RESUMO
OBJECTIVES: To use multi-parametric magnetic resonance imaging (MRI) to test the hypothesis that hypertensives would have higher retrograde venous blood flow (RVBF) in the internal jugular veins (IJV) vs. normotensives, and that this would inversely correlate with arterial inflow and gray matter, white matter, and cerebrospinal fluid volumes. METHODS: Following local institutional review board approval and written consent, a prospective observational 3-T MRI study of 42 hypertensive patients (53 ± 2 years, BMI 28.2 ± 0.6 kg/m2, ambulatory daytime systolic BP 148 ± 2 mmHg, ambulatory daytime diastolic BP 101 ± 2 mmHg) and 35 normotensive patients (48 ± 2 years, BMI 25.2 ± 0.8 kg/m2, ambulatory daytime systolic BP 119 ± 3 mmHg, ambulatory daytime diastolic BP 90 ± 2 mmHg) was performed. Phase contrast imaging calculated percentage retrograde venous blood flow (%RVBF), brain segmentation estimated regional brain volumes from 3D T1-weighted images, and pseudo-continuous arterial spin labeling measured regional cerebral blood perfusion. Statistical analysis included two-sample equal variance Student's T tests, two-way analysis of variance with Tukey's post hoc correction, and permutation-based two-group general linear modeling (p < 0.05). RESULTS: In the left IJV, %RVBF was higher in hypertensives (6.1 ± 1.5%) vs. normotensives (1.1 ± 0.3%, p = 0.003). In hypertensives, there was an inverse relationship of %RVBF (permutation-based general linear modeling) to cerebral blood flow in several brain regions, including the left occipital pole and the cerebellar vermis (p < 0.01). Percentage retrograde flow in the left IJV correlated inversely with the total matter volume (gray plus white matter volume) in hypertensives (r = - 0.49, p = 0.004). CONCLUSION: RVBF in the left IJV is greater in hypertensives vs. normotensives and is linked to regional hypoperfusion and brain total matter volume. KEY POINTS: ⢠Hypertensive humans have higher retrograde cerebral venous blood flow, associated with regional brain hypoperfusion and lower tissue volume, compared with controls. ⢠Cerebral retrograde venous blood flow may add further stress to already hypoperfused tissue in hypertensive patients. ⢠The amount of retrograde venous blood flow in hypertensive patients may predict which patients might be at higher risk of developing cerebral pathologies.
Assuntos
Artérias Cerebrais/fisiopatologia , Hipertensão/fisiopatologia , Veias Jugulares/diagnóstico por imagem , Veias Jugulares/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Circulação Cerebrovascular/fisiologia , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Marcadores de SpinRESUMO
OBJECTIVES: Left atrial enlargement (LAE) predicts cardiovascular morbidity and mortality. Impaired LA function also confers poor prognosis. This study aimed to determine whether left ventricular (LV) interstitial fibrosis is associated with LAE and LA impairment in systemic hypertension. METHODS: Following informed written consent, a prospective observational study of 86 hypertensive patients (49 ± 15 years, 53% male, office SBP 168 ± 30 mmHg, office DBP 97 ± 4 mmHg) and 20 normotensive controls (48 ± 13 years, 55% male, office SBP 130 ± 13 mmHg, office DBP 80 ± 11 mmHg) at 1.5-T cardiovascular magnetic resonance was conducted. Extracellular volume fraction (ECV) was calculated by T1-mapping. LA volume (LAV) was measured with biplane area-length method. LA reservoir, conduit and pump function were calculated with the phasic volumetric method. RESULTS: Indexed LAV correlated with indexed LV mass (R = 0.376, p < 0.0001) and ECV (R = 0.359, p = 0.001). However, ECV was the strongest significant predictor of LAE in multivariate regression analysis (odds ratio [95th confidence interval] 1.24 [1.04-1.48], p = 0.017). Indexed myocardial interstitial volume was associated with significant reductions in LA reservoir (R = -0.437, p < 0.0001) and conduit (R = -0.316, p = 0.003) but not pump (R = -0.167, p = 0.125) function. Multiple linear regression, correcting for age, gender, BMI, BP and diabetes, showed an independent decrease of 3.5% LA total emptying fraction for each 10 ml/m2 increase in myocardial interstitial volume (standard ß coefficient -3.54, p = 0.002). CONCLUSIONS: LV extracellular expansion is associated with LAE and impaired LA reservoir and conduit function. Future studies should identify if targeting diffuse LV fibrosis is beneficial in reverse remodelling of LA structural and functional pathological abnormalities in hypertension. KEY POINTS: ⢠Left atrial enlargement (LAE) and impairment are markers of adverse prognosis in systemic hypertension but their pathophysiology is poorly understood. ⢠Left ventricular extracellular volume fraction was the strongest independent multivariate predictor of LAE and was associated with impaired left atrial reservoir and conduit function. ⢠LV interstitial expansion may play a central role in the pathophysiology of adverse atrioventricular interaction in systemic hypertension.
Assuntos
Volume Cardíaco/fisiologia , Átrios do Coração/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertensão/fisiopatologia , Adulto , Idoso , Feminino , Fibrose/patologia , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
RATIONALE: Data from animal models of hypertension indicate that high blood pressure may develop as a vital mechanism to maintain adequate blood flow to the brain. We propose that congenital vascular variants of the posterior cerebral circulation and cerebral hypoperfusion could partially explain the pathogenesis of essential hypertension, which remains enigmatic in 95% of patients. OBJECTIVE: To evaluate the role of the cerebral circulation in the pathophysiology of hypertension. METHODS AND RESULTS: We completed a series of retrospective and mechanistic case-control magnetic resonance imaging and physiological studies in normotensive and hypertensive humans (n=259). Interestingly, in humans with hypertension, we report a higher prevalence of congenital cerebrovascular variants; vertebral artery hypoplasia, and an incomplete posterior circle of Willis, which were coupled with increased cerebral vascular resistance, reduced cerebral blood flow, and a higher incidence of lacunar type infarcts. Causally, cerebral vascular resistance was elevated before the onset of hypertension and elevated sympathetic nerve activity (n=126). Interestingly, untreated hypertensive patients (n=20) had a cerebral blood flow similar to age-matched controls (n=28). However, participants receiving antihypertensive therapy (with blood pressure controlled below target levels) had reduced cerebral perfusion (n=19). Finally, elevated cerebral vascular resistance was a predictor of hypertension, suggesting that it may be a novel prognostic or diagnostic marker (n=126). CONCLUSIONS: Our data indicate that congenital cerebrovascular variants in the posterior circulation and the associated cerebral hypoperfusion may be a factor in triggering hypertension. Therefore, lowering blood pressure may worsen cerebral perfusion in susceptible individuals.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Adulto , Encéfalo/irrigação sanguínea , Estudos de Casos e Controles , Estudos Transversais , Hipertensão Essencial , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resistência Vascular/fisiologiaRESUMO
OBJECTIVES: European guidelines state left ventricular (LV) end-diastolic wall thickness (EDWT) ≥15mm suggests hypertrophic cardiomyopathy (HCM), but distinguishing from hypertensive heart disease (HHD) is challenging. We identify cardiovascular magnetic resonance (CMR) predictors of HHD over HCM when EDWT ≥15mm. METHODS: 2481 consecutive clinical CMRs between 2014 and 2015 were reviewed. 464 segments from 29 HCM subjects with EDWT ≥15mm but without other cardiac abnormality, hypertension or renal impairment were analyzed. 432 segments from 27 HHD subjects with EDWT ≥15mm but without concomitant cardiac pathology were analyzed. Magnitude and location of maximal EDWT, presence of late gadolinium enhancement (LGE), LV asymmetry (>1.5-fold opposing segment) and systolic anterior motion of the mitral valve (SAM) were measured. Multivariate logistic regression was performed. Significance was defined as p<0.05. RESULTS: HHD and HCM cohorts were age-/gender-matched. HHD had significantly increased indexed LV mass (110±27g/m2 vs. 91±31g/m2, p=0.016) but no difference in site or magnitude of maximal EDWT. Mid-wall LGE was significantly more prevalent in HCM. Elevated indexed LVM, mid-wall LGE and absence of SAM were significant multivariate predictors of HHD, but LV asymmetry was not. CONCLUSIONS: Increased indexed LV mass, absence of mid-wall LGE and absence of SAM are better CMR discriminators of HHD from HCM than EDWT ≥15mm. KEY POINTS: ⢠Hypertrophic cardiomyopathy (HCM) is often diagnosed with end-diastolic wall thickness ≥15mm. ⢠Hypertensive heart disease (HHD) can be difficult to distinguish from HCM. ⢠Retrospective case-control study showed that location and magnitude of EDWT are poor discriminators. ⢠Increased left ventricular mass and midwall fibrosis are independent predictors of HHD. ⢠Cardiovascular magnetic resonance parameters facilitate a better discrimination between HHD and HCM.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Adulto , Idoso , Cardiomiopatia Hipertrófica/complicações , Estudos de Casos e Controles , Meios de Contraste , Diagnóstico Diferencial , Feminino , Fibrose , Gadolínio , Cardiopatias/diagnóstico por imagem , Cardiopatias/etiologia , Ventrículos do Coração/patologia , Humanos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Modelos Logísticos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocárdio/patologia , Tamanho do Órgão , Estudos RetrospectivosRESUMO
The UK-based National Institute for Health and Care Excellence (NICE) has updated its guidance on iron deficiency and anemia management in chronic kidney disease. This report outlines the recommendations regarding iron deficiency and their rationale. Serum ferritin alone or transferrin saturation alone are no longer recommended as diagnostic tests to assess iron deficiency. Red blood cell markers (percentage hypochromic red blood cells, reticulocyte hemoglobin content, or reticulocyte hemoglobin equivalent) are better than ferritin level alone at predicting responsiveness to intravenous iron. When red blood cell markers are not available, a combination of transferrin saturation < 20% and ferritin level < 100ng/mL is an alternative. In comparisons of the cost-effectiveness of different iron status testing and treatment strategies, using percentage hypochromic red blood cells > 6% was the most cost-effective strategy for both hemodialysis and nonhemodialysis patients. A trial of oral iron replacement is recommended in people not receiving an erythropoiesis-stimulating agent (ESA) and not on hemodialysis therapy. For children receiving ESAs, but not treated by hemodialysis, oral iron should be considered. In adults and children receiving ESAs and/or on hemodialysis therapy, intravenous iron should be offered. When giving intravenous iron, high-dose low-frequency administration is recommended. For all children and for adults receiving in-center hemodialysis, low-dose high-frequency administration may be more appropriate.
Assuntos
Anemia Ferropriva/diagnóstico , Anemia Ferropriva/terapia , Guias de Prática Clínica como Assunto , Anemia Ferropriva/etiologia , Eritropoetina/fisiologia , Humanos , Ferro/fisiologia , Metanálise como Assunto , Insuficiência Renal Crônica/complicaçõesRESUMO
AIMS: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology. METHODS: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. RESULTS: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3ß. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs = 0.30, P = 0.03). CONCLUSIONS: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3ß, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain.
Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Dano ao DNA/fisiologia , Neurônios/metabolismo , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/patologia , Western Blotting , Encéfalo/patologia , Feminino , Humanos , Imuno-Histoquímica , Microdissecção e Captura a Laser , Masculino , Neurônios/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologia , TranscriptomaRESUMO
Hypertension is a leading risk factor for the development of several cardiovascular diseases. As the global prevalence of hypertension increases, so too has the recognition of resistant hypertension. Whilst figures vary, the proportion of hypertensive patients that are resistant to multiple drug therapies have been reported to be as high as 16.4 %. Resistant hypertension is typically associated with elevated sympathetic activity and abnormal homeostatic reflex control and is termed neurogenic hypertension because of its presumed central autonomic nervous system origin. This resistance to conventional pharmacological treatment has stimulated a plethora of medical devices to be investigated for use in hypertension, with varying degrees of success. In this review, we discuss a new therapy for drug-resistant hypertension, deep brain stimulation. The utility of deep brain stimulation in resistant hypertension was first discovered in patients with concurrent neuropathic pain, where it lowered blood pressure and improved baroreflex sensitivity. The most promising central target for stimulation is the ventrolateral periaqueductal gray, which has been well characterised in animal studies as a control centre for autonomic outflow. In this review, we will discuss the promise and potential mechanisms of deep brain stimulation in the treatment of severe, resistant hypertension.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Estimulação Encefálica Profunda , Hipertensão/terapia , Sistema Nervoso Simpático/fisiopatologia , Animais , Pressão Sanguínea , Humanos , Hipertensão/fisiopatologiaRESUMO
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development by activating 3 receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3, and by binding to coreceptors such as neuropilin-1 (NRP-1). We investigated how different VEGF-A isoforms, in particular VEGF-A(165)a and VEGF-A(165)b, control the balance between VEGFR-2 recycling, degradation, and signaling. Stimulation of cells with the NRP-1-binding VEGF-A(165)a led to sequential NRP-1-mediated VEGFR-2 recycling through Rab5, Rab4, and Rab11 vesicles. Recycling was accompanied by dephosphorylation of VEGFR-2 between Rab4 and Rab11 vesicles and quantitatively and qualitatively altered signal output. In cells stimulated with VEGF-A(165)b, an isoform unable to bind NRP-1, VEGFR-2 bypassed Rab11 vesicles and was routed to the degradative pathway specified by Rab7 vesicles. Deletion of the GIPC (synectin) binding motif of NRP-1 prevented transition of VEGFR-2 through Rab11 vesicles and attenuated signaling. Coreceptor engagement was specific for VEGFR-2 because EGFR recycled through Rab11 vesicles in the absence of known coreceptors. Our data establish a distinct role of NRP-1 in VEGFR-2 signaling and reveal a general mechanism for the function of coreceptors in modulating RTK signal output.
Assuntos
Células Endoteliais/metabolismo , Neuropilina-1/metabolismo , Transdução de Sinais/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Aorta/citologia , Células Cultivadas , Células Endoteliais/citologia , Éxons/genética , Humanos , Neuropilina-1/química , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Estrutura Terciária de Proteína , Transporte Proteico/fisiologia , Transdução de Sinais/efeitos dos fármacos , Suínos , Vesículas Transportadoras/metabolismo , Veias Umbilicais/citologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rab4 de Ligação ao GTP/metabolismoRESUMO
Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m2 vs. 26.0 ± 4.2 kg/m2; p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone.
Assuntos
Hipertensão , Sistema Nervoso Simpático , Adulto , Idoso , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervação , Sistema Nervoso Simpático/fisiologiaRESUMO
The insulin/insulin-like growth factor 1 (IGF1) signaling pathways are implicated in longevity and in progression of Alzheimer's disease. Previously, we showed that insulin-like growth factor 1 receptor (IGF1R) and downstream signaling transcripts are reduced in astrocytes in human brain with progression of Alzheimer's neuropathology and developed a model of IGF1 signaling impairment in human astrocytes using an IGF1R-specific monoclonal antibody, MAB391. Here, we have established a novel human astrocyte-neuron co-culture system to determine whether loss of astrocytic IGF1R affects their support for neurons. Astrocyte-neuron co-cultures were developed using human primary astrocytes and differentiated Lund Human Mesencephalic Cells (LUHMES). Neurite outgrowth assays, performed to measure astrocytic support for neurons, showed astrocytes provided contact-mediated support for neurite outgrowth. Loss of IGF1R did not affect neurite outgrowth under control conditions but when challenged with hydrogen peroxide IGF1R-impaired astrocytes were less able to protect LUHMES. To determine how loss of IGF1R affects neuronal support MAB391-treated astrocytes were FACS sorted from GFP-LUHMES and their transcriptomic profile was investigated using microarrays. Changes in transcripts involved in astrocyte energy metabolism were identified, particularly NDUFA2 and NDUFB6, which are related to complex I assembly. Loss of complex I activity in MAB391-treated astrocytes validated these findings. In conclusion, reduced IGF1 signaling in astrocytes impairs their support for neurons under conditions of stress and this is associated with defects in the mitochondrial respiratory chain in astrocytes.
Assuntos
Astrócitos/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Neurônios/metabolismo , Receptores de Somatomedina/metabolismo , Anticorpos Monoclonais/administração & dosagem , Técnicas de Cocultura/métodos , Metabolismo Energético , Humanos , Crescimento Neuronal , Estresse Oxidativo , Cultura Primária de Células , Receptor IGF Tipo 1 , Receptores de Somatomedina/imunologia , TranscriptomaRESUMO
We investigate the impact of dipper status on cardiac structure with cardiovascular magnetic resonance (CMR). Ambulatory blood pressure monitoring and 1.5T CMR were performed in 99 tertiary hypertension clinic patients. Subgroup analysis by extreme dipper (n = 9), dipper (n = 39), non-dipper (n = 35) and reverse dipper (n = 16) status was performed, matched in age, gender and BMI. Left ventricular (LV) mass was significantly higher for extreme dippers than dippers after correction for covariates (100 ± 6 g/m2 vs 79 ± 3 g/m2 , P = .004). Amongst extreme dippers and dippers (n = 48), indexed LV mass correlated positively with the extent of nocturnal blood pressure dipping (R = .403, P = .005). On post-hoc ANCOVA, the percentage of nocturnal dip had significant effect on indexed LV mass (P = .008), but overall SBP did not (P = .348). In the tertiary setting, we found a larger nocturnal BP drop was associated with more LV hypertrophy. If confirmed in larger studies, this may have implications on nocturnal dosing of anti-hypertensive medications.
Assuntos
Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Feminino , Humanos , Hipertensão/tratamento farmacológico , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
European guidelines recommend that patients with hypertension be assessed for asymptomatic organ damage and secondary causes. The authors propose that a single magnetic resonance imaging (MRI) scan can provide comprehensive first-line imaging of patients assessed via a specialist hypertension clinic. A total of 200 patients (56% male, aged 51±15 years, office BP 168±30/96±16 mm Hg) underwent MRI of the heart, kidneys, renal arteries, adrenals and aorta. Comparisons were made with other imaging modalities where available. A total of 61% had left ventricular hypertrophy (LVH), 14% had reduced ejection fraction, and 15 patients had myocardial infarcts. Echocardiography overdiagnosed LVH in 15% of patients and missed LVH in 14%. Secondary causes were identified in 14.5% of patients: 12 adrenal masses, 10 renal artery stenoses, seven thyroid abnormalities, one aortic coarctation, one enlarged pituitary gland, one polycystic kidney disease, and one renal coloboma syndrome. This comprehensive MRI protocol is an effective method of screening for asymptomatic organ damage and secondary causes of hypertension.
Assuntos
Hipertensão/complicações , Hipertensão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Idoso , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/epidemiologia , Coloboma/diagnóstico por imagem , Coloboma/epidemiologia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Hipófise/diagnóstico por imagem , Hipófise/patologia , Doenças Renais Policísticas/diagnóstico por imagem , Doenças Renais Policísticas/epidemiologia , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/epidemiologia , Insuficiência Renal/diagnóstico por imagem , Insuficiência Renal/epidemiologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Volume Sistólico , Refluxo Vesicoureteral/diagnóstico por imagem , Refluxo Vesicoureteral/epidemiologiaRESUMO
AIMS: In hypertension, the presence of left ventricular (LV) strain pattern on 12-lead electrocardiogram (ECG) carries adverse cardiovascular prognosis. The underlying mechanisms are poorly understood. We investigated whether hypertensive ECG strain is associated with myocardial interstitial fibrosis and impaired myocardial strain, assessed by multi-parametric cardiac magnetic resonance (CMR). METHODS AND RESULTS: A total of 100 hypertensive patients [50 ± 14 years, male: 58%, office systolic blood pressure (SBP): 170 ± 30 mmHg, office diastolic blood pressure (DBP): 97 ± 14 mmHg) underwent ECG and 1.5T CMR and were compared with 25 normotensive controls (46 ± 14 years, 60% male, SBP: 124 ± 8 mmHg, DBP: 76 ± 7 mmHg). Native T1 and extracellular volume fraction (ECV) were calculated with the modified look-locker inversion-recovery sequence. Myocardial strain values were estimated with voxel-tracking software. ECG strain (n = 20) was associated with significantly higher indexed LV mass (LVM) (119 ± 32 vs. 80 ± 17 g/m2, P < 0.05) and ECV (30 ± 4 vs. 27 ± 3%, P < 0.05) compared with hypertensive subjects without ECG strain (n = 80). ECG strain subjects had significantly impaired circumferential strain compared with hypertensive subjects without ECG strain and controls (-15.2 ± 4.7 vs. -17.0 ± 3.3 vs. -17.3 ± 2.4%, P < 0.05, respectively). In subgroup analysis, comparing ECG strain subjects to hypertensive subjects with elevated LVM but no ECG strain, a significantly higher ECV (30 ± 4 vs. 28 ± 3%, P < 0.05) was still observed. Indexed LVM was the only variable independently associated with ECG strain in multivariate logistic regression analysis [odds ratio (95th confidence interval): 1.07 (1.02-1.12), P < 0.05). CONCLUSION: In hypertension, ECG strain is a marker of advanced LVH associated with increased interstitial fibrosis and associated with significant myocardial circumferential strain impairment.
Assuntos
Eletrocardiografia/métodos , Hipertensão/epidemiologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/epidemiologia , Imagem Cinética por Ressonância Magnética/métodos , Adulto , Estudos de Casos e Controles , Comorbidade , Meios de Contraste , Feminino , Fibrose/diagnóstico por imagem , Fibrose/patologia , Gadolínio , Humanos , Hipertensão/diagnóstico , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.
Assuntos
Pressão Sanguínea/genética , Corpo Carotídeo/metabolismo , Células Quimiorreceptoras/metabolismo , RNA Mensageiro/metabolismo , Receptores Purinérgicos P2X3/genética , Animais , Pressão Sanguínea/efeitos dos fármacos , Corpo Carotídeo/citologia , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Técnicas de Patch-Clamp , Antagonistas do Receptor Purinérgico P2X/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Reflexo Anormal/genética , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismoRESUMO
Hypertensive heart disease is often associated with a preserved left ventricular ejection fraction despite impaired myocardial shortening. The authors investigated this paradox in 55 hypertensive patients (52±13 years, 58% male) and 32 age- and sex-matched normotensive control patients (49±11 years, 56% male) who underwent cardiac magnetic resonance imaging at 1.5T. Long-axis shortening (R=0.62), midwall fractional shortening (R=0.68), and radial strain (R=0.48) all decreased (P<.001) as end-diastolic wall thickness increased. However, absolute wall thickening (defined as end-systolic minus end-diastolic wall thickness) was maintained, despite the reduced myocardial shortening. Absolute wall thickening correlated with ejection fraction (R=0.70, P<.0001). In multiple linear regression analysis, increasing wall thickness by 1 mm independently increased ejection fraction by 3.43 percentage points (adjusted ß-coefficient: 3.43 [2.60-4.26], P<.0001). Increasing end-diastolic wall thickness augments ejection fraction through preservation of absolute wall thickening. Left ventricular ejection fraction should not be used in patients with hypertensive heart disease without correction for degree of hypertrophy.
Assuntos
Cardiopatias/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertensão/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Renal denervation (RDN) is a therapy that targets treatment-resistant hypertension (TRH). The Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity) HTN-1 and Symplicity HTN-2 trials reported response rates of >80%; however, sham-controlled Symplicity HTN-3 failed to reach its primary blood pressure (BP) outcome. The authors address the current controversies surrounding RDN, illustrated with real-world data from two centers in the United Kingdom. In this cohort, 52% of patients responded to RDN, with a 13±32 mm Hg reduction in office systolic BP (SBP) at 6 months (n=29, P=.03). Baseline office SBP and number of ablations correlated with office SBP reduction (R=-0.47, P=.01; R=-0.56, P=.002). RDN appears to be an effective treatment for some patients with TRH; however, individual responses are highly variable. Selecting patients for RDN is challenging, with only 10% (33 of 321) of the screened patients eligible for the study. Medication alterations and nonadherence confound outcomes. Adequate ablation is critical and should impact future catheter design/training. Markers of procedural success and improved patient selection parameters remain key research aims.
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Hipertensão/terapia , Rim/inervação , Simpatectomia/métodos , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Determinação da Pressão Arterial , Ensaios Clínicos como Assunto , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rim/cirurgia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Resultado do Tratamento , Reino UnidoRESUMO
OBJECTIVE: Myocardial intracellular/extracellular structure and aortic function were assessed among hypertensive left ventricular (LV) phenotypes using cardiovascular magnetic resonance (CMR). METHODS: An observational study from consecutive tertiary hypertension clinic patients referred for CMR (1.5 T) was performed. Four LV phenotypes were defined: (1) normal with normal indexed LV mass (LVM) and LVM to volume ratio (M/V), (2) concentric remodelling with normal LVM but elevated M/V, (3) concentric LV hypertrophy (LVH) with elevated LVM but normal indexed end-diastolic volume (EDV) or (4) eccentric LVH with elevated LVM and EDV. Extracellular volume fraction was measured using T1-mapping. Circumferential strain was calculated by voxel-tracking. Aortic distensibility was derived from high-resolution aortic cines and contemporaneous blood pressure measurements. RESULTS: 88 hypertensive patients (49±14â years, 57% men, systolic blood pressure (SBP): 167±30â mmâ Hg, diastolic blood pressure (DBP): 96±14â mmâ Hg) were compared with 29 age-matched/sex-matched controls (47±14â years, 59% men, SBP: 128±12â mmâ Hg, DBP: 79±10â mmâ Hg). LVH resulted from increased myocardial cell volume (eccentric LVH: 78±19â mL/m(2) vs concentric LVH: 73±15â mL/m(2) vs concentric remodelling: 55±9â mL/m(2), p<0.05, respectively) and interstitial fibrosis (eccentric LVH: 33±10â mL/m(2) vs concentric LVH: 30±10â mL/m(2) vs concentricremodelling: 19±2â mL/m(2), p<0.05, respectively). LVH had worst circumferential impairment (eccentric LVH: -12.8±4.6% vs concentric LVH: -15.5±3.1% vs concentric remodelling: -17.1±3.2%, p<0.05, respectively). Concentric remodelling was associated with reduced aortic distensibility, but not with large intracellular/interstitial expansion or myocardial dysfunction versus controls. CONCLUSIONS: Myocardial interstitial fibrosis varies across hypertensive LV phenotypes with functional consequences. Eccentric LVH has the most fibrosis and systolic impairment. Concentric remodelling is only associated with abnormal aortic function. Understanding these differences may help tailor future antihypertensive treatments.
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Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Adulto , Idoso , Estudos de Casos e Controles , Inglaterra , Feminino , Fibrose , Humanos , Hipertensão/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Ambulatório Hospitalar , Fenótipo , Valor Preditivo dos Testes , Centros de Atenção Terciária , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação VentricularRESUMO
AIMS: We sought to determine the prevalence of asymmetric hypertensive heart disease (HHD) overlapping morphologically with hypertrophic cardiomyopathy (HCM) and to determine predictors of this pattern of hypertensive remodelling. METHODS AND RESULTS: One hundred and fifty hypertensive patients underwent 1.5 T cardiovascular magnetic resonance imaging. Twenty-one patients were excluded due to concomitant cardiac pathology that may confound the hypertrophic response, e.g. myocardial infarction, moderate-severe valvular disease, or other cardiomyopathy. Asymmetric HHD was defined as a segmental wall thickness of ≥15 mm and >1.5-fold the opposing wall in ≥1 myocardial segments, measured from short-axis cine stack at end-diastole. Ambulatory blood pressure, myocardial replacement fibrosis, aortic distensibility and aortoseptal angle were investigated as predictors of asymmetric HHD by multivariate logistic regression. Out of 129 hypertensive subjects (age: 51 ± 15 years, 50% male, systolic blood pressure: 170 ± 30 mmHg, diastolic blood pressure: 97 ± 16 mmHg), asymmetric HHD occurred in 21%. Where present, maximal end-diastolic wall thickness (EDWT) was 17.8 ± 1.9 mm and located exclusively in the basal or mid septum. In asymmetric HHD, aortoseptal angle (114 ± 10° vs. 125 ± 9° vs. 123 ± 12°, P < 0.05, respectively) was significantly reduced compared to concentric left ventricular hypertrophy (LVH) and compared to no LVH, respectively. Aortic distensibility in asymmetric HHD (1.01 ± 0.60 vs. 1.83 ± 1.65 mm2/mmHg × 103, P < 0.05, respectively) was significantly reduced compared to subjects with no LVH. Age (odds ratio [95th confidence interval]: 1.10 [1.02-1.18], P < 0.05) and indexed LV mass (1.09 [0.98-1.28], P < 0.0001) were significant, independent predictors of asymmetric HDD. CONCLUSIONS: Asymmetric HHD morphologically overlapping with HCM, according to the current ESC guidelines, is common. Postulating a diagnosis of HCM on the basis of EDWT of ≥15 mm should be made with caution in the presence of arterial hypertension particular in male subjects with elevated LV mass.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/epidemiologia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/epidemiologia , Imagem Cinética por Ressonância Magnética , Adulto , Distribuição por Idade , Idoso , Análise de Variância , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/patologia , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/patologia , Estudos de Coortes , Eletrocardiografia/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prevalência , Prognóstico , Intensificação de Imagem Radiográfica/métodos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Distribuição por SexoRESUMO
Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.
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BACKGROUND: The insulin/IGF1 signalling (IIS) pathways are involved in longevity regulation and are dysregulated in neurons in Alzheimer's disease (AD). We previously showed downregulation in IIS gene expression in astrocytes with AD-neuropathology progression, but IIS in astrocytes remains poorly understood. We therefore examined the IIS pathway in human astrocytes and developed models to reduce IIS at the level of the insulin or the IGF1 receptor (IGF1R). RESULTS: We determined IIS was present and functional in human astrocytes by immunoblotting and showed astrocytes express the insulin receptor (IR)-B isoform of Ir. Immunocytochemistry and cell fractionation followed by western blotting revealed the phosphorylation status of insulin receptor substrate (IRS1) affects its subcellular localisation. To validate IRS1 expression patterns observed in culture, expression of key pathway components was assessed on post-mortem AD and control tissue using immunohistochemistry. Insulin signalling was impaired in cultured astrocytes by treatment with insulin + fructose and resulted in decreased IR and Akt phosphorylation (pAkt S473). A monoclonal antibody against IGF1R (MAB391) induced degradation of IGF1R receptor with an associated decrease in downstream pAkt S473. Neither treatment affected cell growth or viability as measured by MTT and Cyquant® assays or GFAP immunoreactivity. DISCUSSION: IIS is functional in astrocytes. IR-B is expressed in astrocytes which differs from the pattern in neurons, and may be important in differential susceptibility of astrocytes and neurons to insulin resistance. The variable presence of IRS1 in the nucleus, dependent on phosphorylation pattern, suggests the function of signalling molecules is not confined to cytoplasmic cascades. Down-regulation of IR and IGF1R, achieved by insulin + fructose and monoclonal antibody treatments, results in decreased downstream signalling, though the lack of effect on viability suggests that astrocytes can compensate for changes in single pathways. Changes in signalling in astrocytes, as well as in neurons, may be important in ageing and neurodegeneration.