euan ashley - Academia.edu (original) (raw)
Papers by euan ashley
Circulation, Nov 25, 2014
J Card Fail, 2008
exhibiting enhanced therapeutic effects. For LVEF effects heterozygotes have beneficial responses... more exhibiting enhanced therapeutic effects. For LVEF effects heterozygotes have beneficial responses that are similar to Arg homozygotes, with Gly homozygotes having a smaller, statistically insignificant remodeling response. These data suggest that the Gly allele is dominant negative for clinical response to bucindolol, whereas the Arg allele is dominant positive for LVEF response.
A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarco... more A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca 2ϩ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca 2ϩ cycling. To test this hypothesis, we have investigated myocardial Ca 2ϩ handling and contractility in nNOS knockout mice (nNOS Ϫ/Ϫ ) and in control mice C) after acute nNOS inhibition with 100 mol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3Ϯ0.6% in nNOS Ϫ/Ϫ versus 8.1Ϯ0.5% in C; PϽ0.05) and in vivo (LV ejection fraction 53.5Ϯ2.7 in nNOS Ϫ/Ϫ versus 44.9Ϯ1.5% in C; PϽ0.05). nNOS disruption increased I Ca density (in pA/pF, at 0 mV, Ϫ11.4Ϯ0.5 in nNOS Ϫ/Ϫ versus Ϫ9.1Ϯ0.5 in C; PϽ0.05) and prolonged the slow time constant of inactivation of I Ca by 38% (PϽ0.05), leading to an increased Ca 2ϩ influx and a greater SR load in nNOS Ϫ/Ϫ myocytes (in pC/pF, 0.78Ϯ0.04 in nNOS Ϫ/Ϫ versus 0.64Ϯ0.03 in C; PϽ0.05). Consistent with these data, [Ca 2ϩ ] i transient (indo-1) peak amplitude was greater in nNOS Ϫ/Ϫ myocytes (410/495 ratio 0.34Ϯ0.01 in nNOS Ϫ/Ϫ versus 0.31Ϯ0.01 in C; PϽ0.05). These findings have uncovered a novel mechanism by which intracellular Ca 2ϩ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2003;92:e52-e59.)
Circulation, Oct 28, 2008
Circulation, Nov 20, 2012
PLOS Genetics, 2015
High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, ... more High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.
Genome Medicine, 2015
Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet t... more Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet the variation of coverage and sensitivity over medically relevant parts of the genome remains poorly understood. Several sequencing-based assays continue to provide coverage that is inadequate for clinical assessment. Using sequence data obtained from the NA12878 reference sample and pre-defined lists of medically-relevant protein-coding and noncoding sequences, we compared the breadth and depth of coverage obtained among four commercial exome capture platforms and whole genome sequencing. In addition, we evaluated the performance of an augmented exome strategy, ACE, that extends coverage in medically relevant regions and enhances coverage in areas that are challenging to sequence. Leveraging reference call-sets, we also examined the effects of improved coverage on variant detection sensitivity. We observed coverage shortfalls with each of the conventional exome-capture and whole-genome platforms across several medically interpretable genes. These gaps included areas of the genome required for reporting recently established secondary findings (ACMG) and known disease-associated loci. The augmented exome strategy recovered many of these gaps, resulting in improved coverage in these areas. At clinically-relevant coverage levels (100 % bases covered at ≥20×), ACE improved coverage among genes in the medically interpretable genome (>90 % covered relative to 10-78 %…
Circulation, Jan 16, 2015
The field of genetics and genomics has advanced considerably with the achievement of recent miles... more The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.
JACC: Heart Failure, 2015
The study sought to discover the key determinants of exercise capacity, maximal oxygen consumptio... more The study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM). The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear. The study sample included 156 HCM patients consecutively enrolled from 2007 to 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation). Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25,…
Circulation, Nov 25, 2014
J Card Fail, 2008
exhibiting enhanced therapeutic effects. For LVEF effects heterozygotes have beneficial responses... more exhibiting enhanced therapeutic effects. For LVEF effects heterozygotes have beneficial responses that are similar to Arg homozygotes, with Gly homozygotes having a smaller, statistically insignificant remodeling response. These data suggest that the Gly allele is dominant negative for clinical response to bucindolol, whereas the Arg allele is dominant positive for LVEF response.
A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarco... more A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca 2ϩ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca 2ϩ cycling. To test this hypothesis, we have investigated myocardial Ca 2ϩ handling and contractility in nNOS knockout mice (nNOS Ϫ/Ϫ ) and in control mice C) after acute nNOS inhibition with 100 mol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3Ϯ0.6% in nNOS Ϫ/Ϫ versus 8.1Ϯ0.5% in C; PϽ0.05) and in vivo (LV ejection fraction 53.5Ϯ2.7 in nNOS Ϫ/Ϫ versus 44.9Ϯ1.5% in C; PϽ0.05). nNOS disruption increased I Ca density (in pA/pF, at 0 mV, Ϫ11.4Ϯ0.5 in nNOS Ϫ/Ϫ versus Ϫ9.1Ϯ0.5 in C; PϽ0.05) and prolonged the slow time constant of inactivation of I Ca by 38% (PϽ0.05), leading to an increased Ca 2ϩ influx and a greater SR load in nNOS Ϫ/Ϫ myocytes (in pC/pF, 0.78Ϯ0.04 in nNOS Ϫ/Ϫ versus 0.64Ϯ0.03 in C; PϽ0.05). Consistent with these data, [Ca 2ϩ ] i transient (indo-1) peak amplitude was greater in nNOS Ϫ/Ϫ myocytes (410/495 ratio 0.34Ϯ0.01 in nNOS Ϫ/Ϫ versus 0.31Ϯ0.01 in C; PϽ0.05). These findings have uncovered a novel mechanism by which intracellular Ca 2ϩ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org. (Circ Res. 2003;92:e52-e59.)
Circulation, Oct 28, 2008
Circulation, Nov 20, 2012
PLOS Genetics, 2015
High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, ... more High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.
Genome Medicine, 2015
Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet t... more Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet the variation of coverage and sensitivity over medically relevant parts of the genome remains poorly understood. Several sequencing-based assays continue to provide coverage that is inadequate for clinical assessment. Using sequence data obtained from the NA12878 reference sample and pre-defined lists of medically-relevant protein-coding and noncoding sequences, we compared the breadth and depth of coverage obtained among four commercial exome capture platforms and whole genome sequencing. In addition, we evaluated the performance of an augmented exome strategy, ACE, that extends coverage in medically relevant regions and enhances coverage in areas that are challenging to sequence. Leveraging reference call-sets, we also examined the effects of improved coverage on variant detection sensitivity. We observed coverage shortfalls with each of the conventional exome-capture and whole-genome platforms across several medically interpretable genes. These gaps included areas of the genome required for reporting recently established secondary findings (ACMG) and known disease-associated loci. The augmented exome strategy recovered many of these gaps, resulting in improved coverage in these areas. At clinically-relevant coverage levels (100 % bases covered at ≥20×), ACE improved coverage among genes in the medically interpretable genome (>90 % covered relative to 10-78 %…
Circulation, Jan 16, 2015
The field of genetics and genomics has advanced considerably with the achievement of recent miles... more The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.
JACC: Heart Failure, 2015
The study sought to discover the key determinants of exercise capacity, maximal oxygen consumptio... more The study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM). The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear. The study sample included 156 HCM patients consecutively enrolled from 2007 to 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation). Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25,…