Anderson-Fabry cardiomyopathy: prevalence, pathophysiology, diagnosis and treatment.

Anderson-Fabry disease (AFD) is a lysosomal storage disease caused by the inappropriate accumulation of globotriaosylceramide in tissues due to a deficiency in the enzyme α-galactosidase A (α-Gal A). Anderson-Fabry cardiomyopathy is characterized by structural, valvular, vascular and conduction abnormalities, and is now the most common cause of mortality in patients with AFD. Large-scale metabolic and genetic screening studies have revealed AFD to be prevalent in populations of diverse ethnic origins, and the variant form of AFD represents an unrecognized health burden. Anderson-Fabry disease is an X-linked disorder, and genetic testing is critical for the diagnosis of AFD in women. Echocardiography with strain imaging and cardiac magnetic resonance imaging using late enhancement and T1 mapping are important imaging tools. The current therapy for AFD is enzyme replacement therapy (ERT), which can reverse or prevent AFD progression, while gene therapy and the use of molecular chaperones represent promising novel therapies for AFD. Anderson-Fabry cardiomyopathy is an important and potentially reversible cause of heart failure that involves LVH, increased susceptibility to arrhythmias and valvular regurgitation. Genetic testing and cardiac MRI are important diagnostic tools, and AFD cardiomyopathy is treatable if ERT is introduced early.

Improving Documentation of Impulse Control Disorders at a Movement Disorder Program During the COVID-19 Pandemic.

Background and Objectives: Impulse control disorders (ICD) are a group of behaviors in Parkinson disease (PD), (compulsive buying, gambling, binge eating, craving sweets, and hypersexuality) that occur in up to 20% of individuals with PD, sometimes with devastating results. We sought to determine the rate of ICD screening based on 2020 quality measures for PD care by the American Academy of Neurology. Methods: We conducted a quality improvement project to document and improve physician ICD screening in a tertiary movement disorder program. Serial medical records were reviewed for 5 weeks before and 13 weeks after an educational session and documentation tool deployments in 2020. Inclusion criteria included the following: idiopathic PD, PD dementia (PDD), or dementia with Lewy bodies (DLB). Individual encounters for 109 patients preintervention and 276 patients postintervention were reviewed. Results: There was no difference between the preintervention and postintervention (pre-IG vs post-IG, respectively) in terms of age, male to female ratio, proportion of patients with PD, PDD, or DLB, duration of diagnosis, or levodopa equivalents. There was a shift to increased ICD queries above the median for the study period (28.8%) for 7 consecutive weeks in post-IG. The frequency of ICD diagnosis was not different from pre-IG to post-IG (95% confidence interval, 0-32.6 vs 2.7-13.4%, p = 0.444). Discussion: ICD queries immediately after ICD education and dissemination of documentation tools increased. Both preintervention and postintervention groups were similar in demographic and clinical characteristics. This program was instituted at the height of wave 2 of the COVID-19 pandemic in Alberta during staff redeployment and 100% shift to telemedicine ambulatory care. Our results demonstrate that amid a crisis, quality improvement can still be effective with education and provision of tools for clinicians.

Left atrial remodelling, mid-regional pro-atrial natriuretic peptide, and prognosis across a range of ejection fractions in heart failure.

AIMS: Measures of structural and functional remodelling of the left atrium (LA) are emerging as useful biomarkers in heart failure (HF). We hypothesized that LA volume and its contribution to stroke volume (SV) would predict a composite endpoint of HF hospitalization or death in patients with HF. METHODS AND RESULTS: We recruited 57 controls and 86 patients with HF, including preserved and reduced left ventricular ejection fraction (LVEF). Cardiac magnetic resonance imaging was used to evaluate LA volumes and contribution to LV SV. Plasma mid-region pro-atrial natriuretic peptide (MR-proANP) was evaluated. LA volume was negatively correlated with LVEF (P = 0.001) and positively correlated with LV mass in HFrEF (P < 0.001) but not in HFpEF. LA volume at end-diastole was associated with the composite endpoint in HFrEF (hazard ratio 1.26, 95% confidence interval 1.01-1.54; P = 0.044), but not HFpEF (1.06, 0.85-1.30; P = 0.612), per 10 mL/m increase. Active contribution to SV was negatively associated with the composite endpoint in HFpEF (0.32, 0.14-0.66; P = 0.001), but not HFrEF (0.91, 0.38-2.1; P = 0.828) per 10% increase. MR-proANP was associated with the composite endpoint in HFpEF (1.46, 1.03-1.94; P = 0.034), but not in HFrEF (1.14, 0.88-1.37; P = 0.278), per 100 pM increase. CONCLUSION: We found different relationships between LA remodelling and biomarkers in HFrEF and HFpEF. Our results support the hypothesis that the pathophysiologic underpinnings of HFpEF and HFrEF are different, and atrial remodelling encompasses distinct components for each HF subtype.

Pharmacodynamic Properties of Subcutaneous Immunoglobulin in Myasthenia Gravis: Sub-analyses From an Open-Label Trial.

Background: We previously reported an open-label prospective trial of subcutaneous immunoglobulin (SCIg) in mild to moderate exacerbations of myasthenia gravis (MG). The effective dose of SCIg in MG and whether measured immunoglobulin G (IgG) levels correlated with measures of disease burden were not reported. Objectives: To understand the relationship between SCIg dosing and serum IgG levels on measures of disease burden: quantitative MG (QMG), MG activities of daily living (MG-ADL), MG composite (MGC), and manual muscle testing (MMT) scores. Methods: We performed post-hoc analyses of variance to assess change in oculobulbar and generalized sub-scores. We assessed the improvement in QMG, MG-ADL, MGC, or MMT over intervals from baseline to week 2, weeks 2-4, and week 4 to end of study. Improvement was either greater than (coded 1) or was equal to or less than (coded 0) the previous 2 weeks. Binaries were assessed in binary logistic regression as a function of SCIg dose over the two-week interval as the independent variable. We also performed linear regression analyses with change in the clinical scores as the dependent variable and change in IgG level over the entire study period and over the interval from weeks 2 to 4, during which change in IgG level was maximal, as the independent variables. Results: Subanalysis of QMG and MG-ADL scores demonstrated significant reductions in the oculobulbar and the generalized portions of both measures. Binary logistic regression analyses did not find any statistically significant correlations between the odds of improvement and weight-adjusted dose of SCIg over 2-week intervals. There were no significant relationships between changes in scores and IgG level over the entire study period or over the interval from weeks 2 to 4. Conclusions: Although SCIg dose varied over the study period, the odds of improvement were not significantly correlated with this, which suggests that the current dose of 2 g/kg for SCIg should be compared to different, possibly lower, dosing regimens head-to-head. The change in clinical scores was not significantly associated with IgG levels suggesting a complex relationship. SCIg may be effective for both ocular and generalized presentations of MG.

Elevated Inflammatory Plasma Biomarkers in Patients With Fabry Disease: A Critical Link to Heart Failure With Preserved Ejection Fraction.

Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease ( FD ). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and healthy controls (n=40). Plasma levels of the following markers of inflammation and cardiac remodeling were determined: tumor necrosis factor ( TNF ), TNF receptor 1 ( TNFR 1) and 2 ( TNFR 2), interleukin-6, matrix metalloprotease-2 ( MMP -2), MMP -8, MMP -9, galectin-1, galectin-3, B-type natriuretic peptide ( BNP ), midregional pro-atrial natriuretic peptide ( MR -pro ANP ), and globotriaosylsphingosine. Clinical profile, cardiac magnetic resonance imaging, and echocardiogram were reviewed and correlated with biomarkers. Patients with FD had elevated plasma levels of BNP , MR -pro ANP , MMP -2, MMP -9, TNF , TNFR 1, TNFR 2, interleukin-6, galectin-1, globotriaosylsphingosine, and analogues. Plasma TNFR 2, TNF , interleukin-6, MMP -2, and globotriaosylsphingosine were elevated in FD patients with left ventricular hypertrophy, whereas diastolic dysfunction correlated with higher BNP , MR -pro ANP , and MMP -2 levels. Patients with late gadolinium enhancement on cardiac magnetic resonance imaging had greater levels of BNP , MR -pro ANP , TNFR 1, TNFR 2, and MMP -2. Plasma BNP , MR -pro ANP , MMP -2, MMP -8, TNF , TNFR 1, TNFR 2, galectin-1, and galectin-3 were elevated in patients with renal dysfunction. Patients undergoing enzyme replacement therapy who have more severe disease had higher MMP -2, TNF , TNFR 1, TNFR 2, and globotriaosylsphingosine analogue levels. Conclusions Inflammatory and cardiac remodeling biomarkers are elevated in FD patients and correlate with disease progression. These features are consistent with a phenotype dominated by heart failure with preserved ejection fraction and suggest a key pathogenic role of systemic inflammation in FD .

Normal left-atrial structure and function despite concentric left-ventricular remodelling in a cohort of patients with Anderson-Fabry disease.

AIMS: Anderson-Fabry Disease (AFD) is an important cause of cardiomyopathy characterized by concentric left-ventricular hypertrophy (LVH). We evaluated the extent of left-atrial (LA) structural and functional remodelling in this group of patients given that LA remodelling is a marker of adverse outcomes in the presence of LVH. METHODS AND RESULTS: Clinical profiles were obtained and cardiac MRI was performed in cohorts of patients with AFD (n = 31), healthy controls (n = 23), and a positive control cohort with known concentric remodelling and LVH (CR/H, n = 21). Of patients with AFD, 58% were on enzyme-replacement therapy (ERT), 84% were on renin-angiotensin system antagonism, and 65% were on statins. Despite a similar increase in LV mass index in the AFD when compared with the CR/H cohort, mean LA volumes for the AFD group were similar to those seen in the healthy control group. Following from this, we observed that the percentage contribution to LV stroke volume due to elastic/passive and active LA emptying was similar in the AFD and healthy control groups, while passive emptying was significantly lower in the CR/H group. The consequences of LVH in the AFD cohort were manifested in atrioventricular uncoupling, whereby the extent of elastic/passive and active LA emptying was not a function of the extent of longitudinal movement of the mitral annular plane, as it was in healthy control subjects. CONCLUSION: Left-atrial structure and function were relatively normal in our cohort of patients with AFD, who were also judiciously treated with a contemporary strategy that includes renin-angiotensin system antagonism, statins, and ERT.

Gender-specific plasma proteomic biomarkers in patients with Anderson-Fabry disease.

AIMS: Anderson-Fabry disease (AFD) is an important X-linked metabolic disease resulting in progressive end-organ involvement, with cardiac disease being the dominant determinant of survival in a gender-dependent manner. Recent epidemiological screening for AFD suggests the prevalence is much higher than previously recognized, with estimates of 1:3000. Our aim was to discover novel plasma biomarker signatures in adult patients with AFD. METHODS AND RESULTS: We used an unbiased proteomic screening approach to discover novel plasma biomarker signatures. In the discovery cohort of 46 subjects, 14 healthy controls and 32 patients with AFD, we used a mass spectrometry iTRAQ proteomic approach followed by multiple reaction monitoring (MRM) assays to identify biomarkers. Of the 38 protein groups discovered by iTRAQ, 18 already had existing MRM assays. Based on MRM, we identified an eight-protein biomarker panel (22 kDa protein, afamin, α1 antichymotrypsin, apolipoprotein E, ß-Ala His dipeptidase, haemoglobin α-2, isoform 1 of sex hormone-binding globulin, and peroxiredoxin 2) that was very specific and sensitive for male AFD patients. In female AFD patients, we identified a nine-marker panel of proteins with only three proteins, apolipoprotein E, haemoglobin α-2, and peroxiredoxin 2, common to both genders, suggesting a gender-specific alteration in plasma biomarkers in patients with AFD. The biomarkers were validated in plasma samples from 48 subjects using MRM, and they performed inferiorly in patients with heart failure. CONCLUSIONS: We have identified gender-specific plasma protein biomarker panels that are specific and sensitive for the AFD phenotype. The gender-specific panels offer important insight into potential differences in pathophysiology and prognosis between males and females with AFD.

Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.

BACKGROUND: Various pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF). METHODS AND RESULTS: This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF. CONCLUSIONS: Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment.

Drug-induced heart and vascular disease remains an important health burden. Hydroxychloroquine and its predecessor chloroquine are medications commonly used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders. Hydroxychloroquine interferes with malarial metabolites, confers immunomodulatory effects, and also affects lysosomal function. Clinical monitoring and early recognition of toxicity is an important management strategy in patients who undergo long-term treatment with hydroxychloroquine. Retinal toxicity, neuromyopathy, and cardiac disease are recognized adverse effects of hydroxychloroquine. Immediate withdrawal of hydroxychloroquine is essential if toxicity is suspected because of the early reversibility of cardiomyopathy. In addition to recommended ophthalmological screening, regular screening with 12-lead electrocardiogram and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients. Cardiac magnetic resonance imaging and endomyocardial biopsy are valuable tools to provide prognostic insights and confirm the diagnosis of hydroxychloroquine-induced cardiomyopathy. In conclusion, chronic use of hydroxychloroquine can result in an acquired lysosomal storage disorder, leading to a drug-induced cardiomyopathy characterized by concentric hypertrophy and conduction abnormalities associated with increased adverse clinical outcomes and mortality.