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.

Arrhythmogenesis in Fabry Disease.

PURPOSE OF REVIEW: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. RECENT FINDINGS: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual's risk of arrhythmia in FD. In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.

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.

Clinical utilisation of implantable loop recorders in adults with Fabry disease-a multi-centre snapshot study.

Fabry disease (FD) is an X-linked deficiency of alpha-galactosidase-A, leading to lysosomal storage of sphingolipids in multiple organs. Myocardial accumulation contributes to arrhythmia and sudden death, the most common cause of FD mortality. Therefore, there is a need for risk stratification and prediction to target device therapy. Implantable loop recorders (ILRs) allow for continual rhythm monitoring for up to 3 years. Here, we performed a retrospective study to evaluate current ILR utilisation in FD and quantify the burden of arrhythmia that was detected, which resulted in a modification of therapy. This was a snapshot assessment of 915 patients with FD across three specialist centres in England during the period between 1 January 2000 and 1 September 2022. In total, 22 (2.4%) patients underwent clinically indicated ILR implantation. The mean implantation age was 50 years and 13 (59%) patients were female. Following implantation, nine (41%) patients underwent arrhythmia detection, requiring intervention (six on ILR and three post-ILR battery depletion). Three patients experienced sustained atrial high-rate episodes and were started on anticoagulation. Three had non-sustained tachyarrhythmia and were started on beta blockers. Post-ILR battery depletion, one suffered complete heart block and two had sustained ventricular tachycardia, all requiring device therapy. Those with arrhythmia had a shorter PR interval on electrocardiography. This study demonstrates that ILR implantation in FD uncovers a high burden of arrhythmia. ILRs are likely to be underutilised in this pro-arrhythmic cohort, perhaps restricted to those with advanced FD cardiomyopathy. Following battery depletion in three patients as mentioned above, greater vigilance and arrhythmia surveillance are advised for those experiencing major arrhythmic events post-ILR monitoring. Further work is required to establish who would benefit most from implantation.

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05-1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought. PROSPERO DATABASE: CRD42019132045.

Changing trends in the incidence, management and outcomes of coronary artery perforation over an 11-year period: single-centre experience.

INTRODUCTION: Coronary artery perforation (CP) is a rare but life-threatening complication of percutaneous coronary intervention (PCI). This study aimed to assess the incidence, management and outcomes of CP over time. METHODS: A single-centre retrospective cohort study of all PCIs performed between January 2010 and December 2020. Patients with CP were divided into two cohorts (A+B), representing the two halves of the 11-year study. RESULTS: The incidence of CP was 68 of 9701 (0.7%), with an increasing trend over the two 5.5-year periods studied (24 of 4661 (0.5%) vs 44 of 5040 (0.9%); p=0.035). Factors associated with CP included chronic total occlusions (CTOs) (16 of 68 (24%) vs 993 of 9633 (10%); p<0.001), type C lesions (44 of 68 (65%) vs 4280 of 9633 (44%); p<0.001), use of intravascular ultrasound (IVUS) (12 of 68 (18%) vs 541 of 9633 (6%); p<0.001), cutting balloon angioplasty (3 of 68 (4%) vs 98 of 9633 (1%); p<0.001) and hydrophilic wires (24 of 68 (35%) vs 1454 of 9633 (15%); p<0.001). Cohorts A and B were well matched with respect to age (69±11 vs 70±12 years; p=0.843), sex (males: 13 of 24 (54%) vs 31 of 44 (70%); p=0.179) and renal function (chronic kidney disease: 1 of 24 (4%) vs 4 of 44 (9%); p=0.457). In cohort A, CP was most frequently caused by post-dilatation with non-compliant balloons (10 of 24 (42%); p=0.009); whereas in cohort B, common causes included guidewire exits (23 of 44 (52%)), followed by stent implantation (10 of 44 (23%)). The most common treatment modality in cohorts A and B was balloon inflation, which accounted for 16 of 24 (67%) and 13 of 44 (30%), respectively. The use of covered stents (16%) and coronary coils (18%) during cohort B study period did not impact all-cause mortality, which occurred in 2 of 24 (8%) and 7 of 44 (16%) (p=0.378) in cohorts A and B, respectively. CONCLUSION: The incidence of CP is increasing as more complex PCI is performed. Factors associated with perforation include CTO or type C lesions and use of IVUS, cutting balloon angioplasty or hydrophilic wires.

Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond.

Patients with heart failure often develop cardiac arrhythmias. The mechanisms and interrelations linking heart failure and arrhythmias are not fully understood. Historically, research into arrhythmias has been performed on affected individuals or in vivo (animal) models. The latter however is constrained by interspecies variation, demands to reduce animal experiments and cost. Recent developments in in vitro induced pluripotent stem cell technology and in silico modelling have expanded the number of models available for the evaluation of heart failure and arrhythmia. An agnostic approach, combining the modalities discussed here, has the potential to improve our understanding for appraising the pathology and interactions between heart failure and arrhythmia and can provide robust and validated outcomes in a variety of research settings. This review discusses the state of the art models, methodologies and techniques used in the evaluation of heart failure and arrhythmia and will highlight the benefits of using them in combination. Special consideration is paid to assessing the pivotal role calcium handling has in the development of heart failure and arrhythmia.

Atherosclerosis in Fabry Disease-A Contemporary Review.

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Effects of Ivabradine on Hemodynamic and Functional Parameters in Left Ventricular Systolic Dysfunction: a Systematic Review and Meta-analysis.

BACKGROUND: Ivabradine is licensed as add-on therapy in patients with severe left ventricular systolic dysfunction (LVSD), normal sinus rhythm, and suboptimal heart rate (HR) control, but effects are not fully established. This study sought to assess the impact of ivabradine therapy on hemodynamic and functional outcome measures in all patients with LVSD. METHODS: MEDLINE (1996-2017), Embase (1996-2017), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, ClinicalTrials.gov , and ISI Web of Science were searched for randomized clinical trials (RCTs) comparing standard medical therapy (SMT) plus ivabradine to SMT alone for patients with LVSD of any severity. Each trial was assessed using the Cochrane Collaborations Risk of Bias tool. RESULTS: Eight RCTs with 17,823 patients were included. Add-on use of ivabradine reduced resting HR (mean difference [MD] 10.3 bpm; p < 0.001), improved ejection fraction (EF) (MD 3.6%, p < 0.001), and preserved systolic blood pressure (MD 3.4 mmHg; p = 0.09). Stratified analyses according to severity of LVSD did not influence conferred benefits on HR and EF. Small improvements were noted in exercise tolerance (standardized MD 5.9 s; p = 0.004) and peak oxygen consumption (MD 2.9 ml/kg/min; p = 0.02). DISCUSSION: Adjunct therapy with ivabradine in patients with LVSD results in a favorable hemodynamic profile and correlates with improved functional capacity. Benefits appear to be broadly preserved irrespective of baseline EF. This was a meta-analysis of RCTs, though limited by exclusion of post hoc analyses, lack of access to patient level data, and inter-study variability in some baseline characteristics. Further, large-scale RCTs are warranted to evaluate effectiveness of ivabradine in cohorts with non-severe LVSD.

A contemporary review of peripartum cardiomyopathy.

Peripartum cardiomyopathy reflects the presence of cardiac failure in the absence of determinable heart disease and occurs in late third trimester of pregnancy or up to 6 months postpartum. A full understanding of pathophysiological mechanisms is lacking, but excess prolactin levels, haemodynamic alterations, inflammation and nutritional deficiencies have all been implicated. Its clinical presentation has distinct overlap with physiological alterations in healthy pregnancy and this presents a diagnostic challenge. However, echocardiography can provide significant benefit in accurate assessment and narrowing of differentials. Pharmacotherapy is broadly aligned with established guidelines for cardiac failure, but specific therapies are indicated for treatment of clinical sequelae. Moreover, an individualistic approach is required based on clinical context to manage delivery. Further research appears imperative to optimise management strategies and reduce disease burden.

Complicated bile duct stones.

Common bile duct stones (CBDSs) are solid deposits that can either form within the gallbladder or migrate to the common bile duct (CBD), or form de novo in the biliary tree. In the USA around 15% of the population have gallstones and of these, 3% present with symptoms annually. Because of this, there have been major advancements in the management of gallstones and related conditions. Management is based on the patient's risk profile; young and healthy patients are likely to be recommended for surgery and elderly patients with comorbidities are usually recommended for endoscopic procedures. Imaging of gallstones has advanced in the last 30 years with endoscopic retrograde cholangiopancreatography evolving from a diagnostic to a therapeutic procedure in removing CBDSs. We present a complicated case of a patient with a CBDS and periampullary diverticulum and discuss the techniques used to diagnose and remove the stone from the biliary system.

Improving recording of capacity to consent and explanation of medication side effects in a psychiatric service for people with learning disability: audit findings.

This study aimed to examine the practice of psychiatrists in a large learning disability service in recording capacity to consent to treatment and side effect discussion, and the impact of measures aimed at improving this. Three audit cycles were completed between 2007 and 2009, each examining 26 case notes selected at random. Information was gathered on recording of capacity and documentation of explanation of potential side effects. Changes in practice following the introduction of a rubber stamp in 2008, as a visual prompt for clinicians, were examined. Rates of recording of capacity rose from 30% in 2007 to 51% in 2009 (P = 0.000006). Capacity was more likely to have been recorded if the stamp was present (odds ratio 13.5, p < 0.0001). Recording of side effect discussion was consistently higher than that of capacity and showed little change between cycles. We conclude that the use of a rubber stamp in case notes was associated with improvements in the recording of capacity assessments.