RESUMO
Pulse wave velocity (PWV), a measure of arterial stiffness, is an independent risk factor for cardiovascular morbidity and mortality. We investigated the relationship of ambulatory brachial cuff-based oscillometric PWV (oPWV) to 2 known correlates: age and brachial systolic blood pressure (SBP). In 234 participants in the Masked Hypertension Study, we analyzed 7284 validated hourly ambulatory SBP and oPWV readings using the Mobil-O-Graph monitor, which uses a proprietary pulse wave analysis algorithm to determine oPWV. Carotid-femoral PWV (cfPWV) was also measured. Mixed linear models were developed to estimate oPWV from age and ambulatory SBP. Participants were 34% male, with mean (SD) age 52.8 (9.9) years, SBP 123.8 (18.4) mm Hg, and oPWV 7.6 (1.3) m/s and cfPWV of 7.7 (1.7) m/s. The relationship of oPWV to age and SBP is given below: [Formula: see text] Age uniquely accounted for an estimated 75% of the total variation of oPWV, whereas SBP uniquely accounted for 20%; these findings were confirmed in an external validation dataset. Together, age and SBP accounted for 99.1% of the total variance of oPWV but (only) 40.2% of the variance of cfPWV. The correlation between oPWV and cfPWV was 0.58 but was only 0.11 after controlling for age and SBP. We conclude that the Mobil-O-Graph's oPWV is nearly completely explained by age and SBP and its relationship to cfPWV is because of their shared associations with age and SBP. Other hemodynamic variables derived from oscillometric pulse wave analysis may be useful and deserve additional scrutiny.
Assuntos
Monitorização Ambulatorial da Pressão Arterial , Doenças Cardiovasculares/fisiopatologia , Hipertensão Mascarada/diagnóstico , Hipertensão Mascarada/mortalidade , Análise de Onda de Pulso/métodos , Rigidez Vascular/fisiologia , Adulto , Fatores Etários , Idoso , Determinação da Pressão Arterial/métodos , Doenças Cardiovasculares/prevenção & controle , Estudos de Coortes , Bases de Dados Factuais , Feminino , Seguimentos , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Onda de Pulso/efeitos adversos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: Loop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss. METHODS AND RESULTS: Ten healthy participants were crossed over between 20 mg of oral immediate-release or extended-release (ER) torsemide while consuming a fixed diet with 300 mmol·d-1 of Na+. Compared with immediate-release, plasma torsemide after ER was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3-fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after ER, thereby enhancing diuretic efficiency. Compared with immediate-release, ER torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL, P<0.02) and Na+ output (98±15 versus 42±17 mmol, P<0.05) despite an 18% reduction in exposure. Neither formulation increased K+ excretion. CONCLUSIONS: Torsemide ER prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na+ retention, and moderates a fall in glomerular filtration rate. It caused significant Na+ loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.
Assuntos
Rim/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Eliminação Renal/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Área Sob a Curva , Creatinina/urina , Estudos Cross-Over , Preparações de Ação Retardada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Índia , Rim/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio na Dieta/urina , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Torasemida , Adulto JovemRESUMO
BACKGROUND: Because patients with hypertension may require >1 antihypertensive agent to control blood pressure (BP), physicians often prescribe a fixed combination of antihypertensive medications. OBJECTIVE: This study evaluated the effect of adding low-dose hydrochlorothiazide 12.5 mg (HCTZ12.5) to high-dose losartan 100 mg (L100) in patients with hypertension whose BP was inadequately controlled with L100 monotherapy. METHODS: Enrolled in this multicenter, randomized, double-blind, parallel-group, filter study were patients aged > or =18 years with a mean trough sitting diastolic BP (SiDBP) of 95 to 120 mm Hg. Patients were treated with L100 QD for 4 weeks. Patients who did not achieve adequate BP control were randomly assigned to receive L100/HCTZ12.5 or L100 QD for 6 weeks. The primary efficacy measure was the mean change in trough SiDBP from baseline in the 2 groups. Responders were defined as patients with a mean trough SiDBP of <90 mm Hg or patients who had a > or =10-mm Hg decrease in mean trough SiDBP. RESULTS: Demographic characteristics were similar between treatment groups. The patients randomized to the double-blind treatment period were mostly white (65.1%) and male (57.5%), with a mean age of 53.8 years. The mean (SD) duration of hypertension at baseline was 9.7 (8.5) years. The proportion of patients previously treated with antihypertensive therapy was 76.7%. Of the 367 patients enrolled in the L100 filter period, 292 patients had BP inadequately controlled with L100 monotherapy and were randomized to receive L100 (n = 145) or L100/HCTZ12.5 (n = 147). At week 6 after randomization, mean trough SiDBP was significantly lower in the L100/HCTZ12.5 group than in the L100 group (-8.3 vs -5.2, respectively; P < 0.001). The between-group difference was -3.0 mm Hg (95 % CI, -4.6 to -1.40; P < 0.001), and the proportion of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group (63.0% vs 44.4%; P < 0.001). The incidence of adverse events (AEs) occurring in >2% of patients during the double-blind period was similar for both groups. AEs occurring in the L100 group and the L100/HCTZ12.5 group included respiratory tract infection (6.2% vs 3.4%, respectively), dizziness (2.1% vs 0.7%), and headache (0.7% vs 3.4%). CONCLUSIONS: After 6 weeks of therapy, L100/HCTZ12.5 was associated with greater antihypertensive efficacy than L100, as measured by the change in mean trough SiDBP The percentage of responders was significantly greater in the L100/HCTZ12.5 group than in the L100 group.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hidroclorotiazida/uso terapêutico , Losartan/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hidroclorotiazida/administração & dosagem , Losartan/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
The use of pulse wave analysis may guide the provider in making choices about blood pressure treatment in prehypertensive or hypertensive patients. However, there is little clinical guidance on how to interpret and use pulse wave analysis data in the management of these patients. A panel of clinical researchers and clinicians who study and clinically use pulse wave analysis was assembled to discuss strategies for using pulse wave analysis in the clinical encounter. This manuscript presents an approach to the clinical application of pulse waveform analysis, how to interpret central pressure waveforms, and how to use existing knowledge about the pharmacodynamic effect of antihypertensive drug classes in combination with brachial and central pressure profiles in clinical practice. The discussion was supplemented by case-based examples provided by panel members, which the authors hope will provoke discussion on how to understand and incorporate pulse wave analysis into clinical practice.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/diagnóstico , Análise de Onda de Pulso/métodos , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Determinação da Pressão Arterial , Artéria Braquial/fisiologia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fluxo Pulsátil/fisiologia , Análise de Onda de Pulso/estatística & dados numéricos , Análise de Onda de Pulso/tendênciasRESUMO
11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may be involved in several abnormalities associated with the metabolic syndrome. This study evaluated the antihypertensive efficacy and safety of two 11ß-HSD1 inhibitors, MK-0736 and MK-0916, in overweight-to-obese hypertensive patients. Patients aged 18-75 years with sitting diastolic blood pressure (SiDBP) 90-104 mm Hg, systolic BP <160 mm Hg (after washout of prior antihypertensive medications), and BMI ≥27 to <41 kg/m(2) were randomized to receive 2 or 7 mg/d MK-0736, 6 mg/d MK-0916, or placebo for 12 weeks (n = 51-54/group). Patients with BMI ≥20 to <27 kg/m(2) received 6 mg/d MK-0916 or placebo for 24 weeks (n = 19/group). The primary endpoint was placebo-adjusted change from baseline in trough SiDBP in patients treated for 12 weeks with 7 mg/d MK-0736. The primary endpoint was not met (placebo-adjusted reduction = 2.2 mm Hg; P = .157). With 7 mg/d MK-0736, placebo-adjusted LDL-C decreased by 12.3%, high-density lipoprotein cholesterol by 6.3%, and body weight by 1.4 kg. Both 11ß-HSD1 inhibitors were generally well tolerated. In overweight-to-obese patients with hypertension, reduction in SiDBP with MK-0736 was not statistically significant. Nonetheless, MK-0736 was well tolerated and did appear to modestly improve other BP endpoints, LDL-C, and body weight.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1 , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Drogas em Investigação , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/administração & dosagem , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/efeitos adversos , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adolescente , Adulto , Idoso , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/metabolismo , Índice de Massa Corporal , Método Duplo-Cego , Monitoramento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/metabolismo , Feminino , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The growing rate of obesity and diabetes, and an aging population has led to increased demand for new antihypertensive compounds. This review highlights the challenges and opportunities associated with each phase of drug discovery and development of novel antihypertensive agents. Discovery and development starts with identification of a protein hypothesized to be linked to hypertension. Using the information gathered during this early stage, several potential candidates are often synthesized and moved on through preclinical evaluations, eventually leading to selection of one or more compounds for testing in humans. The compounds then enter preclinical safety studies in laboratory animal species and subsequently are tested in tiered clinical studies. As the compounds enter clinical testing, there is an exponential increase in the investment of resources to demonstrate that a new compound is a viable and worthy therapeutic agent for hypertension. The review provides some forecasting of issues that are likely to impact drug development of novel antihypertensives in the future.
Assuntos
Anti-Hipertensivos/farmacologia , Descoberta de Drogas , Animais , Biomarcadores , Ensaios Clínicos como Assunto , Aprovação de Drogas , Humanos , Hipertensão/tratamento farmacológicoRESUMO
Over a century of experience with brachial blood pressure has produced a substantial amount of information on the role of blood pressure as a factor in heart disease, stroke and kidney failure. Successful interventions lowering blood pressure and reducing damage to vital organs testify further to the importance of this vital sign. In recent years attempts to probe deeper into the value of knowledge of blood pressure levels closer to the heart (central blood pressures) suggest that noninvasive measurement of central aortic blood pressure may improve further efforts directed at both understanding drug benefit and uncovering potential drug safety issues. This commentary is a summary of a one-day meeting with the FDA in which the role of central blood pressure measurements as an adjunct to drug efficacy and safety were addressed.
Assuntos
Anti-Hipertensivos/uso terapêutico , Determinação da Pressão Arterial/métodos , Artérias Carótidas , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Descoberta de Drogas , HumanosRESUMO
Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Hipertensão/tratamento farmacológico , Dinitrato de Isossorbida/análogos & derivados , Losartan/administração & dosagem , Doadores de Óxido Nítrico/administração & dosagem , Pré-Hipertensão/tratamento farmacológico , Idoso , Pressão Sanguínea , Artéria Braquial , Estudos Cross-Over , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Frequência Cardíaca , Humanos , Dinitrato de Isossorbida/administração & dosagem , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The use of thiazide diuretics has decreased over the past 30 years despite data from many well-controlled clinical trials demonstrating that the use of these agents as monotherapy or in combination with other antihypertensive agents will reduce blood pressure and decrease cardiovascular as well as cerebrovascular events. METHODS: We reviewed clinical and experimental data on thiazide diuretics since their introduction in the late 1950s. RESULTS: The results of thiazide-based therapy in young and old are consistently positive despite concerns about some metabolic changes, eg, insulin resistance or hypokalemia, that may occur. CONCLUSION: We conclude that these agents are safe, effective, and well tolerated and should continue to be used either as monotherapy or with other medications in the management of hypertension.