RESUMO
Laboratory studies in patients with autosomal-dominant hypertension and brachydactyly showed increased sensitivity to sympathetic stimuli and severe abnormalities in baroreflex buffering. To further elucidate the mechanisms by which impaired baroreflex sensitivity could influence blood pressure (BP), we conducted autonomic testing under field conditions. We studied 17 hypertensive affected (13 to 48 years, BMI 22.7 +/- 6.5 kg/m(2), 160 +/- 23/98 +/- 15 mm Hg) and 12 normotensive non-affected (9 to 60 years, BMI 24.0 +/- 4.7 kg/m(2), 120 +/- 16/70 +/- 10 mm Hg) family members. Pulse intervals and finger BP were measured using the Portapres device. Valsalva ratio, the blood pressure overshoot during phase IV of the Valsalva manoeuver, the Ewing coefficient (RR30/15 ratio), and heart rate and BP variability were similar in affected and non-affected family members. Overall, baroreflex sensitivity calculated using the cross-spectral (BRSLF, BRSHF) and sequence techniques (BRS+, BRS-) was not different between the groups. However, in younger family members, BRS+ was 12 +/- 3.7 and 22 +/- 13 msec/mm Hg in affected and in non-affected family members, respectively. The decline in BRS with age and with increasing blood pressure was absent in affected family members. We conclude that autonomic reflex testing conducted under field conditions is not impaired in patients with monogenic hypertension and brachydactyly. However, noninvasive testing showed impaired baroreflex control of heart rate at a young age. The reduced BRS in young family members with moderate arterial hypertension may suggest that the impaired baroreflex function is not secondary to the hypertension but rather a primary abnormality, which aggravates the progression of hypertension.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Dedos/anormalidades , Hipertensão/genética , Dedos do Pé/anormalidades , Adolescente , Adulto , Fatores Etários , Barorreflexo/genética , Pressão Sanguínea/genética , Estatura/genética , Índice de Massa Corporal , Peso Corporal/genética , Saúde da Família , Frequência Cardíaca/genética , Humanos , Pessoa de Meia-Idade , Saúde da População Rural , Turquia/epidemiologia , Manobra de Valsalva/genéticaAssuntos
Neuropatias Amiloides Familiares/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Pré-Albumina/genética , Vasoconstrição/fisiologia , 3-Iodobenzilguanidina/administração & dosagem , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/genética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/genética , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Cintilografia , Nervo Sural/metabolismo , Nervo Sural/patologia , Manobra de Valsalva/genética , Manobra de Valsalva/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation. PATIENTS AND METHODS: Autonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing. Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein. RESULTS: Both the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases. INTERPRETATION: We have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.
Assuntos
Mutação/genética , Doença de Parkinson/genética , Simpatectomia , Sistema Nervoso Simpático/fisiopatologia , alfa-Sinucleína/genética , Adulto , Pressão Sanguínea/genética , Feminino , Coração/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangue , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologia , Simpatectomia/métodos , Manobra de Valsalva/genéticaAssuntos
Doenças do Sistema Nervoso Autônomo/complicações , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/genética , Mutação/genética , Canais de Cátion TRPV/genética , Feminino , Frequência Cardíaca/genética , Humanos , Pessoa de Meia-Idade , Reflexo/genética , Manobra de Valsalva/genéticaRESUMO
BACKGROUND: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. METHODS: Here we report results of cardiac sympathetic neuroimaging by 6-[(18)F]fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[(18)F] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2 (LRRK2), the most common genetic abnormality identified so far in familial PD. RESULTS: The patient had no detectable 6-[(18)F] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[(18)F] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. CONCLUSION: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process.
Assuntos
Arritmias Cardíacas/genética , Doenças do Sistema Nervoso Autônomo/genética , Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Substância Negra/fisiopatologia , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/genética , Análise Mutacional de DNA , Di-Hidroxifenilalanina/análogos & derivados , Genótipo , Coração/diagnóstico por imagem , Coração/inervação , Coração/fisiopatologia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Neostriado/fisiopatologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Tomografia por Emissão de Pósitrons , Reflexo Anormal/genética , Substância Negra/diagnóstico por imagem , Substância Negra/metabolismo , Manobra de Valsalva/genéticaRESUMO
OBJECTIVE: Congenital connective tissue dysfunction may partly be responsible for female pelvic organ prolapse and urinary incontinence. We undertook a heritability study to determine whether mobility of the bladder neck, one of the main determinants of stress urinary incontinence, is genetically influenced. DESIGN: Heritability study using a twin model and structural equation modelling. SETTING: Queensland Institute of Medical Research, Brisbane, Australia. POPULATION: One hundred and seventy-eight nulliparous Caucasian female twins and their sisters (46 monozygotic pairs, 24 dizygotic pairs and 38 sisters) aged 18-24 years. METHODS: We performed translabial ultrasound, supine and after bladder emptying, for pelvic organ mobility. Urethral rotation and bladder neck descent were calculated using the best of three effective Valsalva manoeuvres. MAIN OUTCOME MEASURES: Bladder and urethral mobility on Valsalva assessed by urethral rotation, vertical and oblique bladder neck descent. RESULTS: Genetic modelling indicated that additive genes accounted for up to 59% of the variance for bladder neck descent. All remaining variance appeared due to environmental influences unique to the individual, including measurement error. CONCLUSION: A significant genetic contribution to the phenotype of bladder neck mobility appears likely.