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1.
J Hum Hypertens ; 37(10): 898-906, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-36528682

RESUMO

The study characterises vascular phenotypes of hypertensive patients utilising machine learning approaches. Newly diagnosed and treatment-naïve primary hypertensive patients without co-morbidities (aged 18-55, n = 73), and matched normotensive controls (n = 79) were recruited (NCT04015635). Blood pressure (BP) and BP variability were determined using 24 h ambulatory monitoring. Vascular phenotyping included SphygmoCor® measurement of pulse wave velocity (PWV), pulse wave analysis-derived augmentation index (PWA-AIx), and central BP; EndoPAT™-2000® provided reactive hyperaemia index (LnRHI) and augmentation index adjusted to heart rate of 75bpm. Ultrasound was used to analyse flow mediated dilatation and carotid intima-media thickness (CIMT). In addition to standard statistical methods to compare normotensive and hypertensive groups, machine learning techniques including biclustering explored hypertensive phenotypic subgroups. We report that arterial stiffness (PWV, PWA-AIx, EndoPAT-2000-derived AI@75) and central pressures were greater in incident hypertension than normotension. Endothelial function, percent nocturnal dip, and CIMT did not differ between groups. The vascular phenotype of white-coat hypertension imitated sustained hypertension with elevated arterial stiffness and central pressure; masked hypertension demonstrating values similar to normotension. Machine learning revealed three distinct hypertension clusters, representing 'arterially stiffened', 'vaso-protected', and 'non-dipper' patients. Key clustering features were nocturnal- and central-BP, percent dipping, and arterial stiffness measures. We conclude that untreated patients with primary hypertension demonstrate early arterial stiffening rather than endothelial dysfunction or CIMT alterations. Phenotypic heterogeneity in nocturnal and central BP, percent dipping, and arterial stiffness observed early in the course of disease may have implications for risk stratification.


Assuntos
Hipertensão , Rigidez Vascular , Humanos , Espessura Intima-Media Carotídea , Análise de Onda de Pulso , Monitorização Ambulatorial da Pressão Arterial , Hipertensão/diagnóstico , Pressão Sanguínea/fisiologia , Fenótipo
2.
Cardiovasc Res ; 117(13): 2589-2609, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34698811

RESUMO

Both animal models and human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage, and cardiovascular risk in humans. In experimental and small clinical studies, both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, and rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (e.g. secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure-related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological anti-hypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are also discussed. The reviewed animal models, observational studies, and trial data in humans, support the therapeutic potential of immune-targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Agentes de Imunomodulação/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pesquisa Translacional Biomédica , Animais , Humanos , Hipertensão/genética , Hipertensão/imunologia , Hipertensão/fisiopatologia , Imunossupressores/uso terapêutico , Inflamação/genética , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/imunologia , Terapia de Alvo Molecular , Transdução de Sinais , Inibidores do Fator de Necrose Tumoral/uso terapêutico
3.
Cardiovasc Res ; 116(10): 1666-1687, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32352535

RESUMO

The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus , Miocardite , Pandemias , Pneumonia Viral , COVID-19 , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Humanos , Miocardite/diagnóstico , Miocardite/tratamento farmacológico , Miocardite/virologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Medição de Risco , SARS-CoV-2
4.
Nephrol Dial Transplant ; 30(7): 1202-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25958400

RESUMO

BACKGROUND: Patients on renal replacement therapy experience higher rates of morbidity and mortality, infection being the second commonest cause of death. In our haemodialysis population, we identify the pathogens, sensitivity patterns, sources of infection and outcomes of Gram-negative bacteraemia. METHODS: Data from the NHS Greater Glasgow & Clyde and NHS Forth Valley haemodialysis population were collected July 2011 to April 2014 through an interrogation of the renal unit electronic patient record, and confirmed by an independent search of the Microbiology database. RESULTS: Over 544 377 haemodialysis days, 84 patients experienced 95 Gram-negative bacteraemia events, a rate of 0.175 events per 1000 haemodialysis days, which varied with dialysis modality: non-tunnelled central venous catheters 4.77, arteriovenous grafts 0.24, tunnelled central venous catheters 0.21, and arteriovenous fistulae 0.11 per 1000 haemodialysis days. The commonest sources of bacteraemia were central venous catheters (CVCs) (16.8%, n = 16), infected ulcers (14.7%, n = 14), urinary (10.5%, n = 10), biliary (9.5%, n = 9) and intra-abdominal (9.5%, n = 9).The principal organisms were Escherichia coli (49.5%, n = 47), Enterobacter spp. (13.1%, n = 13), Klebsiella spp. (11.1%, n = 11), Proteus mirabilis (6.1%, n = 6) and Pseudomonas aeruginosa (5.1%, n = 5). Of the Enterobacteriaceae (n = 84), 88% were sensitive to gentamicin, 81% to ciprofloxacin, 91% to piperacillin-tazobactam and 100% were sensitive to meropenem.Three-month case mortality was 25.3% (n = 24). Ten patients (11.9%) had more than one Gram-negative bacteraemia; of these, nine patients (90.0%) were the same causative organism, predominantly E. coli. CONCLUSIONS: CVCs and diabetic foot ulcers remain significant risk factors for Gram-negative bacteraemia, highlighting the importance of vascular access planning. Despite good levels of antibiotic sensitivity, the early mortality following Gram-negative bacteraemia remains high, supporting aggressive treatment of such pathogens.


Assuntos
Cateterismo Venoso Central/efeitos adversos , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/epidemiologia , Diálise Renal/efeitos adversos , Idoso , Antibacterianos/uso terapêutico , Estudos Transversais , Registros Eletrônicos de Saúde , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Medicina Estatal , Reino Unido/epidemiologia
5.
Scott Med J ; 60(1): 32-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25475974

RESUMO

BACKGROUND: The prevalent population with established renal failure continues to grow. METHOD: Using the Renal Electronic Patient Record, we assess the long-term outcomes of the adult population in the West of Scotland who were awaiting kidney transplantation in 1988 (n = 219), and compare the demographics to the 2011 transplant waiting list (n = 409). RESULTS: Comparing the 2011 transplant waiting list, there are now more patients, but they are older, more likely to be female, and are more likely to have diabetes as a cause of renal failure. Seventy-four percent received a transplant; of these, 41% of the transplants ultimately failed and the patient returned to dialysis; 39% of patients died with a functioning graft and 20% remain alive with continuing transplant function. Life expectancy for those with renal failure was less than 60 years, significantly lower than the general population, though 29% survived for 20 years, half of these with a functioning kidney transplant and half having returned to dialysis. CONCLUSION: As survival with a transplant improves, attention is required to reduce the causes of mortality, in particular cardiovascular disease, and malignancy and infection associated with immunosuppression.


Assuntos
Falência Renal Crônica/mortalidade , Transplante de Rim/mortalidade , Diálise Renal/mortalidade , Obtenção de Tecidos e Órgãos/organização & administração , Adulto , Feminino , Humanos , Falência Renal Crônica/cirurgia , Falência Renal Crônica/terapia , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Prevalência , Diálise Renal/estatística & dados numéricos , Fatores de Risco , Escócia/epidemiologia , Análise de Sobrevida , Obtenção de Tecidos e Órgãos/estatística & dados numéricos , Listas de Espera
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