RESUMO
PURPOSE: Orthostatic hypotension is a common condition with heterogeneous and, in many cases, unclear underlying pathophysiology. Frequent symptoms are syncope and falls with a strong impact on daily life. A two-generation family with eight individuals segregating early-onset severe orthostatic hypotension with persistent tachycardia in upright position and repeated faints was identified. Our aim was to elucidate the underlying pathophysiology. METHODS: One severely affected individual underwent thorough investigation with neurophysiological and blood pressure (BP) measurements, including direct recording of baroreflex-governed sympathetic nerve signalling and induction of BP rise with phenylephrine. Family members underwent parts of the examination. Genetic analysis using exome sequencing was performed. RESULTS: Marked postural hypotension with greatly reduced cardiac preload was observed, but without signs of autonomic nervous system dysfunction: sympathetic nerve signalling was normal, as were catecholamine levels, and phenylephrine stimulation revealed a normal increase in BP. The results of the genetic analysis using exome sequencing comprising all known genes associated with the regulation of BP and catecholamine metabolism were normal. CONCLUSION: The combined findings suggest an autosomal dominant form of early-onset orthostatic hypotension with variable clinical expression and without any additional autonomic dysfunction. It is possible that further investigation will reveal an as yet undescribed entity of orthostatic hypotension transmitted as an autosomal dominant trait.
Assuntos
Doenças do Sistema Nervoso Autônomo , Hipotensão Ortostática , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/genética , Suécia , Síncope , Fenilefrina , CatecolaminasRESUMO
OBJECTIVE: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure. METHODS: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure. RESULTS: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex. CONCLUSIONS: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.
Assuntos
Doenças do Sistema Nervoso Autônomo/genética , Mutação , Receptores Nicotínicos/genética , Adolescente , Adulto , Constipação Intestinal/genética , Feminino , Genes Recessivos , Humanos , Hipotensão Ortostática/genética , Masculino , Miose/genética , Linhagem , Sequenciamento do ExomaAssuntos
Hipotensão Ortostática/genética , Doença por Corpos de Lewy/genética , Doença de Parkinson/genética , alfa-Sinucleína/deficiência , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Duplicação Gênica , Humanos , Hipotensão Ortostática/fisiopatologia , Japão , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Linhagem , Penetrância , alfa-Sinucleína/genéticaRESUMO
Background Evidence suggests that enlarged perivascular spaces (PVSs) may represent a marker for cerebral small-vessel disease. We investigated whether vascular risk factors are correlated with visible PVS in older adults. Methods and Results This population-based study included 530 participants (age ≥60 years) who were free from dementia and functional dependence, derived from the Swedish National study on Aging and Care in Kungsholmen (2001-2003). We collected data on demographics, vascular risk factors, and health conditions through interviews, clinical examinations, laboratory tests, and patient registers. Cerebral PVSs and white matter hyperintensities on magnetic resonance images were visually assessed with semiquantitative visual rating scales. Data were analyzed using the general linear regression models. After controlling for demographics and cardiovascular disease, very high blood pressure (≥160/100 mm Hg) was significantly associated with global PVS score (ß-coefficient, 1.30; 95% CI, 0.06-2.53) and orthostatic hypotension was associated with PVS score in the basal ganglia (ß-coefficient 0.37; 0.03-0.70), but the associations became non-significant when adjusting for white matter hyperintensity load. Orthostatic hypotension was significantly associated with global and lobar PVS scores in carriers but not in noncarriers of the APOE ε4 allele. Global or regional PVS score was not significantly associated with other traditional vascular risk factors such as smoking, diabetes mellitus, physical inactivity, and overweight or obesity. Conclusions This study provides limited evidence supporting a correlation of magnetic resonance imaging-visible PVS with traditional vascular risk factors in older adults. The association of orthostatic hypotension with lobar PVS among APOE ε4 carriers suggests that lobar PVS may be a marker for amyloid-associated small-vessel disease.
Assuntos
Apolipoproteínas E/genética , Doenças de Pequenos Vasos Cerebrais/genética , Genótipo , Sistema Glinfático/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína E4/genética , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Diabetes Mellitus , Feminino , Sistema Glinfático/patologia , Humanos , Hipercolesterolemia , Hipotensão Ortostática/complicações , Hipotensão Ortostática/genética , Vida Independente , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Sobrepeso , Fatores de Risco , Fumar , Substância Branca/diagnóstico por imagemRESUMO
Genome-wide gene expression data for cell model of Parkinson's disease (PD) have considerably improved our understanding of the underlying molecular mechanisms involved in cell death during PD neurodegeneration. Apomorphine (APOM), a nonselective dopamine agonist, has been used to treat patients with advanced PD showing no response to levodopa or other dopamine agonists. Although APOM plays a role as a free radical scavenger with neuroprotective effect, it has been reported that long-term use of APOM in PD treatment brings about side effects such as nausea and orthostatic hypotension. For safe use of APOM in PD treatment, it is crucial to understand the underlying molecular mechanisms of APOM in PD. In this study, two groups of microarray data including PD cell model and APOM added PD cell model were used to survey mediation effects of APOM in PD cell model. Mediation analysis between disease genes obtained from PD cell model and drug genes obtained from APOM added PD cell model was carried out with shortest path model on KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and partial least squares structure equation modeling. Our results suggest that drug genes responding to APOM might contribute to negative regulation of disease genes by direct or indirect ways.
Assuntos
Apomorfina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Transcriptoma/genética , Apomorfina/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Feminino , Humanos , Hipotensão Ortostática/induzido quimicamente , Hipotensão Ortostática/genética , Hipotensão Ortostática/patologia , Análise dos Mínimos Quadrados , Levodopa/metabolismo , Masculino , Análise em Microsséries , Náusea/induzido quimicamente , Náusea/genética , Náusea/patologia , Doença de Parkinson/complicações , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
Orthostatic hypotension (OH) is associated with increased risk of trauma and cardiovascular events. Recent studies have identified new genetic variants that influence orthostatic blood pressure (BP). The aim of this study was to investigate the associations of candidate gene loci with orthostatic BP responses in older adults. A total of 3,430 participants aged ≥50 years from The Irish Longitudinal Study on Ageing (TILDA) with BP measures and genetic data from 12 single-nucleotide polymorphism (SNP) linked to BP responses were analyzed. Orthostatic BP responses were recorded at each 10 s interval and were defined as OH (SBP drop ≥20 mmHg or DBP drop ≥10 mmHg) at the time-points 40, 90, and 110 s. We defined sustained OH (SOH) as a drop that exceeded consensus BP thresholds for OH at 40, 90, and 110 s after standing. Logistic regression analyses modeled associations between the candidate SNP alleles and OH. We report no significant associations between OH and measured SNPs after correction for multiple comparisons apart from the SNP rs5068 where proportion of the minor allele was significantly different between cases and controls for SOH 40 (p = .002). After adjustment for covariates in a logistic regression, those with the minor G allele (compared to the A allele) had a decreased incidence rate ratio (IRR) for SOH 40 (IRR 0.45, p = .001, 95% CI 0.29-0.72). Only one SNP linked with increased natriuretic peptide concentrations was associated with OH. These results suggest that genetic variants may have a weak impact on OH but needs verification in other population studies.
Assuntos
Variação Genética , Hipotensão Ortostática/genética , Idoso , Alelos , Determinação da Pressão Arterial , Feminino , Genótipo , Humanos , Irlanda , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Cytochrome b561 (CYB561) generates ascorbic acid, a cofactor in the enzymatic conversion of dopamine to norepinephrine by dopamine ß-hydroxylase. We propose that the clinical relevance of this pathway can be revealed by characterizing the autonomic and biochemical characteristics of patients with CYB561 mutations. METHODS: We performed autonomic evaluations in 4 patients with lifelong orthostatic hypotension in whom CYB561 mutations were determined by genomic sequencing. RESULTS: Patients had disabling lifelong orthostatic hypotension (OH) and impaired blood pressure response to the Valsalva maneuver (VM), with exaggerated hypotension during phase 2 and lack of overshoot during phase 4. Heart rate ratios for sinus arrhythmia and the VM were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine levels and improved OH. Patients 1 and 2 were sisters and homozygous for a nonsense mutation in exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a missense mutation in exon 2, c157C>T, p.His.53Tyr, and the other had an exon 2 deletion. CONCLUSION: CYB561 deficiency is characterized by selective sympathetic noradrenergic failure with lifelong, disabling OH but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. We report a novel case of CYB561 deficiency due to an exon 2 deletion in one allele and a missense mutation in the other. These patients highlight the critical role CYB561 plays in sympathetic function and cardiovascular regulation.
Assuntos
Grupo dos Citocromos b/genética , Norepinefrina/deficiência , Norepinefrina/genética , Adolescente , Adulto , Feminino , Humanos , Hipotensão Ortostática/genética , Masculino , MutaçãoAssuntos
Neuropatias Amiloides Familiares/fisiopatologia , Insuficiência Cardíaca/metabolismo , Coração/fisiopatologia , Pré-Albumina/genética , 3-Iodobenzilguanidina/administração & dosagem , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/metabolismo , Biópsia , Pressão Sanguínea/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipotensão Ortostática/diagnóstico por imagem , Hipotensão Ortostática/genética , Hipotensão Ortostática/metabolismo , Hipotensão Ortostática/fisiopatologia , Mutação , Norepinefrina/administração & dosagem , Nervo Sural/patologia , Manobra de Valsalva/fisiologia , Sistema Vasomotor/metabolismo , Sistema Vasomotor/fisiopatologiaAssuntos
Neuropatias Amiloides Familiares/genética , Hipotensão Ortostática/genética , Pré-Albumina/genética , Retenção Urinária/genética , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/patologia , Feminino , Humanos , Hipotensão Ortostática/complicações , Hipotensão Ortostática/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Retenção Urinária/patologiaRESUMO
RATIONALE: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. OBJECTIVE: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. METHODS AND RESULTS: As in dopamine ß-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine ß-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine ß-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. CONCLUSIONS: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
Assuntos
Códon sem Sentido , Grupo dos Citocromos b/genética , Hipotensão Ortostática/genética , Glândulas Suprarrenais/metabolismo , Adulto , Animais , Ácido Ascórbico/metabolismo , Encéfalo/metabolismo , Catecolaminas/metabolismo , Feminino , Humanos , Hipotensão Ortostática/patologia , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Linhagem , Vesículas Secretórias/metabolismo , SíndromeAssuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico , Blefaroptose/diagnóstico , Dopamina beta-Hidroxilase/deficiência , Hipotensão Ortostática/diagnóstico , Norepinefrina/deficiência , Adolescente , Doenças do Sistema Nervoso Autônomo/sangue , Doenças do Sistema Nervoso Autônomo/genética , Doenças do Sistema Nervoso Autônomo/patologia , Monoaminas Biogênicas/sangue , Blefaroptose/sangue , Blefaroptose/genética , Consanguinidade , Creatinina/sangue , Dopamina beta-Hidroxilase/sangue , Dopamina beta-Hidroxilase/genética , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Hipotensão Ortostática/sangue , Hipotensão Ortostática/genética , Túbulos Renais/citologia , Túbulos Renais/patologia , Túbulos Renais/ultraestrutura , Microscopia Eletrônica , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Norepinefrina/sangue , Norepinefrina/genéticaAssuntos
Doenças do Sistema Nervoso Autônomo/diagnóstico , Blefaroptose/diagnóstico , Dopamina beta-Hidroxilase/deficiência , Hipotensão Ortostática/diagnóstico , Norepinefrina/deficiência , Adolescente , Doenças do Sistema Nervoso Autônomo/sangue , Doenças do Sistema Nervoso Autônomo/genética , Monoaminas Biogênicas/sangue , Blefaroptose/sangue , Blefaroptose/genética , Consanguinidade , Creatinina/sangue , Dopamina beta-Hidroxilase/sangue , Dopamina beta-Hidroxilase/genética , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Hipotensão Ortostática/sangue , Hipotensão Ortostática/genética , Túbulos Renais/citologia , Túbulos Renais/patologia , Túbulos Renais/ultraestrutura , Microscopia Eletrônica , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Norepinefrina/sangue , Norepinefrina/genéticaRESUMO
BACKGROUND: The genetic background associated with the dysregulation of orthostatic blood pressure remains poorly understood. The sympathetic nervous system plays a pivotal role in the regulation of blood pressure, as well as in response to positional changes. The essential role of adrenergic receptors in the sympathetic nervous system prompted us to hypothesize that common genetic variants of the α2-adrenergic receptor might contribute to the dysregulation of orthostatic blood pressure in general populations. This study is to explore the association between the polymorphisms of the α2-adrenergic receptor genes and the occurrence of orthostatic hypotension in Chinese populations. METHODS: The polymorphisms ADRA2A C-1291G (rs1800544), ADRA2B 301-303 I/D (rs28365031), and ADRA2C 322-325 I/D (rs61767072) were genotyped in 317 patients with orthostatic hypotension and 664 age- and gender-matched controls. Logistic regression analyses, adjusted for multiple comparisons, were used to determine the association between the allele/genotype of each ADRA2 gene and the risk of orthostatic hypotension. RESULTS: No significant association was found between the ADRA2A C-1291G, ADRA2B 301-303 I/D, and ADRA2C 322-325 I/D polymorphisms and orthostatic hypotension. CONCLUSIONS: We concluded that the common polymorphisms in the alpha2-adrenergic receptor gene is not associated with orthostatic hypotension risk in Chinese.
Assuntos
Pressão Sanguínea/genética , Hipotensão Ortostática/genética , Polimorfismo Genético , Receptores Adrenérgicos alfa 2/genética , Adulto , Povo Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , Estudos Transversais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/etnologia , Hipotensão Ortostática/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de RiscoRESUMO
To explore the association between the dopamine ß-hydroxylase (DBH) gene C-1021T polymorphism and the occurrence of orthostatic hypotension (OH) in Chinese patients, the DBH C-1021T polymorphism was genotyped in 317 patients with OH and 664 age- and sex-matched controls with orthostatic normotension. All subjects underwent an upright posture study for the measurement of orthostatic blood pressure. OH was defined as a drop in blood pressure of 20/10 mm Hg or more within 3 min of assuming the upright posture. The allele frequency of the DBH C-1021T polymorphism in the orthostatic hypotensive group was similar to the orthostatic normotensive group (17.4 versus 14.9%, P>0.05). No statistical significant association was found between the distribution of the C-1021T genotypes and the risk of OH in both the orthostatic hypotensive and orthostatic normotensive groups even after adjustment for demographic parameters. Among the three different genotypes, blood pressure levels did not significantly differ in the general population in this study. The changes in orthostatic systolic or diastolic blood pressures among the different genotype groups were not detected (all P>0.05). The C-1021T polymorphism of the DBH was not associated with orthostatic hypotensive risk in a Chinese population.
Assuntos
Dopamina beta-Hidroxilase/genética , Hipotensão Ortostática/genética , Adulto , Povo Asiático/genética , Pressão Sanguínea , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIM: To test the ability of adult-derived human liver stem/progenitor cells (ADHLSC) from large scale cultures to conjugate bilirubin in vitro and in bilirubin conjugation deficient rat. METHODS: ADHLSC from large scale cultures were tested for their phenotype and for their capacity to conjugate bilirubin in vitro after hepatogenic differentiation. In vivo, Gunn rats [uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) deficient animal] were injected with ADHLSC and cryopreserved hepatocytes (positive control). Two, 4, 13 and 27 wk post-transplantation, transplanted Gunn rat bilirubin serum levels were determined by high performance liquid chromatography. Human transplanted cell engraftment was assessed 27 wk post-transplantation using immunohistochemistry and RTqPCR. RESULTS: Large scale culture conditions do not modify ADHLSC phenotype, ADHLSC were able to specifically conjugate bilirubin. ADHLSC were intraportally injected into Gunn rats and blood UCB was measured at different times post-transplantation, infused-Gunn rats exhibited a metabolic effect 3 mo post-transplantation and maintained over a 6 mo period. ADHLSC engraftment into Gunn rat's liver was demonstrated by RTqPCR and immunohistochemistry against albumin and UGT1A1. CONCLUSION: ADHLSC from large scale cultures are efficient in conjugating bilirubin in vitro and in restoring a deficient metabolic function (reducing bilirubin level) in hyperbilirubinemic rats.
Assuntos
Bilirrubina/sangue , Hepatócitos/metabolismo , Hepatócitos/transplante , Hipotensão Ortostática/cirurgia , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Biomarcadores/sangue , Diferenciação Celular , Células Cultivadas , Criança , Modelos Animais de Doenças , Regulação para Baixo , Glucuronosiltransferase/deficiência , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Hepatócitos/enzimologia , Humanos , Hipotensão Ortostática/sangue , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/enzimologia , Hipotensão Ortostática/genética , Masculino , Fenótipo , Ratos Gunn , Albumina Sérica/metabolismo , Células-Tronco/enzimologia , Fatores de TempoRESUMO
BACKGROUND: We describe the clinical characteristics of a Swedish family with autosomal dominant cerebellar ataxia, sensory and autonomic neuropathy, additional neurological features and unknown genetic cause. METHODS: Fourteen affected family members were identified. Their disorder was characterized by neurological examination, MRI, electroneurography, electromyography, MIBG-scintigraphy, and tilt-testing. RESULTS: The disorder presented as a balance and gait disturbance starting between 16 and 47 years of age. Cerebellar ataxia progressed slowly over the course of decades, and MRI showed mild to moderate cerebellar atrophy. Sensory axonal polyneuropathy was the most prominent additional feature and occurred in all patients examined. Autonomic neuropathy caused pronounced orthostatic dysregulation in at least four patients. Several affected members showed muscle wasting, and mild upper or lower motor neuron signs were documented. Patients had no nystagmus but slow or hypometric horizontal saccades and ocular motor apraxia. Cognition remained unimpaired, and there were no non-neurological disease manifestations. The disorder affected men and women in successive generations in a pattern compatible with autosomal dominant inheritance without evidence of anticipation. A second family where 7 members had very similar symptoms was identified and its origin traced back to the same village in southern Sweden as that of the first family's ancestors. All relevant known genetic causes of cerebellar ataxia were excluded by a novel next-generation sequencing approach. CONCLUSION: We present two probably related Swedish families with a characteristic and novel clinical syndrome of cerebellar ataxia and sensory polyneuropathy. The study serves as a basis for the mapping of the underlying genetic cause.
Assuntos
Hipotensão Ortostática/diagnóstico , Transtornos da Motilidade Ocular/diagnóstico , Ataxias Espinocerebelares/diagnóstico , Adulto , Idoso , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Feminino , Humanos , Hipotensão Ortostática/genética , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/genética , Linhagem , Movimentos Sacádicos/genética , Ataxias Espinocerebelares/genéticaRESUMO
The genetic susceptibility to orthostatic blood pressure dysregulation remains poorly understood. The association between polymorphisms of beta-adrenergic receptor (ß-AR) genes and orthostatic blood pressure dysregulation in hypertensive patients was investigated. Two polymorphisms of ß1 -AR (Arg389/Gly) and ß2 -AR (Arg16/Gly) were genotyped in untreated hypertensive patients and normotensive patients. In patients with untreated hypertension, the frequency of ß1 -AR Gly389 homozygote was significantly higher in patients with orthostatic hypotension (OH) (P<.0001) and lower in patients with orthostatic hypertension (OHT) (P=.002) as compared with patients with orthostatic normotension (ONT) even after Bonferroni correction. After analysis by sex and adjustment for conventional risk factors, the ß1 -AR Gly389 homozygote conferred about a 3-fold risk of OH and independently predicted a 6.5 mm Hg greater orthostatic SBP decrease (GG -8.9±13 mm Hg vs CC+CG -2.4±12 mm Hg, P<.001) only in female hypertensive patients. The association of ß2 -AR Arg16/Gly with OH was not significant after adjustment for conventional risk factors. In normotensive patients, no association was identified between these two polymorphisms and OHT or OH. These results indicated that the ß1 -AR Arg389/Gly polymorphism may be associated with increased risk of OH in female hypertensive patients.
Assuntos
Pressão Sanguínea/genética , Tontura/genética , Hipertensão/genética , Hipotensão Ortostática/genética , Polimorfismo Genético/genética , Receptores Adrenérgicos beta/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos Transversais , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Estudos Retrospectivos , Fatores SexuaisRESUMO
Functional autoantibodies to the autonomic receptors are increasingly recognized in the pathophysiology of cardiovascular diseases. To date, no human activating monoclonal autoantibodies to these receptors have been available. In this study, we describe for the first time a ß2-adrenergic receptor (ß2AR)-activating monoclonal autoantibody (C5F2) produced from the lymphocytes of a patient with idiopathic postural hypotension. C5F2, an IgG3 isotype, recognizes an epitope in the N terminus of the second extracellular loop (ECL2) of ß2AR. Surface plasmon resonance analysis revealed high binding affinity for the ß2AR ECL2 peptide. Immunoblotting and immunofluorescence demonstrated specific binding to ß2AR in H9c2 cardiomyocytes, CHO cells expressing human ß2AR, and rat aorta. C5F2 stimulated cyclic AMP production in ß2AR-transfected CHO cells and induced potent dilation of isolated rat cremaster arterioles, both of which were specifically blocked by the ß2AR-selective antagonist ICI-118551 and by the ß2AR ECL2 peptide. This monoclonal antibody demonstrated sufficient activity to produce postural hypotension in its host. Its availability provides a unique opportunity to identify previously unrecognized causes and new pharmacological management of postural hypotension and other cardiovascular diseases.
Assuntos
Anticorpos Monoclonais/imunologia , Autoanticorpos/imunologia , Hipotensão Ortostática/imunologia , Hipotensão Ortostática/fisiopatologia , Imunoglobulina G/imunologia , Receptores Adrenérgicos beta 2/imunologia , Vasodilatadores/imunologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacologia , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Arteríolas/metabolismo , Arteríolas/patologia , Arteríolas/fisiopatologia , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células CHO , Cricetinae , Cricetulus , Humanos , Hipotensão Ortostática/sangue , Hipotensão Ortostática/genética , Hipotensão Ortostática/patologia , Imunoglobulina G/sangue , Imunoglobulina G/farmacologia , Masculino , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Peptídeos/imunologia , Peptídeos/farmacologia , Propanolaminas/farmacologia , Ratos , Receptores Adrenérgicos beta 2/sangue , Receptores Adrenérgicos beta 2/genética , Ressonância de Plasmônio de Superfície , Vasodilatadores/sangue , Vasodilatadores/farmacologiaRESUMO
AIMS: Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. METHODS AND RESULTS: A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥ 20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85-0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75-0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87-0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02-1.24; P = 0.02, rs198358: 1.10, 1.01-1.20; P = 0.04, and rs5068: 1.22, 1.04-1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04). CONCLUSION: The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
Assuntos
Pressão Sanguínea/genética , Hipotensão Ortostática/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Anti-Hipertensivos/uso terapêutico , Aterosclerose/genética , Aterosclerose/fisiopatologia , Métodos Epidemiológicos , Feminino , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Hipotensão Ortostática/tratamento farmacológico , Hipotensão Ortostática/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: A single nucleotide polymorphism in ABCB1, which encodes P-glycoprotein, has retrospectively been associated with symptoms of nortriptyline-induced postural hypotension in depressed patients. This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made. WHAT THIS STUDY ADDS: In a prospective study of healthy volunteers homozygous for ABCB1 (1236-2677-3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change. No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes. The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline. AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. METHODS: Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. RESULTS: There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min(-1) , P = 0.02). At t(max) at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min(-1) on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min(-1) on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. CONCLUSION: The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.