicting new-onset or recurrent stroke/TIA in this cohort (AUC 0.87 vs. 0.75, Pu2009=u2009.199).ConclusionsPrior stroke/TIA, angiokeratoma, renal dysfunction, left ventricular hypertrophy, and global systolic dysfunction are independent risk factors for new-onset or recurrent stroke/TIA in FD patients without AF. It is feasible to predict new or recurrent cerebral events with the Fabry-specific score based on the above defined risk factors. Future studies are warranted to test if FD patients with high risk for new-onset or recurrent stroke/TIA, as defined by the Fabry-specific score (≥u20092 points), might benefit from antithrombotic therapy. Clinical trial registration HEAL-FABRY (evaluation of HEArt invoLvement in patients with FABRY disease, NCT03362164).

Association and diagnostic utility of diastolic dysfunction and myocardial fibrosis in patients with Fabry disease

Objectives Current guidelines highlight important therapy implications of cardiac fibrosis in patients with Fabry disease (FD). However, association between morphological and functional impairments with cardiac fibrosis in hereditary cardiomyopathies remains elusive. We investigated the association between echocardiography-determined cardiac dysfunction and cardiac MRI (cMRI)-detected myocardial fibrosis (late gadolinium enhancement, LE) in patients with FD with preserved left ventricular ejection fraction (≥50%). Methods 146 patients with FD (aged 39±14 years, 57 men) were analysed, all receiving echocardiography and cMRI within a 1u2009week interval. Longitudinal systolic strain (LS_sys), strain rate (LSr_sys) and diastolic strain rate (LSr_E/LSr_A) were assessed using speckle-tracking imaging. Receiver operating characteristic (ROC) analysis was performed to identify the diagnostic performance of various markers for LE. Results LE was detected in 57 (39%) patients with FD. LV wall thickness, left atrial volume, septal E/e′, diastolic dysfunction grade, global LS_sys and E/LSr_E, mid-lateral LS_sys and LSr_E, as well as N-terminal pro-brain natriuretic peptide were all associated with LE independent of age, sex, body mass index, New York Heart Association functional class and kidney function. In ROC curve analysis, septal E/e′ performed best (area under the curve=0.86, 95% CI=0.79 to 0.92). Septal E/e′>14.8 was strongly associated with LE (specificity=97.8%u2009and sensitivity=49.1%). In 9% of patients, localised LE was present even though no other cardiac or kidney abnormalities were detected. Conclusions Echocardiography-derived diastolic dysfunction is closely linked to LE in FD. Septal E/e′ ratio is the best echocardiographic marker suggestive of LE. Diastolic dysfunction is not a prerequisite for LE in FD, since LE can be detected in the absence of measurable cardiac functional impairments. Trial registration number ClinicalTrials.gov Identifier (NCT03362164).

Value of cardiac biomarker measurement in the differential diagnosis of infiltrative cardiomyopathy patients with preserved left ventricular systolic function

BackgroundnThis study aimed to explore the value of cardiac biomarker [serum high sensitive troponin T (hs-TNT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)] measurement in the differential diagnosis of infiltrative cardiomyopathy patients [Friedreichs ataxia (FA), Fabry disease (FD) and light-chain (AL) cardiac amyloidosis (CA)] with preserved left ventricular (LV) systolic function.nnnMethodsnBetween 2012 and 2014, all consecutive patients presenting at our center with infiltrative cardiomyopathy and concomitant symmetrical LV hypertrophy as well as preserved LV systolic function were included in this study. Serum hs-TNT and NT-proBNP, morphologic and functional features derived from echocardiography and cardiac magnetic resonance imaging (cMRI) examinations were compared among these patients.nnnResultsnA total of 57 patients (FA 20, FD 23 and CA 14) were included. Hs-TNT and NT-proBNP levels were significantly higher in the CA group [median: hs-TNT 98 pg/mL, NT-proBNP 4,110 pg/mL] than in the FA group [hs-TNT 14 pg/mL, NT-proBNP 40 pg/mL] and FD group [hs-TNT 18 pg/mL, NT-proBNP 131 pg/mL, both P<0.001]. There was a negative correlation between NT-proBNP and estimated glomerular filtration rate (eGFR) in CA patients (r=-0.72, P=0.012). Both hs-TNT >60 pg/mL (sensitivity 0.79, specificity 0.93) and NT-proBNP >1,000 pg/mL (sensitivity 0.91, specificity 0.93) excellently differentiated CA from FA and FD.nnnConclusionsnIncreased hs-TNT and NT-proBNP levels are suggestive of CA diagnosis among patients with infiltrative cardiomyopathy and preserved LV ejection fraction.

Cardiac amyloidosis mimicking severe aortic valve stenosis – a case report demonstrating diagnostic pitfalls and role of dobutamine stress echocardiography

BackgroundAortic valve stenosis is a common finding diagnosed with high sensitivity in transthoracic echocardiography, but the examiner often finds himself confronted with uncertain results in patients with moderate pressure gradients and concomitant systolic heart failure. While patients with true-severe low-gradient aortic valve stenosis with either reduced or preserved left ventricular systolic function are primarily candidates for valve replacement, there is a relevant proportion of patients with pseudo-severe aortic valve stenosis anticipated not to benefit but actually rather deteriorate by interventional therapy or surgery.Case presentationIn this article we present a case report of a male patient with pseudo-severe aortic valve stenosis due to cardiac amyloidosis highlighting the diagnostic schedule. The patient underwent stress echocardiography because of discrepant findings in transthoracic echocardiography and cardiac catheterization regarding the severity of aortic valve stenosis. After evaluation of the results, it became clear that he had a need for optimum heart failure medication and implantation of a cardiac resynchronization therapy defibrillator.ConclusionDue to the pitfalls in conventional as well as invasive diagnostics at rest, Stress echocardiography should be considered part of the standard optimum diagnostic spectrum in all unclear or borderline cases in order to confirm the correct diagnosis and constitute optimal therapy.