Defining the cardiovascular phenotype of adults with Alström syndrome.

BACKGROUND: >40% of infants with Alström Syndrome (AS) present with a transient, severe cardiomyopathy in the first months of life, with apparent recovery in survivors. One in five individuals then develop a later-onset cardiomyopathy but wide clinical variability is observed, even within the same family. The rationale for this study is to provide a comprehensive evaluation of the cardiovascular phenotype in adults with AS. METHODS: Adults attending the National Centre for AS in England were studied. All patients underwent biochemical, 12- lead electrocardiography, echocardiography, and cardiovascular magnetic resonance imaging. RESULTS: 47 adults with AS (64% male; mean age 33 years; 66% white British) were studied. Seven (15%) survived infantile cardiomyopathy and 23 (49%) developed adult-onset cardiomyopathy. Conventional risk factors for cardiovascular disease were present in 39 (83%). Abnormalities were present on biomarkers in 16 (34%), ECG 30 (64%), echocardiography 19 (40%) and CMR 31 (66%). Coronary artery imaging was performed in six (13%), with abnormalities in two. Cardiac, renal, and liver markers were more often impaired in older patients, with impaired left ventricular ejection fraction, reduced global longitudinal strain and late enhancement. 6 (13%) had severe pulmonary hypertension (mean pulmonary artery pressure 46 mmHg) due to left heart disease on invasive testing. CONCLUSION: Cardiomyopathy is common in adults with AS, complicated in a significant proportion by atherosclerotic coronary artery disease and restrictive cardiomyopathy, confirmed on CMR and invasive testing. With advancing age, cardiovascular complications are compounded by contemporaneous renal and liver disease.

Structural Progression in Patients with Definite and Non-Definite Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Major Adverse Cardiac Events.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited disease characterised by early arrhythmias and structural changes. Still, there are limited echocardiography data on its structural progression. We studied structural progression and its impact on the occurrence of major adverse cardiovascular events (MACE). In this single-centre observational cohort study, structural progression was defined as the development of new major or minor imaging 2010 Task Force Criteria during follow-up. Of 101 patients, a definite diagnosis of ARVC was made in 51 patients, while non-definite 'early' disease was diagnosed in 50 patients. During 4 years of follow-up (IQR: 2-6), 23 (45%) patients with a definite diagnosis developed structural progression while only 1 patient in the non-definite (early) group gained minor imaging Task Force Criteria. Male gender was strongly associated with structural progression (62% of males progressed structurally, while 88% of females remained stable). Patients with structural progression were at higher risk of MACE (64% of patients with MACE had structural progression). Therefore, the rate of structural progression is an essential factor to be considered in ARVC studies.

Giant left sinus of Valsalva aneurysm as a rare cause of acute myocardial infarction: a case report.

Background: Sinus of Valsalva aneurysm (SVA) is a rare but potentially life-threatening condition. Acute myocardial infarction (MI) is a rare consequence of aneurysmal dilatation of one or more sinuses of Valsalva. We present a case of an unruptured and partially thrombosed left SVA, presenting as anterior MI and congestive heart failure. Case summary: A 55-year-old gentleman was admitted with pulmonary oedema and a late presenting ST-elevation MI with Q wave. After initial treatment on furosemide infusion, a coronary angiography showed significant stenosis in both his left main stem (LMS) and left anterior descending artery (LAD). This is likely a result of external compression, potentially from the enlarged left sinus of Valsalva. A subsequent transthoracic echocardiogram and transoesophageal echocardiogram (TOE) confirmed large SVA involving the left coronary cusp measured 9.9 cm compressing both LMS and LAD. Discussion: Left SVAs are rare and frequently asymptomatic, typically being identified incidentally. Due to the close proximity of the left coronary system, they can present with myocardial ischaemia due to extrinsic compression of the coronary system. We were able to perform a comprehensive multi-modality assessment of left SVA, which helped establish this unusual diagnosis and guide management. Transthoracic echocardiogram and TOE helped assess the SVA and demonstrated the thrombus in situ, aortic valve insufficiency, and cardiac function. The computed tomography scan aided in accurately defining the extent of the aneurysm and the extent of compression of the left coronary system and cardiac magnetic resonance scan was able to demonstrate viability in LAD and circumflex territory.

Extending the reach of expert amyloidosis care: A feasibility study exploring the staged implementation of a UK amyloidosis network.

There has been an exponential increase in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CA). In response, the Midlands Amyloidosis Service was launched with the aim of providing patients with a timely diagnosis, remote expertise from the National Amyloidosis Centre and access to emerging transthyretin (TTR)-directed therapies. This was a descriptive study of a pilot hub-and-spoke model of delivering specialist amyloidosis care. Patients with suspected amyloidosis were referred from the wider Midlands region, and seen in a consultant-led multidisciplinary clinic. The diagnosis of ATTR-CA was established according to either the validated non-biopsy criteria or histological confirmation of ATTR deposits with imaging evidence of amyloid. Study endpoints were the volume of service provision and the time to diagnosis from the receipt of referral. Patients (n=173, age 75±2 years; male 72 %) were referred between 2019 and 2021. Eighty patients (46 %) were found to have cardiac amyloidosis, of whom 68 (85 %) had ATTR-CA. The median time from referral to diagnosis was 43 days. By removing the need for patients to travel to London, an average of 187 patient-miles was saved. Fifteen (9 %) patients with wild-type ATTR-CA received tafamidis under the Early Access to Medicine scheme; 10 (6 %) were enrolled into phase 3 clinical trials of RNA interference or antisense oligonucleotide therapies. Our results suggest that implementing a UK amyloidosis network appears feasible and would enhance equity of access to specialised amyloidosis healthcare for the increasing numbers of older patients found to have ATTR-CA.

Phenoage and longitudinal changes on transthoracic echocardiography in Alström syndrome: a disease of accelerated ageing?

Alström syndrome (AS) is an ultra-rare disorder characterised by early-onset multi-organ dysfunction, such as insulin resistance, obesity, dyslipidaemia, and renal and cardiovascular disease. The objective is to explore whether AS is a disease of accelerated ageing and whether changes over time on echocardiography could reflect accelerated cardiac ageing. Cross-sectional measurement of Phenoage and retrospective analysis of serial echocardiography were performed between March 2012 and November 2022. The setting is a single national tertiary service jointly run by health service and patient charity. Forty-five adult patients aged over 16 years were included, 64% were male and 67% of White ethnicity. The median Phenoage was 48 years (interquartile range [IQR]: 35-72) in the 34 patients for whom this was calculable, which was significantly higher than the median chronological age of 29 years (IQR: 22-39, p<0.001). Phenoage was higher than chronological age in 85% (N=29) of patients, with a median difference of +18 years (IQR: +4, +34). On echocardiography, significant decreases were observed over time in left ventricular (LV) size at end-diastole (average of 0.046 cm per year, p<0.001) and end-systole (1.1% per year, p=0.025), with significant increase in posterior wall thickness at end-diastole (0.009 cm per year, p=0.008). LV systolic function measured by global longitudinal strain reduced (0.34 percentage points per year, p=0.020) and E/e'lat increased (2.5% per year, p=0.019). Most AS patients display a higher Phenoage compared to chronological age. Cardiac changes in AS patients were also reflective of accelerated ageing, with a reduction in LV size and increased wall thickening. AS may be a paradigm disease for premature ageing.

Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.

AIM: To examine the real-world efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). METHODS: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non-alcoholic fatty liver disease. RESULTS: In total, 30 patients, with a mean age of 31 ± 11 years and a male to-female ratio of 2:1, completed 6 months of treatment with GLP-1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP-1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6-7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7-15.3) mmol/mol, equating to 6% weight loss (P < .01) and 1.1% absolute reduction in HbA1c (P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. CONCLUSIONS: Data from our centre highlight the non-inferiority of GLP-1 RAs in monogenic syndromic obesity to the available GLP-1 RA-use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.

Adipose tissue function and insulin sensitivity in syndromic obesity of Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function with detailed metabolic phenotype has not been investigated yet. OBJECTIVE: To investigate adipose tissue function in BBS. DESIGN: A prospective cross-sectional study. MAIN OUTCOME MEASURE: To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls. METHOD: 9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers. RESULTS: Adipose tissue structure, gene expression and in vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines, pro-inflammatory markers and adipose tissue RNA transcriptomic. CONCLUSION: Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

Reverse Myocardial Remodeling Following Valve Repair in Patients With Chronic Severe Primary Degenerative Mitral Regurgitation.

OBJECTIVES: The aims of this study were to quantify preoperative myocardial fibrosis using late gadolinium enhancement (LGE), extracellular volume fraction (ECV%), and indexed extracellular volume (iECV) on cardiac magnetic resonance; determine whether this varies following surgery; and examine the impact on postoperative outcomes. BACKGROUND: Myocardial fibrosis complicates chronic severe primary mitral regurgitation and is associated with left ventricular dilatation and dysfunction. It is not known if this nonischemic fibrosis is reversible following surgery or if it affects ventricular remodeling and patient outcomes. METHODS: A multicenter prospective study was conducted among 104 subjects with primary mitral regurgitation undergoing mitral valve repair. Cardiac magnetic resonance and cardiopulmonary exercise stress testing were performed preoperatively and ≥6 months after surgery. Symptoms were assessed using the Minnesota Living With Heart Failure Questionnaire. RESULTS: Mitral valve repair was performed for Class 2a indications in 65 patients and Class 1 indications in 39 patients. Ninety-three patients were followed up at 8.8 months (IQR: 7.4 months-10.6 months). Following surgery, there were significant reductions in both ECV% (from 27.4% to 26.6%; P = 0.027) and iECV (from 17.9 to 15.4 mL/m2; P < 0.001), but the incidence of LGE was unchanged. Neither preoperative ECV% nor LGE affected postoperative function, but iECV predicted left ventricular end-systolic volume index (ß = 1.04; 95% CI: 0.49 to 1.58; P < 0.001) and left ventricular ejection fraction (ß = -0.61; 95% CI: -1.05 to -0.18; P = 0.006). Patients with above-median iECV of ≥17.6 mL/m2 had significantly larger postoperative values of left ventricular end-systolic volume index (30.5 ± 12.7 mL/m2 vs 23.9 ± 8.0 mL/m2; P = 0.003), an association that remained significant in subcohort analyses of patients in New York Heart Association functional class I. CONCLUSIONS: Mitral valve surgery results in reductions in ECV% and iECV, which are surrogates of diffuse myocardial fibrosis, and preoperative iECV predicts the degree of postoperative remodeling irrespective of symptoms. (The Role of Myocardial Fibrosis in Degenerative Mitral Regurgitation; NCT02355418).

Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors at 5 Years.

[Figure: see text].

Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance.

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Alms flin/flin ) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Alms flin/flin ; Adipo-Cre +/- ) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.

Accuracy and Prognostic Value of Physiologist-Led Stress Echocardiography for Coronary Disease.

BACKGROUND: We demonstrated that physiologist-led stress echocardiography (PLSE) is feasible for coronary artery disease (CAD) assessment. We sought to extend our work by assessing its accuracy and prognostic value. METHODS: Retrospective study of 898 subjects undergoing PLSE (n=393) or cardiologist-led stress echocardiography (CLSE) (n=505) for CAD assessment using exercise or dobutamine. For accuracy assessment, the primary outcome was the ability of stress echocardiography to identify significant CAD on invasive coronary angiography (ICA). Incidence of 24-month non-fatal MI, total and cardiac mortality, revascularisation and combined major adverse cardiac events (MACE) were assessed. RESULTS: Demographics, comorbidities, CAD predictors, CAD pre-test probability and cardiac medications were matched between the PLSE and CLSE groups. PLSE had high sensitivity, specificity, positive and negative predictive value and accuracy (85%, 74%, 69%, 88%, 78% respectively). PLSE accuracy measures were similar and non-inferior to CLSE. There was a similar incidence of individual and combined outcomes in PLSE and CLSE subjects. Negative stress echocardiography conferred a comparably low incidence of non-fatal MI (PLSE 1.4% vs. CLSE 0.9%, p=0.464), cardiac mortality (0.6% vs. 0.0%, p=0.277) and MACE (6.8% vs. 3.1%, p=0.404). CONCLUSION: This is the first study of the accuracy compared with gold standard of ICA, and prognostic value of PLSE CAD assessment. PLSE demonstrates high and non-inferior accuracy compared with CLSE for CAD assessment. Negative PLSE and CLSE confer a similarly very low incidence of cardiac outcomes, confirming for the first time the important prognostic value of PLSE.

Defining Myocardial Abnormalities Across the Stages of Chronic Kidney Disease: A Cardiac Magnetic Resonance Imaging Study.

OBJECTIVES: A proof of concept cross-sectional study investigating changes in myocardial abnormalities across stages of chronic kidney disease (CKD). Characterizing noninvasive markers of myocardial fibrosis on cardiac magnetic resonance, echocardiography, and correlating with biomarkers of fibrosis, myocardial injury, and functional correlates including exercise tolerance. BACKGROUND: CKD is associated with an increased risk of cardiovascular death. Much of the excess mortality is attributed to uremic cardiomyopathy, defined by increased left ventricular hypertrophy, myocardial dysfunction, and fibrosis. The prevalence of these abnormalities across stages of CKD and their impact on cardiovascular performance is unknown. METHODS: A total of 134 nondiabetic, pre-dialysis subjects with CKD stages 2 to 5 without myocardial ischemia underwent cardiac magnetic resonance (1.5-T) including; T1 mapping (biomarker of diffuse fibrosis), T2 mapping (edema), late gadolinium enhancement, and assessment of aortic distensibility. Serum biomarkers including collagen turnover (P1NP, P3NP), troponin T, and N-terminal pro-B-type natriuretic peptide were measured. Cardiovascular performance was quantified by bicycle cardiopulmonary exercise testing and echocardiography. RESULTS: Native myocardial T1 times increased incrementally from stage 2 to 5 (966 ± 21 ms vs. 994 ± 33 ms; p < 0.001), independent of hypertension and aortic distensibility. Left atrial volume, E/e', N-terminal pro-B-type natriuretic peptide, P1NP, and P3NP increased with CKD stage (p < 0.05), while effort tolerance (% predicted VO2Peak, %VO2VT) decreased (p < 0.001). In multivariable linear regression models, estimated glomerular filtration rate was the strongest predictor of native myocardial T1 time (p < 0.001). Native myocardial T1 time, left atrial dilatation, and high-sensitivity troponin T were independent predictors of % predicted VO2Peak (p < 0.001). CONCLUSIONS: Imaging and serum biomarkers of myocardial fibrosis increase with advancing CKD independent of effects of left ventricular afterload and might be a key intermediary in the development of uremic cardiomyopathy. Further studies are needed to determine whether these changes lead to the increased rates of heart failure and death in CKD. (Left Ventricular Fibrosis in Chronic Kidney Disease [FibroCKD]; NCT03176862).

Prospective cardiovascular magnetic resonance imaging in adults with Alström syndrome: silent progression of diffuse interstitial fibrosis.

BACKGROUND: Alström syndrome (ALMS) is a rare ciliopathy characterised by early onset insulin resistance, obesity, and dyslipidaemia and is a model for diseases that have huge social, health and economic impact. Cardiomyopathy develops in the majority, with high rates of morbidity and mortality, the definitive features of which are coarse replacement fibrosis and diffuse myocardial fibrosis (DIF). The pathogenesis of heart failure is thought to involve fibroblast accumulation and expansion of the extracellular matrix with excess protein deposition, leading to distorted organ architecture and impaired contractile function. Consecutive adults with genetically proven ALMS attending the National Centre for Rare Disease in Birmingham, England were studied. All patients underwent serial CMR, echocardiography and venous blood sampling, with computed tomography coronary angiography (CTCA) performed to assess severity of CAD. The aims of this study were: 1) to evaluate changes over time in DIF by cardiovascular magnetic resonance tissue characterization in ALMS; 2) to examine whether changes in DIF are associated with alteration in systolic or diastolic function; and 3) to evaluate the frequency and severity of coronary artery disease as a confounder for progression of ischaemic versus non-ischaemic fibrosis. RESULTS: In total, 30/32 adults (63% male; 67% White British) participated. The median age at first scan was 21.3 years (interquartile range: 19.0-32.6) and participants were followed for a maximum of 67 months. Only 4 patients had significant coronary artery stenosis on post-mortem, invasive coronary angiography or CTCA. Mid short axis myocardial T1 times, myocardial extracellular volume, and left ventricular mass increased significantly over time, by an average of 21.8 ms (95% CI 17.4-26.1; p < 0.001), 1.1 percentage points (0.6-1.6, p < 0.001), and 2.8 g/m2 (1.9-3.7; p < 0.001) per year, respectively. These changes were not associated with significant deterioration in myocardial structure or function. CONCLUSIONS: This is the first comprehensive prospective study demonstrating progression of DIF in ALMS over time, although no structural or functional consequences were noted within a median three and a half years' follow up. Further study is warranted to define whether DIF is a by-stander or the driver to impaired contractile function, heart failure and death.

Myocardial Edema, Myocyte Injury, and Disease Severity in Fabry Disease.

Background Cardiovascular magnetic resonance can demonstrate myocardial processes in Fabry disease (FD), such as low native T1 (sphingolipid storage) and late gadolinium enhancement (LGE, scar). Recently, high T2 (edema) has been observed in the basal inferolateral wall along with troponin elevation. We hypothesized that edema and myocyte injury would be chronically associated and have electrical, mechanical, and disease associations in FD. Methods A prospective international multicenter study was conducted on 186 consecutive FD patients (45.2±1.1 years, 58% females). Additionally, 28 patients with hypertrophic cardiomyopathy, 30 with chronic myocardial infarction and 59 healthy volunteers were included. All study participants underwent comprehensive cardiovascular magnetic resonance with T1 and T2 mapping, cines, and LGE imaging. Results LGE in the basal inferolateral wall in FD had T2 elevation (FD 58.2±5.0 ms versus hypertrophic cardiomyopathy 55.6±4.3 ms, chronic myocardial infarction 53.7±3.4 ms and healthy volunteers 48.9±2.5 ms, P<0.001), but when LGE was present there was also global T2 elevation (53.1±2.9 versus 50.6±2.2 ms, P<0.001). Thirty-eight percent of FD patients had high troponin. The strongest predictor of increased troponin was high basal inferolateral wall T2 (odds ratio, 18.2 [95% CI, 3.7-90.9], P<0.0001). Both T2 and troponin elevations were chronic over 1 year. High basal inferolateral wall T2 was associated with baseline global longitudinal strain impairment (P=0.005) and electrocardiographic abnormalities (long PR, complete bundle branch block, left ventricular hypertrophy voltage criteria, long QTc, and T-wave inversion, all P<0.05) and predicted clinical worsening after 1 year (Fabry stabilization index >20%, P=0.034). Conclusions LGE in Fabry has chronic local T2 elevation that is strongly associated with chronic troponin elevation. In addition, there is slight global T2 elevation. Both are associated with ECG and mechanical changes and clinical worsening over 1 year.

Superior Aerobic Capacity and Indices of Skeletal Muscle Morphology in Chronically Trained Master Endurance Athletes Compared With Untrained Older Adults.

The study aim was to comprehensively assess physiological function and muscle morphology in chronically trained older individuals against untrained young and older individuals. In a cross-sectional design, 15 young untrained controls (YC) (20 ± 2.7 years, 78.9 ± 13.3 kg), 12 untrained older controls (OC) (69.8 ± 4.1 years, 77.5 ± 14.2 kg), and 14 endurance-trained master athletes (MA) (67.1 ± 4.1 years, 68.7 ± 6.5 kg) underwent assessments of body composition, aerobic capacity, strength, muscle architecture, and fiber-type morphology. Skeletal muscle index was lower and body fat greater in OC versus MA. Estimated VO2max (mL·kg-1·minute-1) was similar between MA and YC, but lower in OC. Isometric leg strength normalized to fat-free mass was similar between groups, whereas normalized isometric arm strength was greater in YC than MA. Myosin heavy chain (MHC) I fiber area was greater in MA than OC, while MHC II fiber area was greater in YC than OC. MHC II fiber myonuclear domain size was greater in YC than OC and MA, whereas MA had greater MHC I and MHC II fiber capillarization than OC and YC. Satellite cell content was similar between groups. Chronic endurance training enhances indices of muscle morphology and improves body composition and aerobic capacity in older age, with potentially important implications for healthspan extension.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

The clinical utility of total concentration of urinary globotriaosylsphingosine plus its analogues in the diagnosis of Fabry disease.

BACKGROUND: Fabry disease (FD) is a genetic disorder caused by defective α-galactosidase-A enzyme due to mutations in the GLA gene. A reliable diagnosis in classical FD males can be made by measuring the enzyme activity while diagnosing classical FD females and non-classical FD patients requires mutation analysis. Plasma globotriaosylsphingosine (Lyso-Gb3) has progressively gained more importance as a diagnostic biomarker for FD in recent years. Having another biomarker to complement plasma Lyso-Gb3 will increase the diagnostic accuracy in the era of mass screening, and also precision medicine. This study aims to highlight the clinical utility of the total concentration of urinary Lyso-Gb3 plus its analogues in diagnosing FD. METHOD: Random urine samples collected from 42 FD patients and 48 healthy individuals. Lyso-Gb3 and its analogues were enriched by solid phase extraction and analysed by liquid chromatography tandem mass spectrometry. RESULTS: The total concentration of Lyso-Gb3 plus its analogues in classical FD male and female patients were 1124.4 ±â€¯181.2 and 308.6 ±â€¯78.6 pmol/mmol creat., respectively. The levels in non-classical FD male and female patients were 229.2 ±â€¯169.4 and 314.4 ±â€¯156.4 pmol/mmol creat., respectively. Urinary Lyso-Gb3 and its analogues were virtually undetectable in healthy volunteers making it 100% specific for FD diagnosis. For FD male and female patients, total concentration of urinary Lyso-Gb3 plus its analogue levels ≥0.25 pmol/mmol creat. yielded a diagnostic sensitivity and specificity of 100% (AUC = 1, p < 0.00001). CONCLUSIONS: Our study findings support that the total concentration of Lyso-Gb3 plus its analogues in urine is specific to FD and may provide extra diagnostic utility for both classical and non-classical FD patients.

Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy.

BACKGROUND: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation. METHODS: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control). RESULTS: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation:29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size. CONCLUSIONS: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation.

Early effects of kidney transplantation on the heart - A cardiac magnetic resonance multi-parametric study.

Increased native myocardial T1 times in chronic kidney disease (CKD) may be due to diffuse interstitial myocardial fibrosis (DIF) or due to interstitial edema/inflammation. Concerns relating to nephrogenic systemic fibrosis with gadolinium-based contrast agents (GBCA) limit their use in end-stage kidney disease (ESKD) to measure extracellular volume (ECV) and characterise myocardial fibrosis. This study aimed to examine stability of myocardial T1 and T2 times before, and within 2 months after kidney transplantation; a time frame when volume status normalises but myocardial remodelling is unlikely to have occurred, and to compare these with ECV using GBCA after transplantation. Twenty-four patients with ESKD underwent serial cardiovascular magnetic resonance imaging, including T1 and T2 mapping. GBCA was administered on follow-up provided eGFR was >30 ml/min/1.73 m2. Eighteen age- and sex-matched controls were studied at one timepoint. ECV (ECV 28 ±â€¯2% vs. 24 ±â€¯2%, p = 0.001) and T2 times were higher in ESKD compared to controls. After transplantation, septal T1 times increased (MOLLI 985 ms ±â€¯25 vs. 1002 ms ±â€¯30, p = 0.014; ShMOLLI 974 ms ±â€¯39 vs. 992 ms ±â€¯33, p = 0.113), LV volumes reduced (LVEDvol indexed 79 ±â€¯24 vs. 63 ±â€¯20 ml/m2, p = 0.005) but LV mass was unchanged (LV mass index 89 g/m2 ±â€¯38 to 83 g/m2 ±â€¯23, p = 0.141). T2 times did not change after transplantation. Both ECV and myocardial T1 times are elevated in ESKD, supporting the theory that elevated T1 times are due to DIF, although a contribution from myocardial edema cannot be fully excluded. The lack of any fall in T1 or T2 times after transplantation suggests that myocardial T1 times are a stable measure of DIF in CKD.