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The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by absence or deficient activity of α-galactosidase A (α-Gal A) due to mutations in the α-galactosidase A gene (GLA), leading to progressive accumulation of globotriaosylceramide (Gb3) in tissues and organs including heart, kidney, the eyes, vascular endothelium, the nervous system and the skin. Cardiac involvement is leading to fatal complications and reduced life expectancy. FD is treatable with disease-specific treatment (enzyme replacement therapy (ERT) or with chaperone therapy). Therefore, the early diagnosis of FD is crucial for reducing the morbidity and mortality. Screening of high-risk populations (eg, patients with unexplained left ventricular hypertrophy (LVH), young patients with unexplained stroke, and patients with unexplained renal failure proteinuria or microalbuminuria) yields good results. The diagnostic algorithm is gender-specific. Initially, the measurement of α-Gal A activity is recommended in males, and optionally in females. In males with non-diagnostic residual activity (5– 10%) activity, genetic testing is afterwards done for confirming the diagnosis. In fact, diagnosis of FD is not possible without genetic testing for both males and females. Globotriaosysphingosine (lyso-Gb3) for identification of atypical FD variants and high- sensitive troponin T (hsTNT) for identification of cardiac involvement are also important diagnostic biomarkers. The aim of this review was to provide an update on diagnosis and screening of patients with FD.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central mediators of cardiac hypertrophy and are discussed as potential therapeutic targets. However, direct inhibition of ERK1/2 leads to exacerbated cardiomyocyte death and impaired heart function. We have previously identified ERK ᵀʰʳ¹⁸⁸ autophosphorylation as a regulatory phosphorylation of ERK1/2 that is a key factor in cardiac hypertrophy. Here, we investigated whether interference with ERK ᵀʰʳ¹⁸⁸ phosphorylation permits the impairment of ERK1/2-mediated cardiac hypertrophy without increasing cardiomyocyte death. The impact of ERK ᵀʰʳ¹⁸⁸ phosphorylation on cardiomyocyte hypertrophy and cell survival was analyzed in isolated cells and in mice using the mutant ERK2 ᵀ¹⁸⁸ᴬ, which is dominant-negative for ERK ᵀʰʳ¹⁸⁸ signaling. ERK2 ᵀ¹⁸⁸ᴬ efficiently attenuated cardiomyocyte hypertrophic responses to phenylephrine and to chronic pressure overload, but it affected neither antiapoptotic ERK1/2 signaling nor overall physiological cardiac function. In contrast to its inhibition of pathological hypertrophy, ERK2 ᵀ¹⁸⁸ᴬ did not interfere with physiological cardiac growth occurring with age or upon voluntary exercise. A preferential role of ERK ᵀʰʳ¹⁸⁸ phosphorylation in pathological types of hypertrophy was also seen in patients with aortic valve stenosis: ERK ᵀʰʳ¹⁸⁸ phosphorylation was increased 8.5 ± 1.3-fold in high-gradient, rapidly progressing cases (≥40 mmHg gradient), whereas in low-gradient, slowly progressing cases, the increase was not significant. Because interference with ERK ᵀʰʳ¹⁸⁸ phosphorylation (i) inhibits pathological hypertrophy and (ii) does not impair antiapoptotic ERK1/2 signaling and because ERK ᵀʰʳ¹⁸⁸ phosphorylation shows strong prevalence for aortic stenosis patients with rapidly progressing course, we conclude that interference with ERK ᵀʰʳ¹⁸⁸ phosphorylation offers the possibility to selectively address pathological types of cardiac hypertrophy.

Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holter electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in “loco typico.” No patients previously exhibited clinically relevant arrhythmias on Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 ± 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses ≥3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter–defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder.

In the present study, we assessed the role of Global Longitudinal Strain (GLS) as a predictor of all-cause mortality in patients with severe aortic valve stenosis (AS), irrespective of their type of treatment. Data of 807 patients with AS receiving complete echocardiographic and clinical examination were retrospectively analyzed. Valve area <1 cm2 and sufficient image quality were inclusion criteria; patients with severe concomitant valvulopathy were excluded. Patients were grouped into treatment (aortic valve replacement [AVR]) and conservative (non-AVR) groups. Multivariable Cox analysis was used to assess predictors of all-cause mortality. Five hundred fourteen patients were included and 53.3% were of male gender. Mean age at inclusion was 76.4 ± 9.8 years; 326 received AVR. Death from any cause occurred in 72.9% of non-AVR group and 17.8% of AVR group (p <0.001). GLS (expressed as |%|) was found to be an independent predictor of all-cause mortality in non-AVR group (hazard ratio [HR] 0.933, 95% CI 0.854 to 0.987, p = 0.038). In patients receiving AVR, GLS and history of coronary artery bypass graft were found to be independent predictors of all-cause mortality (HR for GLS 0.912, 95% CI 0.730 to 0.999, p = 0.048; HR for coronary artery bypass graft 2.977, 95% CI 1.014 to 6.273, p = 0.013). In non-AVR patients, GLS <9.7% showed a higher 1- and 5-year mortality (log rank p values of 0.002 and 0.010, respectively). In conclusion, GLS is an independent predictor of all-cause mortality in severe AS, irrespective of their type of treatment. GLS <9.7% indicates a significantly higher 1- and 5-year mortality in non-AVR patients. Therefore, GLS should be regularly assessed for enhanced risk stratification and clinical decision-making.

[...]there are still a number of patients in whom the disease is detected only at an advanced stage.2 In these patients, an additional, organ-targeted adjuvant treatment is of particular importance.3 Thus, for the regression of left ventricular hypertrophy, therapy with an angiotensin-converting enzyme inhibitor might be necessary. [...]all patients with tachyarrhythmia should be prescribed β-blocker therapy, which at the same time protects against potential ventricular arrhythmias.

Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%). Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients. Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views. Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5-35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6 ± 2 vs. 8 ± 3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p < 0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.17-3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08-25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54-5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S-1 (sensitivity 68%, specificity 67%). Global LSRdias < 0.85 S-1 predicted a 4-fold increased mortality in CA patients with preserved LVEF. STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF.

In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed. Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy.

The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.

A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males-females; normal-impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.