Cardiopulmonary determinants of reduced exercise tolerance in Fabry disease.

Fabry disease (FD), also known as Anderson-Fabry disease, is a hereditary disorder of glycosphingolipid metabolism, caused by a deficiency of the lysosomal alpha-galactosidase A enzyme. This causes a progressive accumulation of glycosphingolipids in tissues and organs which represents the main pathogenetic mechanism of FD. The disease is progressive and multisystemic and is characterized by early symptoms and late complications (renal, cardiac and neurological dysfunction). Fatigue and exercise intolerance are early common symptoms in FD patients but the specific causes are still to be defined. In this narrative review, we deal with the contribution of cardiac and pulmonary dysfunctions in determining fatigue and exercise intolerance in FD patients.

Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

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.

Experimental evidence and clinical implications of Warburg effect in the skeletal muscle of Fabry disease.

Skeletal muscle (SM) pain and fatigue are common in Fabry disease (FD). Here, we undertook the investigation of the energetic mechanisms related to FD-SM phenotype. A reduced tolerance to aerobic activity and lactate accumulation occurred in FD-mice and patients. Accordingly, in murine FD-SM we detected an increase in fast/glycolytic fibers, mirrored by glycolysis upregulation. In FD-patients, we confirmed a high glycolytic rate and the underutilization of lipids as fuel. In the quest for a tentative mechanism, we found HIF-1 upregulated in FD-mice and patients. This finding goes with miR-17 upregulation that is responsible for metabolic remodeling and HIF-1 accumulation. Accordingly, miR-17 antagomir inhibited HIF-1 accumulation, reverting the metabolic-remodeling in FD-cells. Our findings unveil a Warburg effect in FD, an anaerobic-glycolytic switch under normoxia induced by miR-17-mediated HIF-1 upregulation. Exercise-intolerance, blood-lactate increase, and the underlying miR-17/HIF-1 pathway may become useful therapeutic targets and diagnostic/monitoring tools in FD.

Incremental value of 18F-FDG cardiac PET imaging over dobutamine stress echocardiography in predicting myocardial ischemia in patients with suspected coronary artery disease.

BACKGROUND: To assess the incremental value of 18F-fluorodeoxyglucose (FDG) cardiac positron emission tomography (PET) over dobutamine stress echocardiography (DSE) in predicting myocardial ischemia in patients with suspected coronary artery disease (CAD). METHODS: Forty-one patients with suspected CAD underwent within 7 days apart rest-stress cardiac PET with 82Rb and DSE followed by cardiac 18F-FDG PET imaging. 18F-FDG images were scored on a 0 (no discernible uptake) to 2 (intense uptake) scale. Logistic regression analysis was performed to identify predictors of stress-induced ischemia. The incremental value of 18F-FDG PET over DSE in detecting ischemia at 82Rb PET cardiac imaging was assessed by the likelihood ratio chi-square and net reclassification index. RESULTS: On 82Rb-PET imaging, myocardial ischemia (ischemic total perfusion defect ≥ 5%) was detected in 20 (49%) patients. Inducible ischemia was found in 22 (54%) patients on DSE (biphasic or worsening response pattern in ≥ 1 segment) and in 21 (51%) patients on 18F-FDG PET (uptake score of 2 in ≥ 1 segment). 18F-FDG PET resulted as statistically significant predictor of ischemia on 82Rb-PET. The addition of 18F-FDG PET to DSE increased the likelihood of ischemia on 82Rb-PET (P < .05). 18F-FDG PET was able to reclassify the probability of stress-induced myocardial ischemia on both patient and vessel analyses. CONCLUSION: 18F-FDG PET performed after dobutamine stress test may provide incremental value to DSE in the evaluation of myocardial ischemia. These results suggest that stress-induced myocardial ischemia can be imaged directly using 18F-FDG PET after dobutamine stress test.

Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson-Fabry disease.

Enzyme replacement therapy (ERT) is a mainstay of treatment for Anderson-Fabry disease (AFD), a pathology with negative effects on the heart and kidneys. However, no reliable biomarkers are available to monitor its efficacy. Therefore, we tested a panel of four microRNAs linked with cardiac and renal damage in order to identify a novel biomarker associated with AFD and modulated by ERT. To this end, 60 patients with a definite diagnosis of AFD and on chronic ERT, and 29 age- and sex-matched healthy individuals, were enrolled by two Italian university hospitals. Only miR-184 met both conditions: its level discriminated untreated AFD patients from healthy individuals (c-statistic = 0.7522), and it was upregulated upon ERT (P < 0.001). On multivariable analysis, miR-184 was independently and inversely associated with a higher risk of cardiac damage (odds ratio = 0.86; 95% confidence interval [CI] = 0.76-0.98; P = 0.026). Adding miR-184 to a comprehensive clinical model improved the prediction of cardiac damage in terms of global model fit, calibration, discrimination, and classification accuracy (continuous net reclassification improvement = 0.917, P < 0.001; integrated discrimination improvement [IDI] = 0.105, P = 0.017; relative IDI = 0.221, 95% CI = 0.002-0.356). Thus, miR-184 is a circulating biomarker of AFD that changes after ERT. Assessment of its level in plasma could be clinically valuable in improving the prediction of cardiac damage in AFD patients.

Role of serial cardiac 18F-FDG PET-MRI in Anderson-Fabry disease: a pilot study.

AIM: We investigated the value of serial cardiac 18F-FDG PET-MRI in Anderson-Fabry disease (AFD) and the potential relationship of imaging results with FASTEX score. METHODS AND RESULTS: Thirteen AFD patients underwent cardiac 18F-FDG PET-MRI at baseline and follow-up. Coefficient of variation (COV) of FDG uptake and FASTEX score were assessed. At baseline, 9 patients were enzyme replacement therapy (ERT) naïve and 4 patients were under treatment. Two patients presented a FASTEX score of 0 indicating stable disease and did not show any imaging abnormality at baseline and follow-up PET-MRI. Eleven patients had a FASTEX score > 20% indicating disease worsening. Four of these patients without late gadolinium enhancement (LGE) and with normal COV at baseline and follow-up had a FASTEX score of 35%. Three patients without LGE and with abnormal COV at baseline and follow-up had a FASTEX score ranging from 30 to 70%. Three patients with LGE and abnormal COV at baseline and follow-up had a FASTEX score between 35 and 75%. Finally, one patient with LGE and normal COV had a FASTEX score of 100%. Of the 12 patients on ERT at follow-up, FASTEX score was significantly higher in those 4 showing irreversible cardiac injury at baseline compared to 8 with negative LGE (66 ± 24 vs. 32 ± 21, p = 0.03). CONCLUSION: 18F-FDG PET-MRI may be effective to monitor cardiac involvement in AFD.

Impact of drug-eluting stents on left ventricular wall motion after successful reperfusion of first anterior ST elevation myocardial infarction.

BACKGROUND: Timely myocardial reperfusion by primary percutaneous coronary intervention (pPCI) prevents the development of left ventricular (LV) dysfunction after myocardial infarction (MI). We aimed to investigate whether bare-metal stents (BMS) and drug eluting stents (DES) differently affect the recovery of LV function in patients with ST-elevation MI (STEMI). METHODS: Overall 103anterior STEMI patients were retrospectively analyzed. All patients had single vessel disease with culprit lesion at the left anterior descending coronary artery. Patients were categorized in DES group (N.=67) and BMS group (N.=36). Changes in LV contractility were assessed by trans-thoracic echocardiogram as Left Ventricular Wall Motion Score Index (LVWMSI). Follow-up visits were performed between 6 and 12 months after hospital discharge. RESULTS: Compared to baseline, LV ejection fraction (EF) remained unchanged between the two groups at the follow-up; LVWMSI significantly improved in patients treated with DES (1.95±0.25 vs. 1.78±0.38, P<0.05), whereas did not change in those treated with BMS (2.09±0.21 vs. 1.98±0.33, P: not significant). At follow-up the LVWMSI was significantly higher in patients with DES than with BMS (P=0.048). LV end-systolic and end-diastolic volumes (LVESV, LVEDV) significantly increased in patients receiving a BMS, whereas it did not change in those receiving a DES (P<0.05). Multivariate analysis adjusted for age, gender, type of stent (DES or BMS), and type of revascularization (primary PCI or rescue PCI or thrombolysis + PCI) showed that DES implantation was an independent predictor of LVWMSI improvement (OR: 3.8 [1.143-12.969] P=0.03). CONCLUSIONS: DES implantation is associated with a favorable impact on LV remodeling and regional contractility.

Focal reduction in left ventricular 123I-metaiodobenzylguanidine uptake and impairment in systolic function in patients with Anderson-Fabry disease.

BACKGROUND: Abnormalities of cardiac sympathetic innervation have been demonstrated in Anderson-Fabry disease (AFD). We aimed to investigate the relationship between regional left ventricular (LV) denervation and regional function abnormalities. METHODS: Twenty-four AFD patients (43.7 ± 12.8 years) were studied by 123I-metaiodobenzylguanidine (MIBG) cardiac imaging and speckle-tracking echocardiography. Segmental tracer uptake was estimated according to 0 to 4 score, and total defect score (TDS) was calculated for each patient. RESULTS: Segmental longitudinal strain worsened as MIBG uptake score increased (P < 0.001). By ROC analysis, a segmental longitudinal strain > - 16.2% predicted a segmental MIBG uptake score ≥1, with 79.7% sensitivity and 65.3% specificity. Segmental MIBG uptake defects were found in 13 out 24 AFD patients. LV mass index (60.8 ± 10.1 vs. 41.4 ± 9.8 g/h2.7), relative wall thickness (0.51 ± 0.06 vs. 0.40 ± 0.06), systolic pulmonary artery pressure (35.2 ± 6.7 vs. 27.2 ± 4.2 mmHg), and longitudinal strain (- 14.3 ± 2.7 vs. -19.4 ± 1.8%) were significantly higher in patients with segmental defect (all P < 0.01). At multivariate linear regression analysis, global longitudinal strain was independently associated with TDS (B = 3.007, 95% confidence interval 1.384 to 4.630, P = 0.001). CONCLUSIONS: Reduced cardiac MIBG uptake reflects the severity of cardiac involvement in AFD patients. LV longitudinal function impairment seems to be an earlier disease feature than regional myocardial denervation.

Does left ventricular function predict cardiac outcome in Anderson-Fabry disease?

In Anderson-Fabry disease (AFD) the impact of left ventricular (LV) function on cardiac outcome is unknown. Noninvasive LV pressure-strain loop analysis is a new echocardiographic method to estimate myocardial work (MW). We aimed to evaluate whether LV function was associated with outcome and whether MW had a prognostic value in AFD. Ninety-six AFD patients (41.8 ± 14.7 years, 43.7% males) with normal LV ejection fraction were retrospectively evaluated. Inclusion criteria were sinus rhythm and ≥ 2-year follow-up. Standard echocardiography measurements, myocardial mechano-energetic efficiency (MEE) index, global longitudinal strain (GLS) and MW were evaluated. Adverse cardiac events were defined as composite of cardiac death, malignant ventricular tachycardia, atrial fibrillation and severe heart failure development. During a median follow-up of 63 months (interquartile range 37-85), 14 events occurred. Patient age, cardiac biomarkers, LV mass index, left atrium volume, E/Ea ratio, LV ejection fraction, MEE index, GLS and all MW indices were significantly related to adverse outcome at univariate analysis. After adjustment for clinical and echocardiographic parameters, which were significant at univariate analysis, GLS and MW resulted independent predictors of adverse events (p < 0.01). By ROC curve analysis, constructive MW ≤ 1513 mmHg% showed the highest sensitivity and specificity in predicting adverse outcome (92.9% and 86.6%, respectively). MW did not improve the predictive value of a model including clinical data, LV diastolic function and GLS. LV function impairment (both systolic and diastolic) is associated with adverse events in AFD. MW does not provide additive information over clinical features and systolic and diastolic function.

The Retinal Vessel Density as a New Vascular Biomarker in Multisystem Involvement in Fabry Disease: An Optical Coherence Tomography Angiography Study.

In this study, we evaluated the possible relationship between the changes in retinal vessel density (VD) by optical coherence tomography angiography (OCTA) and the vascular alterations involving renal, cardiovascular and central nervous systems in patients affected by Fabry disease (FD). In 50 FD patients, the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) in macular region were evaluated by OCTA examination. The patients also underwent a brain magnetic resonance imaging scan, renal and echocardiographic examinations with quantification of systolic pulmonary arterial pressure (PAPs) and left atrial volume index (LAVi). The VD of SCP and DCP was inversely related with E/e' ratio, LAVi, interventricular septal thickness, global longitudinal strain (GLS) and PAPs (p < 0.05). No relationship was found, with a multivariate analysis, between OCTA parameters and kidney function and neuroradiological signs of central nervous system involvement. OCTA could be a new vascular biomarker in FD, revealing a strong correlation between retinal capillary damage and myocardial impairment, possibly preceding both renal dysfunction and cerebrovascular involvement.

Left ventricular radial strain impairment precedes hypertrophy in Anderson-Fabry disease.

In Anderson-Fabry disease (AFD), left ventricular (LV) radial function has been scarcely investigated. We hypothesized that LV function may be affected by disease specific mechanisms and sought to comprehensively evaluate LV radial, circumferential and longitudinal function in a large population of AFD patients looking at the influence of LV geometry and fibrosis. We prospectively studied 94 consecutive AFD patients (41.5 ± 14.5 years; 41 men) with preserved LV ejection fraction (EF) utilizing speckle-tracking echocardiography. A subset of patients underwent gadolinium-enhanced cardiac magnetic resonance. Cases were compared to 48 healthy subjects matched for age and sex. LV concentric hypertrophy was found in 33 AFD patients while LV concentric remodeling (relative wall thickness ≥ 0.43) in 16 out 61 patients with normal LV mass. AFD patients had lower radial, longitudinal and circumferential strains than controls, independently by LV geometry pattern. Patients with LV hypertrophy showed reduced global longitudinal strain (p < 0.001) and early diastolic untwisting rate (p = 0.002) as compared to patients with normal geometry. In the whole AFD population, neither radial strain nor circumferential strain correlated with LV mass, while global longitudinal strain and early diastolic untwisting rate did (both p < 0.001). Late gadolinium enhancement was significantly associated with longitudinal strain, twisting rate and early diastolic untwisting rate, with twisting rate being the most powerful independent predictor (ß = - 0.461; p = 0.002). Findings demonstrate impairment of LV radial strain in AFD patients with preserved EF, even in a pre-hypertrophic stage. Development of LV hypertrophy and fibrosis make worse mostly longitudinal dysfunction.

Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study.

PURPOSE: Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. METHODS: In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. RESULTS: GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. CONCLUSIONS: The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.

Optical Coherence Tomography Angiography Findings in Fabry Disease.

BACKGROUND: Fabry disease (FD) is a X-linked recessive lysosomal storage disorder characterized by altered biodegradation of glycosphingolipids. It is a multisystem pathology, also involving ophthalmological systems that show modifications of the vessel wall due to glycosphingolipid deposits. Optical coherence tomography angiography (OCT-A) allows for an objective analysis of retinal microvasculature alterations, evaluating retinal vessel density in macular region. METHODS: A total of 54 FD patients (34 females, 20 males, mean age 44.1 ± 15.6 years) and 70 controls (36 females, 34 males, mean age 42.3 ± 15.6 years) were included in this study. We evaluated vessel density in different macular areas (whole image, fovea, and parafovea) of both the superficial capillary plexus (SCP) and of the deep capillary plexus (DCP). RESULTS: In the SCP there was a significantly lower vascular density in patients compared with controls in whole image (49.95 ± 5.17% vs. 51.99 ± 2.52%; p < 0.001), parafovea (52.01 ± 6.69% vs. 54.30 ± 2.61%; p = 0.002), and fovea (22.38 ± 9.01% vs. 29.31 ± 5.84%; p < 0.0001). In the DCP the vessel density was statistically increased in each macular area in patients compared with controls (54.82 ± 8.07% vs. 50.93 ± 5.46%; p = 0.005, 57.76 ± 7.26% vs. 53.59 ± 5.46%; p = 0.0001, and 39.75 ± 8.59% vs. 34.43 ± 8.68%; p < 0.0001 for whole image, parafovea, and fovea, respectively). CONCLUSION: OCT-A analysis showed that the macular vessel density was significantly reduced in the SCP and increased in the DCP in FD patients compared with controls. These findings, which might be a consequence of the alteration of vascular wall occurring in FD, support the hypothesis that the evaluation of early retinal microvascular network changes could be a useful tool in the clinical evaluation of the disease.

Hybrid positron emission tomography-magnetic resonance imaging for assessing different stages of cardiac impairment in patients with Anderson-Fabry disease: AFFINITY study group.

AIMS: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder associated with multi-organ dysfunction. While native myocardial T1 mapping by magnetic resonance (MR) allow non-invasive measurement of myocyte sphingolipid accumulation, 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and MR are able to identify different pathological patterns of disease progression. We investigated the relationship between T1 mapping and 18F-FDG uptake by hybrid PET-MR cardiac imaging in AFD female patients. METHODS AND RESULTS: Twenty AFD females without cardiac symptoms underwent cardiac PET-MR using 18F-FDG for glucose uptake. In all patients and in seven age- and sex-matched control subjects, T1 mapping was performed using native T1 Modified Look-Locker Inversion-recovery prototype sequences. 18F-FDG myocardial uptake was quantified by measuring the coefficient of variation (COV) of the standardized uptake value using a 17-segment model. T1 values of AFD patients were lower compared with control subjects (1236 ± 49 ms vs. 1334 ± 27 ms, P < 0.0001). Focal 18F-FDG uptake with COV >0.17 was detected in seven patients. COV was 0.32 ± 0.1 in patients with focal 18F-FDG uptake and 0.12 ± 0.04 in those without (P < 0.001). Patients with COV >0.17 had higher T1 values of lateral segments of the mid ventricular wall, compared with those with COV ≤0.17 (1216 ± 22 ms vs. 1160 ± 59 ms, P < 0.05). CONCLUSION: In females with AFD, focal 18F-FDG uptake with a trend towards a pseudo-normalization of abnormal T1 mapping values, may represent an intermediate stage before the development of myocardial fibrosis. These findings suggest a potential relationship between progressive myocyte sphingolipid accumulation and inflammation.

Prominent longitudinal strain reduction of left ventricular basal segments in treatment-naïve Anderson-Fabry disease patients.

AIMS: Little is known about regional longitudinal strain (LS) distribution in early stages of Anderson-Fabry disease (AFD) cardiomyopathy. We investigated regional left ventricular (LV) patterns of LS strain and base-to-apex behaviour of LS in treatment-naïve AFD patients. METHODS AND RESULTS: Twenty-three consecutive AFD patients at diagnosis and 23 healthy controls without cardiovascular risk factors and matched for age and sex to the patients, underwent a comprehensive evaluation of target organs. An echo-Doppler exam, including determination of regional and global LS strain (GLS) was obtained. The average LS of 6 basal (BLS), 6 middle (MLS), and 5 apical (ALS) segments and relative regional strain ratio [ALS/(BLS + MLS)] were also calculated. Ejection fraction and diastolic indices did not differ between the two groups. LV mass index was greater in AFD (P < 0.01). GLS (P = 0.006), BLS (P < 0.0001), and MLS (P = 0.003), but not ALS, were lower in AFD patients and relative regional strain ratio was higher in AFD (P < 0.01) than in controls. These analyses were confirmed separately in the two genders and even after excluding patients with wall hypertrophy. By subdividing AFD patients according to lysoGB3 levels, 9 patients with lysoGB3 ≥ 1.8 ng/L had lower ALS compared to 11 patients with lysoGB3 < 1.8 ng/L (P < 0.01). CONCLUSION: In naïve AFD patients, we observed an early reduction of LV LS, involving mainly LV basal myocardial segments. Nevertheless, the association found between the higher lysoGB3 levels and the lower apical cap LS demonstrates that apical segments LS, despite still normal, is not spared at diagnosis.

Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease.

BACKGROUND AND OBJECTIVES: Progressive nephropathy is one of the main features of Fabry disease (FD). It has been supposed that an early phase, clinically silent disease occurs in childhood and adolescence and is characterized by glomerular hyperfiltration (HF). Surprisingly, although HF has been reported in several studies, its prevalence is at present unknown. The focus of our study was to determine the prevalence of HF in a cohort of patients with FD and to identify the factors associated with a high risk of HF. METHODS: To address this issue, a retrospective observational study of 87 patients with genetically confirmed FD was performed. HF was defined as an estimated glomerular filtration rate (eGFR) > 130 mL/min/1.73 m2 corrected for age (> 40 years: -1 mL/min/1.73 m2/year). RESULTS: HF occurred in 21 patients (24% of our population), and increased to 50% when only young adults were considered. Hyperfiltrating patients were younger and had lower proteinuria levels than those without HF. The prevalence of cardiovascular and other manifestations of FD was significantly lower in hyperfiltering patients. CONCLUSIONS: Our study showed a negative correlation between eGFR and age, and with proteinuria levels and the presence of cardiovascular and other manifestations of FD. These data favor the view that HF in Fabry patients could be related predominantly to a predisease state. Even in the absence of a "measured" GFR, HF should be regarded as an early marker of Fabry nephropathy, and its recognition and confirmation by true GFR seems a relevant feature to address the issue of the potential benefit of nephroprotective treatments at the early stage of Fabry nephropathy.

Left ventricular dysfunction in ADPKD and effects of octreotide-LAR: A cross-sectional and longitudinal substudy of the ALADIN trial.

BACKGROUND AND AIM: In autosomal dominant polycystic kidney disease (ADPKD) cardiac abnormalities have been observed before the onset of hypertension or renal dysfunction. We sought to characterize, in ADPKD patients, left ventricular (LV) function and its changes after somatostatin-analogue octreotide-LAR treatment. METHODS: In a 1:1:1 cross-sectional study, we evaluated LV function by speckle-tracking echocardiography in 34 ADPKD patients from one ALADIN-trial center and in 34 age- and gender-matched healthy controls and 34 equally-matched renal controls with non-cystic chronic kidney disease. Changes in LV function were compared in the 16 and 18 ADPKD patients originally randomized to 3 year-treatment with octreotide-LAR or placebo, respectively. RESULTS: LV twist and untwisting rates were lower in ADPKD patients that in healthy or renal controls (6.1 ±â€¯2.6° vs. 11.1 ±â€¯2.1° and 10.2 ±â€¯3.7°; -49.5 ±â€¯18.1°/s vs. -79.8 ±â€¯12.2°/s and -84.3 ±â€¯25.9°/s, respectively, all p < 0.001). The correlation between LV mass or diastolic BP and untwisting rate was positive in ADPKD patients (r = 0.38, p = 0.025 and r = 0.44, p = 0.011, respectively), not significant in healthy controls and negative in renal controls (r = -0.38; p = 0.023 and r = -0.40, p = 0.012, respectively. LV untwisting rate improved from -49.9 ±â€¯18.6°/s to -70.3 ±â€¯27.5°/s with octreotide-LAR, but did not change with placebo (p = 0.027 for treatment effect). At adjusted linear regression analysis, octreotide-LAR therapy emerged as the only independent predictor of untwisting rate improvement at final visit [beta coefficient -0.504 (95% CI -46.905--6.367), p = 0.014]. CONCLUSIONS: In ADPKD patients LV function is early impaired. Somatostatin-analogue therapy might help in preventing or ameliorating LV dysfunction in this population. Clinical Trial Registration http://www.clinicaltrials.gov, NCT0030928.