Publications by authors named "Thomas Hey"

24 Publications

  • Page 1 of 1

Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives.

Circ Heart Fail 2020 Oct 6;13(10):e006701. Epub 2020 Oct 6.

Department of Cardiology, Odense University Hospital, Denmark (T.M.H., S.K.N., J.E.M., J.M.).

Background: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center.

Methods: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (<0.001).

Results: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing.

Conclusions: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006701DOI Listing
October 2020

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the Gene.

Circ Heart Fail 2020 Oct 23;13(10):e006832. Epub 2020 Sep 23.

Department of Inherited Cardiovascular Diseases, Bart's Heart Centre, St. Bartholomew's Hospital, London, United Kingdom (M.M.A., M.L., L.R.L., P.M.E.).

Background: Truncating variants in the gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.

Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).

Results: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (=0.07).

Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006832DOI Listing
October 2020

Left atrial volume index and left ventricular global longitudinal strain predict new-onset atrial fibrillation in patients with transient ischemic attack.

Int J Cardiovasc Imaging 2019 Jul 28;35(7):1277-1286. Epub 2019 Mar 28.

Department of Cardiology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Odense, Denmark.

This study aimed to investigate different echocardiographic parameters for predicting atrial fibrillation (AF) in patients with transient ischemic attack (TIA). Echocardiography was performed in 110 patients (median age 65.8 years, 53% males) with TIA and no history of stroke or AF. All patients underwent monitoring with ECG and 72 h Holter-monitoring, and if no AF was found, an insertable cardiac monitor (ICM) was implanted and patients were followed for a median of 2.2 years. AF was found in 14 patients: five with Holter-monitoring and nine with ICM. AF patients had significantly larger left atrial (LA) volumes indexes compared to patients without AF (26.7 vs. 33.7 ml/m, P = 0.03 for 2D images and 26.5 vs. 33.5 ml/m, P = 0.0008 for 3D images). Patients with AF also had depressed LA function assessed with LA emptying fraction measured with 2D echocardiography (46.3 vs. 57.3%, P = 0.005 for patients with and without AF, respectively). Patients with AF also had depressed left ventricular (LV) function compared to patients without AF. LV ejection fraction was 55 versus 61%, P = 0.04 in patients with and without AF, respectively. LV global longitudinal strain (absolute value) was 16.7 in patients with AF compared to 21.2 in patients without AF (P = 0.001). Echocardiographic measurements of LA and LV size and function can noninvasively predict AF in patients with TIA and could potentially be used to guide AF monitoring strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-019-01586-wDOI Listing
July 2019

Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy.

Circ Heart Fail 2019 03;12(3):e005700

Department of Cardiology, Odense University Hospital, Denmark (T.M.H., J.E.M., J.M.).

Background As pathogenic variants in the gene for RBM20 appear with a frequency of 6% among Danish patients with dilated cardiomyopathy (DCM), it was the aim to investigate the associated disease expression in affected families. Methods and Results Clinical investigations were routinely performed in DCM index-patients and their relatives. In addition, ≥76 recognized and likely DCM-genes were investigated. DNA-sequence-variants within RBM20 were considered suitable for genetic testing when they fulfilled the criteria of (1) being pathogenic according to the American College of Medical Genetics and Genomics-classification, (2) appeared with an allele frequency of <1:10.000, and (3) segregated with DCM in ≥7 affected individuals. A total of 80 individuals from 15 families carried 5 different pathogenic RBM20-variants considered suitable for genetic testing. The penetrance was 66% (53/80) and age-dependent. Males were both significantly younger and had lower ejection fraction at diagnosis than females (age, 29±11 versus 48±12 years; P<0.01; ejection fraction, 29±13% versus 38±9%; P<0.01). Furthermore, 11 of 31 affected males needed a cardiac transplant while none of 22 affected females required this treatment ( P<0.001). Thirty percent of RBM20-carriers with DCM died suddenly or experienced severe ventricular arrhythmias although no adverse events were identified among healthy RBM20-carriers with a normal cardiac investigation. The event-free survival of male RBM20-carriers was significantly shorter compared with female carriers ( P<0.001). Conclusions The disease expression associated with pathogenic RBM20-variants was severe especially in males. The findings of the current study suggested that close clinical follow-up of RBM20-carriers is important which may ensure early detection of disease development and thereby improve management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005700DOI Listing
March 2019

Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.

J Am Coll Cardiol 2018 11;72(20):2471-2481

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART); University Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain. Electronic address:

Background: The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood.

Objectives: This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort.

Methods: The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry.

Results: At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc.

Conclusions: DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2018.08.2181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688826PMC
November 2018

The clinical outcome of LMNA missense mutations can be associated with the amount of mutated protein in the nuclear envelope.

Eur J Heart Fail 2018 10 26;20(10):1404-1412. Epub 2018 Jun 26.

Department of Cardiology, Odense University Hospital, Odense, Denmark.

Aims: Lamin A/C mutations are generally believed to be associated with a severe prognosis. The aim of this study was to investigate disease expression in three affected families carrying different LMNA missense mutations. Furthermore, the potential molecular disease mechanisms of the mutations were investigated in fibroblasts obtained from mutation carriers.

Methods And Results: A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. Disease expression was unusual with a late onset and a favourable prognosis. Two smaller families with severe disease expression were shown to carry a LMNA-p.Arg471Cys and LMNA-p.Arg471His mutation, respectively. LMNA gene and protein expression was investigated in eight different mutation carriers by quantitative reverse transcriptase polymerase chain reaction, Western blotting, immunohistochemistry, and protein mass spectrometry. The results showed that all mutation carriers incorporated mutated lamin protein into the nuclear envelope. Interestingly, the ratio of mutated to wild-type protein was only 30:70 in LMNA-p.Arg216Cys carriers with a favourable prognosis while LMNA-p.Arg471Cys and LMNA-p.Arg471His carriers with a more severe outcome expressed significantly more of the mutated protein by a ratio of 50:50.

Conclusion: The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1241DOI Listing
October 2018

The Stop-Only-While-Shocking algorithm reduces hands-off time by 17% during cardiopulmonary resuscitation - a simulation study.

Eur J Emerg Med 2016 Dec;23(6):413-417

aDepartment of Gastroenterology and Hepatology, Vejle Hospital, a part of Lillebaelt Hospital, Vejle bDepartment of Pulmonary diseases, Bispebjerg Hospital, Copenhagen cCentre of Cancer Immunotherapy, Herlev Hospital, Herlev dDepartment of Emergency Medicine, Hospital of South-West Jutland, Esbjerg Departments of eEndocrinology fGastroenterology and Hepatology gCardiology hClinical Chemistry and Pharmacology iEmergency Medicine, Odense University Hospital jDepartment of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

Introduction: Reducing hands-off time during cardiopulmonary resuscitation (CPR) is believed to increase survival after cardiac arrests because of the sustaining of organ perfusion. The aim of our study was to investigate whether charging the defibrillator before rhythm analyses and shock delivery significantly reduced hands-off time compared with the European Resuscitation Council (ERC) 2010 CPR guideline algorithm in full-scale cardiac arrest scenarios.

Methods: The study was designed as a full-scale cardiac arrest simulation study including administration of drugs. Participants were randomized into using the Stop-Only-While-Shocking (SOWS) algorithm or the ERC2010 algorithm. In SOWS, chest compressions were only interrupted for a post-charging rhythm analysis and immediate shock delivery. A Resusci Anne HLR-D manikin and a LIFEPACK 20 defibrillator were used. The manikin recorded time and chest compressions.

Results: Sample size was calculated with an α of 0.05 and 80% power showed that we should test four scenarios with each algorithm. Twenty-nine physicians participated in 11 scenarios. Hands-off time was significantly reduced 17% using the SOWS algorithm compared with ERC2010 [22.1% (SD 2.3) hands-off time vs. 26.6% (SD 4.8); P<0.05].

Conclusion: In full-scale cardiac arrest simulations, a minor change consisting of charging the defibrillator before rhythm check reduces hands-off time by 17% compared with ERC2010 guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MEJ.0000000000000282DOI Listing
December 2016

A Systematic Review of Phenotypic Features Associated With Cardiac Troponin I Mutations in Hereditary Cardiomyopathies.

Can J Cardiol 2015 Nov 23;31(11):1377-85. Epub 2015 Jun 23.

Department of Cardiology, Odense University Hospital, Odense, Denmark.

Background: Genetic investigations have established that mutations in proteins of the contractile unit of the myocardium, known as the sarcomere, may be associated with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). It has become clinical practice to offer genetic testing in affected individuals to identify causative mutations, which provides the basis for presymptomatic testing of relatives who are at risk of disease development. This ensures adequate clinical follow-up of mutation carriers, whereas noncarriers can be discharged. However, before genetic testing can be used for individual risk assessment and prediction of prognosis, it is important to investigate if there is a relation between the clinical disease expression (phenotype) of the condition and mutations in specific disease genes (genotype).

Methods: We reviewed the literature in relation to phenotypic features reported to be associated with mutations in cardiac troponin I (cTnI; TNNI3), which is a recognized sarcomeric disease gene in all 3 cardiomyopathies.

Results: The results of this review did not identify specific genotype-phenotype relations in HCM or DCM, and cTnI appeared to be the most frequent disease gene in RCM.

Conclusions: To further explore if there is a genotype-phenotype relation, long-term follow-up studies are needed. It is essential to investigate the natural history of the condition among affected individuals and to provide clinical follow-up on disease development among healthy mutation carriers. Such information is required to provide evidence-based counselling for affected families and to elucidate if knowledge about specific genotypes can be used in future risk prediction models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cjca.2015.06.015DOI Listing
November 2015

Freeze-drying of HESylated IFNα-2b: Effect of HESylation on storage stability in comparison to PEGylation.

Int J Pharm 2015 Nov 24;495(1):608-611. Epub 2015 Sep 24.

Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximillians-University Munich, Butenandtstr. 5-8, 81377 Munich, Germany.

A comparison of lyophilized PEGylated and HESylated IFNα was carried out to investigate the influence of protein conjugation, lyoprotectants as well as storage temperature on protein stability. Results show that PEG tends to crystallize during freeze-drying, reducing protein stability upon storage. In contrast, HESylation(®) drastically improved the stability over PEGylation by remaining totally amorphous during lyophilization, with and without lyoprotectants while providing a high glass transition temperature of the freeze-dried cakes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2015.09.031DOI Listing
November 2015

Embolisation of pheochromocytoma to stabilise and wean a patient in cardiogenic shock from emergency extracorporeal life support.

BMJ Case Rep 2015 Mar 3;2015. Epub 2015 Mar 3.

Odense University Hospital, Odense, Denmark.

Pheochromocytoma is a catecholamine-secreting tumour associated with varying symptoms ranging from episodic headache, sweating, paroxysmal hypertension and tachycardia to intractable cardiogenic shock. Cardiogenic shock is rare but well-described and the timing of correct management is crucial since mortality is high. Fifty per cent of pheochromocytomas are diagnosed on autopsy. We report on a case of embolisation of the adrenal artery during ongoing extracorporeal life support (ECLS) in order to stabilise and wean the patient from ECLS as a bridge to final surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2014-206069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368962PMC
March 2015

Head to head comparison of the formulation and stability of concentrated solutions of HESylated versus PEGylated anakinra.

J Pharm Sci 2015 Feb 1;104(2):515-26. Epub 2014 Dec 1.

Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximillians-University Munich, Munich, 81377, Germany.

Although PEGylation of biologics is currently the gold standard for half-life extension, the technology has a number of limitations, most importantly the non-biodegradability of PEG and the extremely high viscosity at high concentrations. HESylation is a promising alternative based on coupling to the biodegradable polymer hydroxyethyl starch (HES). In this study, we are comparing HESylation with PEGylation regarding the effect on the protein's physicochemical properties, as well as on formulation at high concentrations, where protein stability and viscosity can be compromised. For this purpose, the model protein anakinra is coupled to HES or PEG by reductive amination. Results show that coupling of HES or PEG had practically no effect on the protein's secondary structure, and that it reduced protein affinity by one order of magnitude, with HESylated anakinra more affine than the PEGylated protein. The viscosity of HESylated anakinra at protein concentrations up to 75 mg/mL was approximately 40% lower than that of PEG-anakinra. Both conjugates increased the apparent melting temperature of anakinra in concentrated solutions. Finally, HESylated anakinra was superior to PEG-anakinra regarding monomer recovery after 8 weeks of storage at 40°C. These results show that HESylating anakinra offers formulation advantages compared with PEGylation, especially for concentrated protein solutions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jps.24253DOI Listing
February 2015

Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra.

Eur J Pharm Biopharm 2014 Jul 27;87(2):378-85. Epub 2014 Mar 27.

Department of Pharmacy, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximillians-University Munich, Munich, Germany. Electronic address:

Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein. Characterization using size exclusion chromatography and dynamic light scattering confirmed conjugation and the increase in molecular size, while Fourier transform infrared spectroscopy showed that the secondary structure of the conjugate was not affected by coupling. Meanwhile, microcalorimetry and aggregation studies showed a significant increase in protein stability. Surface plasmon resonance and microscale thermophoresis showed that the conjugate retained its nanomolar affinity, and finally, the pharmacokinetics of the HESylated protein exhibited a 6.5-fold increase in the half-life, and a 45-fold increase in the AUC. These results indicate that HESylation(®) is a promising HLE technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2014.03.010DOI Listing
July 2014

Biventricular hypertrophy and heart failure as initial presentation of Cushing's disease.

BMJ Case Rep 2013 Nov 1;2013. Epub 2013 Nov 1.

Department of Cardiology, University Hospital of Odense, Odense, Denmark.

We present a unique case of a 32-year-old woman with severe biventricular hypertrophy and acute heart failure with reduced left ventricular ejection fraction of 25-30% due to Cushing's disease. The patient was admitted to a specialised cardiac unit and treated with conventional therapy against heart failure. The department of endocrinology was consulted because of clinical suspicion of Cushing's syndrome. Initial biochemistry indicated the presence of adrenocorticotropic hormone (ACTH) dependent Cushing's syndrome and a dexamethasone suppression test confirmed the diagnosis. A cerebral MRI scan revealed a pituitary adenoma and a sinus petrosus inferior catheterisation confirmed increased production of ACTH from the pituitary. The patient was referred to the neurosurgical department and the adenoma was successfully removed by transsphenoidalic catheterisation and ablation. Five months following the initial hospitalisation the patient was nearly in full recovery with respect to her cardiac function and biochemically there were no signs of Cushing's syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2013-201307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830406PMC
November 2013

Left ventricular diastolic function is associated with symptom status in severe aortic valve stenosis.

Circ Cardiovasc Imaging 2014 Jan 30;7(1):142-8. Epub 2013 Oct 30.

Department of Cardiology, Odense University Hospital, Odense, Denmark.

Background: In aortic valve stenosis (AS), the occurrence of heart failure symptoms does not always correlate with severity of valve stenosis and left ventricular (LV) function. Therefore, we tested the hypothesis that symptomatic patients with AS have impaired diastolic, longitudinal systolic function, and left atrial dilatation compared with asymptomatic patients.

Methods And Results: In a retrospective descriptive study, we compared clinical characteristics and echocardiographic parameters in 99 symptomatic and 139 asymptomatic patients with severe AS and LV ejection fraction ≥50%. Independent predictors of symptomatic state were identified using logistic regression analysis. Symptomatic patients were younger (72±10 versus 76±12 years of age; P=0.002), presented less often with atrial fibrillation (13% versus 24%; P=0.05) and chronic obstructive pulmonary disease (2% versus 19%; P<0.001), and had a lower prevalence of hypertension (73% versus 40%; P<0.001). Despite similar AS severity, symptomatic patients had higher LV mass index (120±39 versus 95±25 g/m2; P<0.0001), increased relative wall thickness (0.61±0.15 versus 0.50±0.11; P<0.0001), shorter mitral deceleration time (199±58 versus 268±62 ms; P<0.0001), and increased left atrial volume index (49±18 versus 42±15 mL/m2; P=0.02). When adjusting for age, history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease in a multivariable logistic regression analysis, LV mass index, relative wall thickness, left atrial volume index, and deceleration time were still associated with the presence of symptoms.

Conclusions: The present study demonstrates that symptomatic status in severe AS is associated with impaired diastolic function, LV hypertrophy, concentric remodeling, and left atrial dilatation when corrected for indices of AS severity.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00294775.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.113.000636DOI Listing
January 2014

Left atrial volume index: relation to long-term clinical outcome in type 2 diabetes.

J Am Coll Cardiol 2013 Dec 24;62(25):2416-2421. Epub 2013 Sep 24.

Department of Cardiology, Odense University Hospital, Odense, Denmark.

Objectives: The study sought to determine the prognostic importance of left atrial (LA) dilation in patients with type 2 diabetes mellitus (T2DM) and no history of cardiovascular disease (CVD).

Background: T2DM is associated with the development of CVD, and morphological changes in the heart may appear before symptoms arise.

Methods: A total of 305 T2DM patients without known CVD referred to a diabetes clinic were included consecutively (age 58.6 ± 11.3 years, diabetes duration 2.0 [interquartile range: 0 to 6.0] years). Each patient underwent a comprehensive echocardiogram and a myocardial perfusion scintigraphy (MPS) at inclusion. Patients were divided according to left atrial volume index (LAVi) ≥32 ml/m(2). Patients were followed for median of 5.6 (interquartile range: 5.1 to 6.1) years for the occurrence of major cardiac events and death.

Results: LAVi ≥32 ml/m(2) was found in 105 patients (34%). During follow-up, 60 patients (20%) experienced the composite endpoint, of whom 28 (9%) died. Patients with LAVi ≥32 ml/m(2) had a significantly higher cardiac event rate and death rate (p < 0.001 and p = 0.002, respectively). Univariate predictors of the composite endpoint were age, hypertension, left ventricular diastolic function, E/e'septum-ratio and LAVi ≥32 ml/m(2); however, myocardial ischemia on MPS was not a predictor. When adjusting for age and hypertension, only LAVi ≥32 ml/m(2) was a predictor of the composite endpoint (hazard ratio: 1.82 [95% confidence interval: 1.08 to 3.07], p = 0.024).

Conclusions: Increased LAVi was an independent and incremental predictor of cardiovascular morbidity and mortality in T2DM patients with no history of CVD. (Presence of Macrovascular Disease in Type 2 Diabetes Mellitus; NCT00298844).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2013.08.1622DOI Listing
December 2013

Isomerization polymerization of the phosphaalkene MesP=CPh2: an alternative microstructure for poly(methylenephosphine)s.

Angew Chem Int Ed Engl 2013 Jul 5;52(27):6967-70. Epub 2013 Jun 5.

Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201301881DOI Listing
July 2013

Cyclopropenylidene carbene ligands in palladium catalysed coupling reactions: carbene ligand rotation and application to the Stille reaction.

Dalton Trans 2011 May 7;40(19):5316-23. Epub 2011 Apr 7.

School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK BS8 1TS.

Reaction of [Pd(PPh(3))(4)] with 1,1-dichloro-2,3-diarylcyclopropenes gives complexes of the type cis-[PdCl(2)(PPh(3))(C(3)(Ar)(2))] (Ar = Ph 5, Mes 6). Reaction of [Pd(dba)(2)] with 1,1-dichloro-2,3-diarylcyclopropenes in benzene gave the corresponding binuclear palladium complexes trans-[PdCl(2)(C(3)(Ar)(2))](2) (Ar = Ph 7, p-(OMe)C(6)H(4)8, p-(F)C(6)H(4)9). Alternatively, when the reactions were performed in acetonitrile, the complexes trans-[PdCl(2)(NCMe)(C(3)(Ar)(2))] (Ar = Ph 10, p-(OMe)C(6)H(4)11 and p-(F)C(6)H(4)) 12) were isolated. Addition of phosphine ligands to the binuclear palladium complex 7 or acetonitrile adducts 11 and 12 gave complexes of the type cis-[PdCl(2)(PR(3))(C(3)(Ar)(2))] (Ar = Ph, R = Cy 13, Ar = p-(OMe)C(6)H(4), R = Ph 14, Ar = p-(F)C(6)H(4), R = Ph 15). Crystal structures of complexes 6·3.25CHCl(3), 10, 11·H(2)O and 12-15 are reported. DFT calculations of complexes 10-12 indicate the barrier to rotation about the carbene-palladium bond is very low, suggesting limited double bond character in these species. Complexes 5-9 were tested for catalytic activity in C-C coupling (Mizoroki-Heck, Suzuki-Miyaura and, for the first time, Stille reactions) and C-N coupling (Buchwald-Hartwig amination) showing excellent conversion with moderate to high selectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c1dt10109aDOI Listing
May 2011

Ligand effects in chromium diphosphine catalysed olefin co-trimerisation and diene trimerisation.

Dalton Trans 2010 Jan 16(2):560-7. Epub 2009 Oct 16.

School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK BS8 1TS.

A series of symmetric and unsymmetric N,N-bis(diarylphosphino)amine ('PNP') ligands (Ar2PN(R)PNAr'2: R = Me, Ar2 = o-anisyl, Ar'2 = Ph, 1, R = Me, Ar2 = o-tolyl, Ar'2 = Ph, 2, R = Me, Ar2 = Ph(o-ethyl), Ar'2 = Ph, 3, R = Me, Ar2 = Ar'2 = o-anisyl, 4, R = iPr, Ar2 = Ar'2 = Ph, 5) and symmetric N,N'-bis(diarylphosphino)dimethylhydrazine ('PNNP') ligands (Ar2PN(Me)N(Me)PAr2: Ar2 = o-tolyl, 6, Ar2 = o-anisyl, 7) have been synthesised. Catalytic screening for ethene/styrene co-trimerisation and isoprene trimerisation was performed via the in situ complexation to [CrCl3(THF)3] followed by activation with methylaluminoxane (MAO). PNNP catalytic systems showed a significant increase in activity and selectivity over previously reported PNP systems in isoprene trimerisation. Comparing the symmetric and unsymmetric variants in ethene and styrene co-trimerisation resulted in a switch in selectivity, an unsymmetric catalytic (o-anisyl)2PN(Me)PPh2 (1) ligand system affording unique incorporation of two styrenic monomers into the co-trimer product distribution differing from the familiar two ethene and one styrene -substituted alkenes. Complexes of the type [(diphosphine)Cr(CO)4] 8-11 were also synthesised, the single-crystal X-ray diffraction of which are reported. We propose the mechanisms of these catalytic transformations and an insight into the effect of the ligand series on the chromacyclic catalytic intermediates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/b913302jDOI Listing
January 2010

Affilin molecules selected against the human papillomavirus E7 protein inhibit the proliferation of target cells.

J Mol Biol 2009 Jul 21;390(4):710-21. Epub 2009 May 21.

Institute of Biochemistry/Biotechnology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Intracellular binding proteins can be applied as research tools for target validation and study of protein function in cells and potentially as therapeutics. The success of intracellular binding reagents depends on their affinity and specificity for target molecules, although their stability and functionality in the intracellular environment actually determine their usefulness for such application. Alternative binding proteins derived from scaffolds devoid of disulfide bonds are well suited for intracellular use, as their folding and stability are usually not impaired under reducing conditions. Here, we describe the generation of intracellular binding reagents called Affilin, based on the human gammaB-crystallin scaffold. The target was human papillomavirus E7 protein implicated in the development of cervical cancer. E7 binders were selected from the combinatorial gammaB-crystallin library by conventional phage display technique. Affilin variants specifically bound the E7 protein with affinities in the nanomolar range. Intracellular expression of Affilin molecules in E7-positive cells led to inhibition of cellular proliferation. The effect was specific, as the growth of E7-negative cells or cells expressing the wild-type gammaB-crystallin scaffold remained unaffected. These results demonstrate that the gammaB-crystallin scaffold allows the de novo generation of alternative binding proteins, which are suitable for intracellular applications as they retain their functionality in the reducing environment of mammalian cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmb.2009.05.027DOI Listing
July 2009

Cyclopropenylidene carbene ligands in palladium C-C coupling catalysis.

Chem Commun (Camb) 2007 Jul 17(26):2704-6. Epub 2007 Apr 17.

School of Chemistry, University of Bristol, Cantock's Close, Bristol, UKBS8 1TS.

A palladium complex supported by a 2,3-diphenylcyclopropenylidene carbene ligand is a highly active and robust catalyst for Heck and Suzuki coupling reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/b702827jDOI Listing
July 2007

Expression and purification of His-tagged HPV16 E7 protein active in pRb binding.

Protein Expr Purif 2006 Aug 20;48(2):281-91. Epub 2006 May 20.

Institut für Biotechnologie, Martin-Luther-Universität Halle/Wittenberg, Halle (Saale), Germany.

Human papillomavirus type 16 (HPV16) protein E7 is the major oncogenic factor associated with the development of human cervical cancer. The transforming activity of the E7 protein is linked to its interaction with host regulatory proteins such as the retinoblastoma tumor suppressor protein. The recombinant production of E7 protein is a prerequisite for its structural and functional characterization as well as for the development of various preventive and therapeutic strategies. We present an approach to enhance the soluble expression of His-tagged E7 protein by optimization of the E7 gene and the expression conditions in the host Escherichia coli. We also report a detailed protocol for the purification of E7 protein by standard chromatographic methods. The binding of E7 protein to the recombinant non-phosphorylated form of retinoblastoma protein was examined by ELISA and surface plasmon resonance analysis. These studies confirm that the recombinant His-tagged E7 protein retains its conformational properties and biological activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pep.2006.04.017DOI Listing
August 2006

Artificial, non-antibody binding proteins for pharmaceutical and industrial applications.

Trends Biotechnol 2005 Oct;23(10):514-22

Scil Proteins GmbH, Heinrich-Damerow-Str.1, 06120 Halle/Saale, Germany.

Using combinatorial chemistry to generate novel binding molecules based on protein frameworks ('scaffolds') is a concept that has been strongly promoted during the past five years in both academia and industry. Non-antibody recognition proteins derive from different structural families and mimic the binding principle of immunoglobulins to varying degrees. In addition to the specific binding of a pre-defined target, these proteins provide favourable characteristics such as robustness, ease of modification and cost-efficient production. The broad spectrum of potential applications, including research tools, separomics, diagnostics and therapy, has led to the commercial exploitation of this technology by various small- and medium-sized companies. It is predicted that scaffold-based affinity reagents will broaden and complement applications that are presently covered by natural or recombinant antibodies. Here, we provide an overview on current approaches in the biotech industry, considering both scientific and commercial aspects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tibtech.2005.07.007DOI Listing
October 2005

The XPC-HR23B complex displays high affinity and specificity for damaged DNA in a true-equilibrium fluorescence assay.

Biochemistry 2002 May;41(21):6583-7

Lehrstuhl für Biochemie, Universität Bayreuth, Universitätsstrasse 30, 95447 Bayreuth, Germany.

The XPC-HR23B complex is a prime candidate for the initial damage recognition step during global genome nucleotide excision repair. A specific interaction between the XPC-HR23B complex and various types of damaged DNA substrates has been demonstrated in recent work by electrophoretic mobility shift assays or immunoprecipitation. Although these studies allowed the estimation of relative binding affinities for the different types of lesions, the presence of large amounts of competitor DNA or the need for glutaraldehyde fixation prevented the quantification of equilibrium constants. We have performed a quantitative study on the binding of XPC to damaged DNA using fluorescence anisotropy measurements. The XPC-HR23B complex binds with high affinity (K(D) approximately 1-3 nM) to fluorescent 36 bp DNA fragments containing a single cisplatin 1,3-intrastrand adduct or a six-nucleotide mispaired region. From stoichiometric titration experiments, it is concluded that approximately 70% of the XPC-HR23B preparation is active in DNA binding. Binding experiments employing fluorescent probes with a single defined photoproduct reveal a 30-fold preference of XPC for 6,4-photoproducts as compared to a cyclobutane dimer. Competition experiments with undamaged and damaged plasmid DNA indicate that the XPC-HR23B complex discriminates between damaged and undamaged sites with high specificity. The specificity factor is between 100 and 3000, depending on the number of nonspecific sites considered in the calculations. Upon addition of XPA to the XPC binding reaction mixtures, it was not possible to detect cooperative ternary complex formation on the platinated 36 bp probe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi012202tDOI Listing
May 2002