[Show abstract][Hide abstract] ABSTRACT: Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
The American Journal of Human Genetics 09/2015; DOI:10.1016/j.ajhg.2015.08.011 · 10.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dubowitz syndrome is a presumed autosomal recessive disorder characterized by multiple congenital abnormalities: microcephaly, learning and developmental delay, growth failure, and a predisposition to allergies and eczema. There have been more than 150 individuals reported to have this diagnosis, but no unifying genetic alteration has been identified indicating genetic heterogeneity. We report on a pair of monozygotic twins diagnosed clinically with Dubowitz syndrome by Professor Dubowitz over 30 years ago and identified to have a de novo heterozygous 3.2-Mb deletion at 19q13.11q13.12. Exome sequencing did not identify either a putative pathogenic variant on the trans allele supporting recessive inheritance or any other causative sequence variants. Comparison of the phenotype in our cases shows considerable overlap with the 19q13.11 microdeletion syndrome, suggesting that a subset of individuals diagnosed with Dubowitz syndrome may be due to deletions at 19q13. Our finding further reinforces the genetic and phenotypic heterogeneity of Dubowitz syndrome.Journal of Human Genetics advance online publication, 17 September 2015; doi:10.1038/jhg.2015.111.
Journal of Human Genetics 09/2015; DOI:10.1038/jhg.2015.111 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Digoxin is the oldest known treatment for heart failure (HF) and has been demonstrated to reduce admissions for worsening heart failure in a large randomised trial recruiting patients in sinus rhythm with heart failure and ejection fraction <45%. This study forms the basis for current international guidelines recommending that digoxin should be considered in patients with symptomatic HF despite optimal doses of angiotensin-converting-enzyme-inhibitors / angiotensin-receptor-blockers, β-blockers and mineralocorticoid-receptor-antagonists in addition to device therapy, if indicated. However, definitive evidence of digoxin efficacy as add-on therapy in this context is lacking since most landmark trials of modern HF disease modifying agents post-date the randomised studies of digoxin. Furthermore, questions remain regarding the optimum dose of digoxin and there are signals that digoxin may be harmful in some patients with HF. All contemporary data for digoxin in HF are derived from observational studies and the findings are conflicting. Despite two centuries of experience using cardiac glycosides to treat HF, fundamental questions regarding the efficacy and safety of digoxin in HF remain unanswered. This paper reviews the historical and recent data. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Introduction: There is an association between heart failure (HF) and testosterone deficiency. Salivary testosterone (ST) has been described as a marker of the free fraction of testosterone in healthy populations and has not commonly been utilized clinically. This study aimed to assess the clinical utility of ST in a HF population with a broad range of testosterone concentrations compared with more traditional serum parameters. Methods: A total of 40 men with HF were recruited. Traditional serum testosterone measures and ST measures were collected on two separate occasions. Patients performed a 6-min walk, underwent echocardiography and completed quality of life questionnaires. Bland–Altman plots were constructed to assess the agreement between ST and free testosterone (FT) levels, and to assess the repeatability between traditional and ST measures. Pearson’s correlation was used to determine the relationship between ST levels, traditional serum testosterone parameters and important health outcomes. Results: There was excellent agreement between ST and FT measures [bias 0.087 nmol/l, SD 0.056 nmol/l, 95% limits of agreement (LoA) of +2 SD 0.104 nmol/l and −2 SD −0.122 nmol/l]. ST and FT measures show excellent reproducibility (bias 0.0137 nmol/l, SD 0.021 nmol/l, 95% LoA +2 SD 0.041 nmol/l and −2 SD −0.041 nmol/l for ST, and bias 0.004 nmol/l, SD ±0.0025 nmol/l, 95% LoA ±2 SD +0.055 nmol/l and −0.046 nmol/l). There are similar levels of moderately strong positive correlation between ST levels, other testosterone fractions and endurance capacity/physical domains of quality of life assessed using the Short Form-36 questionnaire. Conclusion: ST can be used as an alternative marker of traditional testosterone parameters in HF without semi-invasive blood sampling. There is a correlation between exercise capacity and physical quality of life domains with all testosterone fractions.
[Show abstract][Hide abstract] ABSTRACT: Agnathia-otocephaly complex is a malformation characterized by absent/hypoplastic mandible and abnormally positioned ears. Mutations in two genes, PRRX1 and OTX2, have been described in a small number of families with this disorder. We performed clinical and genetic testing in an additional family. The proband is a healthy female with a complicated pregnancy history that includes two offspring diagnosed with agnathia-otocephaly during prenatal ultrasound scans. Exome sequencing was performed in fetal DNA from one of these two offspring revealing a heterozygous duplication in OTX2: c.271_273dupCAG, p.(Gln91dup). This change leads to the insertion of a glutamine within the OTX2 homeodomain region, and is predicted to alter this signaling molecule's ability to interact with DNA. The same variant was also identified in the proband's clinically unaffected 38-year-old husband and their 9-year-old daughter, who presented with a small mandible, normal ears and velopharyngeal insufficiency due to a short hemi-palate. This unusual presentation of OTX2-related disease suggests that OTX2 might have a role in palatal hypoplasia cases. A previously unreported OTX2 variant associated with extreme intrafamilial variability is described and the utility of exome sequencing as a tool to confirm the diagnosis of agnathia-otocephaly and to inform the reproductive decisions of affected families is highlighted.Journal of Human Genetics advance online publication, 15 January 2015; doi:10.1038/jhg.2014.122.
Journal of Human Genetics 01/2015; 60(4). DOI:10.1038/jhg.2014.122 · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acidovorax oryzae is a bacterium that has never before been reported as pathogenic in human subjects. Here we describe the first case of a
successfully treated A. oryzae catheter-associated bloodstream infection in an immunocompetent patient prior to heart transplantation.
Journal of Clinical Microbiology 10/2014; DOI:10.1128/JCM.00657-14 · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims:
We wish to assess the clinical and cost-effectiveness of remote monitoring of heart failure patients with cardiac implanted electronic devices.
REM-HF is a multicentre, randomized, non-blinded, parallel trial designed to compare weekly remote monitoring-driven management with usual care for patients with cardiac implanted electronic devices (ICD, CRT-D, or CRT-P). The trial is event driven, and the final analysis will be performed when 546 events have been observed or the study is terminated at the interim analysis. We have randomized 1650 patients to be followed up for a minimum of 2 years. Patients will remain in the trial up to study termination. The first patient was randomized in September 2011 and the study is expected to complete in early 2016. The primary combined endpoint is time to first event of all-cause death or unplanned hospitalization for cardiovascular reasons. An economic evaluation will be performed, estimating the cost per quality-adjusted life year, with direct costs estimated from the National Health Service perspective and quality of life assessed by the EQ-5D, Short-Form 12, and Kansas City Cardiomyopathy Questionnaires. The study design has been informed by a feasibility study.
REM-HF is a multicentre randomized study that will provide important data on the effect of remote monitoring-driven management of implanted cardiac devices on morbidity and mortality, as well as the cost-effectiveness of this approach.
European Journal of Heart Failure 09/2014; 16(9). DOI:10.1002/ejhf.149 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation.
All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant.
88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (−12.7 ± 2.5% vs. -13.7 ± 3.6%, p = 0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised.
This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR during the early phase post-transplantation.
[Show abstract][Hide abstract] ABSTRACT: The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the diagnostic performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting cardiac allograft vasculopathy (CAV) using contemporary invasive epicardial artery and microvascular assessment techniques as reference standards, and to compare the performance of CMR with that of angiography.
CAV continues to limit the long-term survival of heart transplant recipients. Coronary angiography has a class I recommendation for CAV surveillance and annual or biannual surveillance angiography is performed routinely in most centers.
All transplant recipients referred for surveillance angiography at a single UK center over a 2-year period were prospectively screened for study eligibility. Patients prospectively underwent coronary angiography followed by coronary intravascular ultrasound, fractional flow reserve and index of microcirculatory resistance. Within one month patients underwent multiparametric CMR, including assessment of regional and global ventricular function, absolute myocardial blood flow quantification and myocardial tissue characterization. In addition, 10 healthy volunteers underwent CMR.
Forty-eight patients were recruited; median 7.1 years (IQR 4.6-10.3) since transplantation. CMR myocardial perfusion reserve was the only independent predictor of both epicardial (β = -0.57, p<0.001) and microvascular disease (β = -0.60, p<0.001) on stepwise multivariable regression. CMR myocardial perfusion reserve significantly outperformed angiography for detecting moderate CAV (AUC 0.89 (0.79-1.0) v 0.59 (0.42-0.77), p=0.01) and severe CAV (AUC 0.88 (0.78-0.98) v 0.67 (0.52-0.82), p=0.05).
CAV, including epicardial and microvascular components, can be detected more accurately using non-invasive CMR-based absolute myocardial blood flow assessment than with invasive coronary angiography, the current clinical surveillance technique.
Journal of the American College of Cardiology 12/2013; 63(8). DOI:10.1016/j.jacc.2013.07.119 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heart transplantation (HTX) is the gold standard surgical treatment for patients with advanced heart failure. The prevalence of hepatitis B and hepatitis C infection in HTX recipients is over 10%. Despite its increased prevalence, the long-term outcome in this cohort is still not clear. There is a reluctance to place these patients on transplant waiting list given the increased incidence of viral reactivation and chronic liver disease after transplant. The emergence of new antiviral therapies to treat this cohort seems promising but their long-term outcome is yet to be established. The aim of this paper is to review the literature and explore whether it is justifiable to list advanced heart failure patients with coexistent hepatitis B/C infection for HTX.
Journal of Transplantation 11/2013; 2013:748578. DOI:10.1155/2013/748578
[Show abstract][Hide abstract] ABSTRACT: Background:
Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T1-mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV); however, the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of (1) dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T1 values measured before and after gadolinium bolus; and (2) isolated measurement of myocardial T1, used as an ECV surrogate.
Methods and results:
Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction, obtained from each of 16 segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR before transplantation (median interval between CMR and transplantation, 29 days). DynEq-CMR-derived ECV was calculated from T1 measurements made using a modified Look-Locker inversion recovery sequence before and 10 and 15 minutes post contrast. In addition, ECV was measured 2 to 20 minutes post contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR-derived ECV and histological collagen volume fraction (P<0.001; within-subject: r=0.745; P<0.001; r(2)=0.555 and between-subject: r=0.945; P<0.01; r(2)=0.893; for ECV calculated using 15-minute postcontrast T1). Correlation was maintained throughout the entire heart. Isolated postcontrast T1 measurement showed significant within-subject correlation with histological collagen volume fraction (r=-0.741; P<0.001; r(2)=0.550 for 15-minute postcontrast T1), but between-subject correlations were not significant. DynEq-CMR-derived ECV varied significantly according to contrast dose, myocardial region, and sex.
DynEq-CMR-derived ECV shows a good correlation with histological collagen volume fraction throughout the whole heart. Isolated postcontrast T1 measurement is insufficient for ECV assessment.
[Show abstract][Hide abstract] ABSTRACT: Increased resting heart rate is an independent modifiable risk factor for the development of cardiovascular disease. Numerous studies have demonstrated improved clinical outcomes with heart rate reduction in patients with coronary artery disease and heart failure, but its role in transplanted hearts is not yet established. Sinus tachycardia is more common in heart transplant recipients due to graft denervation. Although a large number of studies have recognized increased heart rate as a predictor of native coronary artery atherosclerosis and overall cardiac mortality, contradicting results have been observed in heart transplant recipients. There is no clear consensus about what the normal range of heart rate should be following heart transplantation. The aim of this article was to review the literature to evaluate whether heart rate reduction should be considered in heart transplant recipients. Dr. Simon G. Williams and Dr. Steven M. Shaw have received honoraria from Servier for advisory work. The authors have no other funding, financial relationships, or conflicts of interest to disclose.