Left atrial structural and functional remodelling in Fabry disease and cardiac amyloidosis: A comparative analysis.

BACKGROUND: Fabry disease (FD) and transthyretin cardiac amyloidosis (TTR CA) are cardiomyopathies with hypertrophic phenotype that share several features, including left atrial (LA) enlargement and dysfunction, but direct comparative data are lacking. Aim of the present study was to perform a comparative analysis of LA remodelling between the two diseases. METHODS AND RESULTS: In this prospective study, a total of 114 patients (31 FD and 83 TTR CA) were included; all of them had left ventricular hypertrophy (LVH), defined as left ventricular (LV) wall thickness ≥ 12 mm. Despite similar degree of LVH, patients with TTR CA showed worse LV systolic and diastolic function. LA maximal volume index was not significantly different between the two groups (p = 0.084), while patients with TTR CA showed larger LA minimal volume index (p = 0.001). Moreover, all phases of LA mechanics were more impaired in the TTR CA group vs FD (reservoir: 6.9[4.2-15.5] vs 19.0[15.5-29.5], p < 0.001). After excluding patients with atrial fibrillation (AF), these differences remained clearly significant. In multivariable regression analyses, LA reservoir strain showed an independent correlation with TTR CA, controlling for demographic characteristics, AF and LV systolic and diastolic performance (p ≤ 0.001), whereas LV global longitudinal strain did not. Finally, among echocardiographic parameters, LA function demonstrated the highest accuracy in discriminating the two diseases. CONCLUSIONS: TTR CA is characterized by a more advanced LA structural and functional remodelling in comparison to patients with FD and similar degree of LVH. The association between TTR CA and LA dysfunction remains consistent after adjustment for potential confounders.

Isolated Valve Amyloid Deposition in Aortic Stenosis: Potential Clinical and Pathophysiological Relevance.

Amyloid deposition within stenotic aortic valves (AVs) also appears frequent in the absence of cardiac amyloidosis, but its clinical and pathophysiological relevance has not been investigated. We will elucidate the rate of isolated AV amyloid deposition and its potential clinical and pathophysiological significance in aortic stenosis (AS). In 130 patients without systemic and/or cardiac amyloidosis, we collected the explanted AVs during cardiac surgery: 57 patients with calcific AS and 73 patients with AV insufficiency (41 with AV sclerosis and 32 without, who were used as controls). Amyloid deposition was found in 21 AS valves (37%), 4 sclerotic AVs (10%), and none of the controls. Patients with and without isolated AV amyloid deposition had similar clinical and echocardiographic characteristics and survival rates. Isolated AV amyloid deposition was associated with higher degrees of AV fibrosis (p = 0.0082) and calcification (p < 0.0001). Immunohistochemistry analysis suggested serum amyloid A1 (SAA1), in addition to transthyretin (TTR), as the protein possibly involved in AV amyloid deposition. Circulating SAA1 levels were within the normal range in all groups, and no difference was observed in AS patients with and without AV amyloid deposition. In vitro, AV interstitial cells (VICs) were stimulated with interleukin (IL)-1ß which induced increased SAA1-mRNA both in the control VICs (+6.4 ± 0.5, p = 0.02) and the AS VICs (+7.6 ± 0.5, p = 0.008). In conclusion, isolated AV amyloid deposition is frequent in the context of AS, but it does not appear to have potential clinical relevance. Conversely, amyloid deposition within AV leaflets, probably promoted by local inflammation, could play a role in AS pathophysiology.

Valvular heart disease and cardiomyopathy: reappraisal of their interplay.

Cardiomyopathies and valvular heart diseases are typically considered distinct diagnostic categories with dedicated guidelines for their management. However, the interplay between these conditions is increasingly being recognized and they frequently coexist, as in the paradigmatic examples of dilated cardiomyopathy and hypertrophic cardiomyopathy, which are often complicated by the occurrence of mitral regurgitation. Moreover, cardiomyopathies and valvular heart diseases can have a shared aetiology because several genetic or acquired diseases can affect both the cardiac valves and the myocardium. In addition, the association between cardiomyopathies and valvular heart diseases has important prognostic and therapeutic implications. Therefore, a better understanding of their shared pathophysiological mechanisms, as well as of the prevalence and predisposing factors to their association, might lead to a different approach in the risk stratification and management of these diseases. In this Review, we discuss the different scenarios in which valvular heart diseases and cardiomyopathies coexist, highlighting the need for an improved classification and clustering of these diseases with potential repercussions in the clinical management and, particularly, personalized therapeutic approaches.

Impact of GLA Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies.

BACKGROUND: The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD. METHODS: We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS: Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q. CONCLUSIONS: This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data. REGISTRATION: URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.

Temporal trends of frame expansion and paravalvular leak reduction after transcatheter aortic valve replacement with self-expandable prostheses.

BACKGROUND: Paravalvular leakage (PVL) is a common finding after transcatheter aortic valve replacement (TAVR) and affects late clinical outcome. It is more frequent with self-expandable (SE) transcatheter-heart-valve (THV). Few is known about SE-THV expansion after implantation. The purpose is to assess SE-THV frame expansion and its possible influence on PVL. METHODS: We designed a prospective pilot study to assess the time-course of SE-THV frame dimensions and PVL after TAVR. Consecutive patients undergoing TAVR with SE-THV were enrolled. Prosthesis fluoroscopy and echocardiography were prospectively performed immediately after TAVR (T0) and before discharge (T1) to grade PVL. Prosthesis diameters were assessed in 2 fluoroscopic orthogonal views. PVL reduction ≥1+ from T0 to T1 at echocardiography was the primary study endpoint. RESULTS: Twenty-five patients were enrolled. Mean interval between T0 and T1 evaluations was 5 days. Grade 1 or 2 was present in 76% of patients at T0 and in 68% at T1 (P=0.034). A total of 7 patients (28%) improved PVL ≥1 grade from T0 to T1. Differences between T0 and T1 fluoroscopic diameters were not statistically significant. When comparing the diameter changes according to PVL evolution, patients with PVL improvement (as compared with those without) had significantly larger minimum diameter increase at both annulus/inflow (P=0.016) and outflow/distal edge (P=0.027). CONCLUSIONS: PVL may improve in the early days after SE-THV and those patients with PVL improvement may have THV frame expansion. Further studies are needed to confirm such preliminary observations and to establish the clinical relevance of this phenomenon.

Clinical staging of Anderson-Fabry cardiomyopathy: An operative proposal.

As a slowly progressive form of hypertrophic cardiomyopathy (HCM), Anderson-Fabry disease (FD) resembles the phenotype of the most common sarcomeric forms, although significant differences in presentation and long-term progression may help determine the correct diagnosis. A variety of electrocardiographic and imaging features of FD cardiomyopathy have been described at different times in the course of the disease, and considerable discrepancies remain regarding the assessment of disease severity by individual physicians. Therefore, we here propose a practical staging of FD cardiomyopathy, in hopes it may represent the standard for cardiac evaluation and facilitate communication between specialized FD centres and primary care physicians. We identified 4 main stages of FD cardiomyopathy of increasing severity, based on available evidence from clinical and imaging studies: non-hypertrophic, hypertrophic - pre-fibrotic, hypertrophic - fibrotic, and overt dysfunction. Each stage is described and discussed in detail, following the principle that speaking a common language is critical when managing such complex patients in a multi-disciplinary and sometimes multi-centre setting.

Prognostic Implications of the Extent of Cardiac Damage in Patients With Fabry Disease.

BACKGROUND: There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD). OBJECTIVES: This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort. METHODS: Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m2); stage 3, ventricular impairment (LV ejection fraction <50% or E/e' ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke. RESULTS: A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy. CONCLUSIONS: In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification.

Clinical manifestation of patients with Fabry disease and R356W GLA variant.

BACKGROUND: The R356W GLA variant is an ultra-rare cause of Fabry disease (FD). The clinical manifestations of adult patients carrying this variant have never been reported. This study aims to describe the clinical phenotype of the R356W GLA variant. METHODS: The cohort consisted of consecutive patients diagnosed with FD and carrying the R356W GLA variant. An observational, longitudinal, retrospective cohort study design was used. Clinical, laboratory, and imaging data have been collected from the baseline evaluation to the last clinical review. RESULTS: Six families, including 36 patients with FD and the R356W GLA variant (age 41.1 ± 15.9 years, 67% females), were evaluated. Eleven patients (31%) showed left ventricular hypertrophy (LVH), and 6 (17%) had chronic kidney disease (CKD). Patients with LVH were older (53.4 ± 8.5 vs. 35.7 ± 15.5, p-value 0.001), showed a higher prevalence of CKD (45% vs. 4%, p-value 0.002), and worse structural and functional cardiac parameters at echocardiographic evaluation. During a median follow-up of 42 (IQR 21-98) months, one patient experienced advanced atrioventricular block requiring pacemaker implantation and one end-stage renal disease requiring dialysis. No patients experienced major adverse events. CONCLUSION: This study suggests that the R356W GLA variant could be a late-onset FD-causing variant with incomplete penetrance and predominantly cardiac manifestations.

Evolution and Prognostic Impact of Right Ventricular-Pulmonary Artery Coupling After Transcatheter Aortic Valve Replacement.

BACKGROUND: There is limited evidence regarding the association between right ventricular-to-pulmonary artery (RV-PA) coupling and outcomes after transcatheter aortic valve replacement (TAVR). OBJECTIVES: This study aimed to explore the evolution of RV-PA coupling in patients with severe aortic stenosis undergoing TAVR and its prognostic impact. METHODS: A total of 900 patients who underwent TAVR in 2 tertiary centers and with echocardiographic analysis performed within 3 months before and after the procedure were included. RV-PA coupling was measured as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP). RV-PA uncoupling was defined by TAPSE/PASP <0.55, whereas a TAPSE/PASP <0.32 identified a severe uncoupling. The primary endpoint was all-cause mortality. RESULTS: A total of 520 patients (58%) showed RV-PA uncoupling before TAVR, whereas post-TAVR RV-PA uncoupling was observed in 407 patients (45%). During a median follow-up of 40 months, 250 deaths (28%) occurred. Post-TAVR RV-PA uncoupling was independently associated with an increased risk of mortality (adjusted HR: 1.474; 95% CI: 1.115-1.948; P = 0.006), whereas pre-TAVR uncoupling did not. Among patients with post-TAVR RV-PA uncoupling, the presence of severe uncoupling identified a subgroup with the worst survival (P = 0.008). Patients with RV-PA coupling recovery after TAVR showed similar outcomes as compared with patients with normal coupling. Conversely, the presence of either persistent or new-onset RV-PA uncoupling following TAVR was associated with an increased mortality risk. CONCLUSIONS: Post-TAVR RV-PA uncoupling is an independent predictor of long-term mortality, irrespective of coupling before intervention. Assessment of TAPSE/PASP response after TAVR may be helpful to improve risk stratification.

Comparison of De-Kay repair versus De Vega suture for functional tricuspid regurgitation: a preliminary experience.

BACKGROUND: In patients undergoing mitral valve surgery, restrictive suture annuloplasty (De Vega) for less-than-severe functional tricuspid regurgitation has been proven to be safe and effective. The aim of this study is to determine whether the adjunct of the plication of the posterior tricuspid leaflet with the same running suture (bicuspidized De Vega or "De Kay") is equally safe and effective. METHODS: Single center, retrospective study on patients submitted to suture repair of the tricuspid valve during mitral valve surgery, with either conventional or De Kay, between January 2014 and December 2020. Comparison was based on degree of residual tricuspid valve regurgitation and right ventricular assessment at discharge. RESULTS: Over the course of the study period, 255 patients undergoing mitral valve surgery had a dilated (>40 mm or >20 mm/m2) tricuspid valve annulus, with less-than-severe tricuspid regurgitation. Conventional De Vega was employed in 166 patients (65.1%) and De Kay in the remaining 89 (34.9%). At discharge the adjunct of postero-septal commissure plication has similar outcomes to the classic De Vega repair. It seems to preserve right ventricular function. CONCLUSIONS: De Kay repair guarantees the same tricuspidal regurgitation reduction as compared with conventional De Vega early after surgery.

Impact of Impella protected-percutaneous coronary intervention on left ventricle function recovery of patients with extensive coronary disease and poor left ventricular function.

BACKGROUND: The use of Impella support is increasingly adopted to "protect" patients with severe coronary artery disease (CAD) and left ventricle (LV) dysfunction undergoing percutaneous coronary intervention (PCI). AIMS: To evaluate the impact of Impella-protected (Abiomed, Danvers, Massachusetts, USA) PCIs on myocardial function recovery. METHODS: Patients with significant LV dysfunction undergoing multi-vessel PCIs with pre-intervention Impella implantation were evaluated by echocardiography before PCI and at median follow up of 6 months: global and segmental LV contractile function were assessed by LV ejection fraction (LVEF) and wall motion score index (WMSI), respectively. Extent of revascularization was graded using the British Cardiovascular Intervention Society Jeopardy score (BCIS-JS). Study endpoints were LVEF and WMSI improvement, and its correlation with revascularization. RESULTS: A total of 48 high surgical risk (mean EuroSCORE II 8) patients with median LVEF value of 30%, extensive wall motion abnormalities (median WMSI 2.16), and severe multi-vessel CAD (mean SYNTAX score 35) were included. PCIs brought a significant reduction of ischemic myocardium burden with BCIS-JS decrease from mean value of 12 to 4 (p < 0.001). At follow-up, WMSI reduced from 2.2 to 2.0 (p = 0.004) and LVEF increased from 30% to 35% (p = 0.016). WMSI improvement was proportional to the baseline impairment (R - 0.50, p < 0.001), and confined to revascularized segments (from 2.1 to 1.9, p < 0.001). CONCLUSIONS: In patients with extensive CAD and severe LV dysfunction, multi-vessel Impella-protected PCI was associated to an appreciable contractile recovery, mainly determined by regional wall motion improvement in revascularized segments.

Early improvement of strain imaging parameters predicts long-term response to sacubitril/valsartan in patients with heart failure with reduced ejection fraction: An observational prospective study.

BACKGROUND: Management of patients affected by heart failure with reduced ejection fraction (HFrEF) has deeply changed thanks to novel pharmacological therapies, such as Sacubitril/Valsartan, which assured morbidity and mortality advantages in this population. These effects may be mediated by both left atrial (LA) and ventricular reverse remodeling, although left ventricular ejection fraction (LVEF) recovery still represents the main parameter of treatment response. METHODS: In this prospective, observational study, 66 patients with HFrEF and naïve from Sacubitril/Valsartan were enrolled. All patients were evaluated at baseline, at 3 months and 12 months from therapy initiation. Echocardiographic parameters, including speckle tracking analysis, LA functional and structural metrics, were collected at three timepoints. The endpoints of our study were: (1) to evaluate the effects of Sacubitril/Valsartan on echo measurements; (2) to assess the predictive role of early modifications of these parameters (expressed as ∆ 3-0 months) on long-term LVEF significant recovery, defined as >15% improvement from baseline. RESULTS: The majority of echocardiographic parameters evaluated progressively improved during the observation period, including LVEF, ventricular volumes and LA metrics. ∆(3-0 months) of LV Global Longitudinal Strain (LVGLS) and LA Reservoir Strain (LARS) were associated with significant LVEF improvement at 12 months (p < 0.001 and p = 0.019 respectively). A cut-off of ∆(3-0 months) LVGLS of 3% and of ∆(3-0 months) LARS of 2% could predict LVEF recovery with satisfactory sensitivity and specificity. CONCLUSIONS: LV and LA strain analysis may identify patients who adequately respond to HFrEF medical treatment and should be routinely used in the evaluation of these patients.

Inflammation across the spectrum of hypertrophic cardiac phenotypes.

The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.

Left atrial strain analysis improves left ventricular filling pressures non-invasive estimation in the acute phase of Takotsubo syndrome.

AIMS: The aim of our study is to assess the ability of left atrial (LA) strain values to improve left ventricular and diastolic pressure (LVEDP) non-invasive estimation as compared with traditional echocardiographic indexes in the acute phase of Takotsubo syndrome (TTS) and to predict adverse in-hospital outcomes in this population. METHODS AND RESULTS: Consecutive TTS patients were prospectively enrolled. Left ventricular and diastolic pressure was measured at the time of catheterization. Transthoracic echocardiography was performed within 48 h from hospital admission. In-hospital complications (acute heart failure, death from any cause, and life-threatening arrhythmias) were collected. A total of 62 patients were analysed (72.2 ± 10.1 years, female 80%) and in-hospital complications occurred in 25 (40.3%). Left ventricular and diastolic pressure mean value was 24.53 ± 7.92 mmHg. Left atrial reservoir and pump strain values presented higher correlation with LVEDP (r -0.859, P < 0.001 and r -0.848, P < 0.001, respectively) in comparison with E/e ' ratio, left atrial volume index (LAVi), and tricuspid regurgitation (TR) peak velocity. In addition, at receiver-operating characteristic curve analysis, LA reservoir and pump strain resulted to be better predictors of LVEDP above the mean of our population [0.909 (95% CI 0.818-0.999, P < 0.001) and 0.889 (95% CI 0.789-0.988, P < 0.001)], respectively] as compared with E/e' ratio, LAVi, and TR peak velocity.Finally, LA reservoir strain resulted to be an independent predictor of worse in-hospital outcomes, together with LVEDP and left ventricular ejection fraction (all P < 0.001). CONCLUSION: In our study, lower LA reservoir and pump strain values were better predictors of LVEDP as compared with traditional echocardiographic indexes in the acute phase of TTS syndrome. Moreover, LA reservoir strain was an independent predictor of adverse in-hospital outcomes.

Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study.

BACKGROUND: A small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET). METHODS: Sixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat. RESULTS: No change in LV mass was detected at 18 months compared to baseline (95.2 g/m2 (66.0-184.0) vs 99.0 g/m2 (69.0-121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848-882) vs 860.0 ms (833.0-875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70-21.50) vs 14.50 mL/kg/min (11.70-18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2 (72.0 (63.0-80.0) vs 69.0 (53.0-77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6-76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance. CONCLUSION: In treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others. TRIAL REGISTRATION NUMBER: NCT03838237.

Comparative analysis of right ventricular strain in Fabry cardiomyopathy and sarcomeric hypertrophic cardiomyopathy.

AIMS: To perform a comparative analysis of right ventricle (RV) myocardial mechanics, assessed by 2D speckle-tracking echocardiography (2D-STE), between patients with Fabry disease and patients with sarcomeric disease. METHODS AND RESULTS: Patients with Fabry cardiomyopathy (FC) (n = 28) were compared with patients with sarcomeric hypertrophic cardiomyopathy (HCM), matched for degree of left ventricle hypertrophy (LVH) and demographic characteristics (n = 112). In addition, patients with Fabry disease and no LVH [phenotype-negative carriers of pathogenic α-galactosidase gene mutations (GLA LVH-)] (n = 28) were compared with age and sex-matched carriers of sarcomeric gene mutations without LVH [Phenotype-negative carriers of pathogenic sarcomeric gene mutations (Sarc LVH-)] (n = 56). Standard echocardiography and 2D-STE were performed in all participants. Despite a subtle impairment of RV global longitudinal strain (RV-GLS) was common in both groups, patients with FC showed a more prominent reduction of RV free wall longitudinal strain (RV-FWS) and lower values of difference between RV-FWS and RV-GLS (ΔRV strain), in comparison to individuals with HCM (P < 0.001 and P = 0.002, respectively). RV-FWS and ΔRV strain demonstrated an independent and additive value in discriminating FC from HCM, over the presence of symmetric LVH, systolic anterior motion of the mitral valve and RV hypertrophy. Similar results were found in GLA LVH- patients: they had worse RV-FWS and lower values of ΔRV strain as compared to Sarc LVH- patients (both P < 0.001). CONCLUSION: Patients with FC show a specific pattern of RV myocardial mechanics, characterized by a larger impairment of RV-FWS and lower ΔRV strain in comparison to patients with HCM, which may be helpful in the differential diagnosis between these two diseases.