RESUMO
BACKGROUND: The association between socioeconomic status (SES), sex, race / ethnicity and outcomes during hospitalization for heart failure (HF) has not previously been investigated. METHODS AND RESULTS: We analyzed HF hospitalizations in the United States National Inpatient Sample between 2015 and 2017. Using a hierarchical, multivariable Poisson regression model to adjust for hospital- and patient-level factors, we assessed the association between SES, sex, and race / ethnicity and all-cause in-hospital mortality. We estimated the direct costs (USD) across SES groups. Among 4,287,478 HF hospitalizations, 40.8% were in high SES, 48.7% in female, and 70.0% in White patients. Relative to these comparators, low SES (homelessness or lowest quartile of median neighborhood income) (relative risk [RR] 1.02, 95% confidence interval [CI] 1.00-1.05) and male sex (RR 1.09, 95% CI 1.07-1.11) were associated with increased risk, whereas Black (RR 0.79, 95% CI 0.76-0.81) and Hispanic (RR 0.90, 95% CI 0.86-0.93) race / ethnicity were associated with a decreased risk of in-hospital mortality (5.1% of all hospitalizations). There were significant interactions between race / ethnicity and both, SES (P < .01) and sex (Pâ¯=â¯.04), such that racial/ethnic differences in outcome were more pronounced in low SES groups and in male patients. The median direct cost of admission was lower in low vs high SES groups ($9324.60 vs $10,940.40), female vs male patients ($9866.60 vs $10,217.10), and Black vs White patients ($9077.20 vs $10,019.80). The median costs increased with SES in all demographic groups primarily related to greater procedural utilization. CONCLUSIONS: SES, sex, and race / ethnicity were independently associated with in-hospital mortality during HF hospitalization, highlighting possible care disparities. Racial/ethnic differences in outcome were more pronounced in low SES groups and in male patients.
Assuntos
Etnicidade , Insuficiência Cardíaca , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Masculino , Classe Social , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
AIMS: To identify and critically appraise measures that use clinical data to grade the severity of Type 2 diabetes. METHODS: We searched MEDLINE, Embase and PubMed between inception and June 2018. Studies reporting on clinical data-based diabetes-specific severity measures in adults with Type 2 diabetes were included. We excluded studies conducted solely in participants with other types of diabetes. After independent screening, the characteristics of the eligible measures including design and severity domains, the clinical utility of developed measures, and the relationship between severity levels and health-related outcomes were assessed. RESULTS: We identified 6798 studies, of which 17 studies reporting 18 different severity measures (32 314 participants in 17 countries) were included: a diabetes severity index (eight studies, 44%); severity categories (seven studies, 39%); complication count (two studies, 11%); and a severity checklist (one study, 6%). Nearly 89% of the measures included diabetes-related complications and/or glycaemic control indicators. Two of the severity measures were validated in a separate study population. More severe diabetes was associated with increased healthcare costs, poorer cognitive function and significantly greater risks of hospitalization and mortality. The identified measures differed greatly in terms of the included domains. One study reported on the use of a severity measure prospectively. CONCLUSIONS: Health records are suitable for assessment of diabetes severity; however, the clinical uptake of existing measures is limited. The need to advance this research area is fundamental as higher levels of diabetes severity are associated with greater risks of adverse outcomes. Diabetes severity assessment could help identify people requiring targeted and intensive therapies and provide a major benchmark for efficient healthcare services.
Assuntos
Regras de Decisão Clínica , Diabetes Mellitus Tipo 2/diagnóstico , Técnicas de Diagnóstico Endócrino , Adulto , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Técnicas de Diagnóstico Endócrino/normas , Técnicas de Diagnóstico Endócrino/estatística & dados numéricos , Humanos , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To determine whether selected metabolic factors are associated with greater amounts of radiographic hand osteoarthritis (OA) incidence and progression. METHODS: The study identified 706 adults, aged 50-69 years, with hand pain and hand radiographs at baseline, from two population-based cohorts. Metabolic factors (body mass index, hypertension, dyslipidaemia, and diabetes) were ascertained at baseline by direct measurement and medical records. Analyses were undertaken following multiple imputation of missing data, and in complete cases (sensitivity analyses). Multivariable regression models estimated associations between metabolic factors and two measures of radiographic change at 7 years for all participants, individuals free of baseline radiographic OA, and in baseline hand OA subsets. Estimates were adjusted for baseline values and other covariates. RESULTS: The most consistent and strong associations observed were between the presence of diabetes and the amount of radiographic progression in individuals with nodal OA [adjusted mean differences in Kellgren-Lawrence summed score of 4.50 (-0.26, 9.25)], generalized OA [3.27 (-2.89, 9.42)], and erosive OA [3.05 (-13.56, 19.67)]. The remaining associations were generally weak or inconsistent, although numbers were limited for analyses of incident radiographic OA and erosive OA in particular. CONCLUSION: Overall metabolic risk factors were not independently or collectively associated with greater amounts of radiographic hand OA incidence or progression over 7 years, but diabetes was associated with radiographic progression in nodal, and possibly generalized and erosive OA. Diabetes has previously been associated with prevalent but not incident hand OA. Further investigation in hand OA subsets using objective measures accounting for disease duration and control is warranted.
Assuntos
Articulação da Mão/diagnóstico por imagem , Síndrome Metabólica/complicações , Osteoartrite/epidemiologia , Vigilância da População/métodos , Radiografia/métodos , Medição de Risco , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Osteoartrite/etiologia , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Reino Unido/epidemiologiaRESUMO
The co-existence of stroke and HIV has increased in recent years, but the impact of HIV on post-stroke outcomes is poorly understood. We examined the impact of HIV on inpatient mortality, length of acute hospital stay and complications (pneumonia, respiratory failure, sepsis and convulsions), in hospitalized strokes in Thailand. All hospitalized strokes between 1 October 2004 and 31 January 2013 were included. Data were obtained from a National Insurance Database. Characteristics and outcomes for non-HIV and HIV patients were compared and multivariate logistic and linear regression models were constructed to assess the above outcomes. Of 610 688 patients (mean age 63·4 years, 45·4% female), 0·14% (866) had HIV infection. HIV patients were younger, a higher proportion were male and had higher prevalence of anaemia (P < 0·001) compared to non-HIV patients. Traditional cardiovascular risk factors, hypertension and diabetes, were more common in the non-HIV group (P < 0·001). After adjusting for age, sex, stroke type and co-morbidities, HIV infection was significantly associated with higher odds of sepsis [odds ratio (OR) 1·75, 95% confidence interval (CI) 1·29-2·4], and inpatient mortality (OR 2·15, 95% CI 1·8-2·56) compared to patients without HIV infection. The latter did not attenuate after controlling for complications (OR 2·20, 95% CI 1·83-2·64). HIV infection is associated with increased odds of sepsis and inpatient mortality after acute stroke.
Assuntos
Infecções por HIV/complicações , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Adulto , Idoso , Feminino , Humanos , Incidência , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Sepse/epidemiologia , Análise de Sobrevida , Tailândia/epidemiologiaRESUMO
BACKGROUND: We aimed to examine the association between chocolate intake and the risk of incident heart failure in a UK general population. We conducted a systematic review and meta-analysis to quantify this association. METHODS AND RESULTS: We used data from a prospective population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Chocolate intake was quantified based on a food frequency questionnaire obtained at baseline (1993-1997) and incident heart failure was ascertained up to March 2009. We supplemented the primary data with a systematic review and meta-analysis of studies which evaluated risk of incident heart failure with chocolate consumption. A total of 20,922 participants (53% women; mean age 58 ± 9 years) were included of whom 1101 developed heart failure during the follow up (mean 12.5 ± 2.7 years, total person years 262,291 years). After adjusting for lifestyle and dietary factors, we found 19% relative reduction in heart failure incidence in the top (up to 100 g/d) compared to the bottom quintile of chocolate consumption (HR 0.81 95%CI 0.66-0.98) but the results were no longer significant after controlling for comorbidities (HR 0.87 95%CI 0.71-1.06). Additional adjustment for potential mediators did not attenuate the results further. We identified five relevant studies including the current study (N = 75,408). The pooled results showed non-significant 19% relative risk reduction of heart failure incidence with higher chocolate consumption (HR 0.81 95%CI 0.66-1.01). CONCLUSIONS: Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure.
Assuntos
Doces , Chocolate , Comportamento Alimentar , Insuficiência Cardíaca/epidemiologia , Idoso , Doces/efeitos adversos , Chocolate/efeitos adversos , Inglaterra/epidemiologia , Feminino , Voluntários Saudáveis , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Soft drink consumption is associated with adverse health behaviours that predispose to adverse cardiovascular risk factor profiles; however, it is unclear whether their intake independently leads to an increased risk of cardiovascular events and mortality. We conducted a systematic review and meta-analysis to evaluate this. METHODS: Medline and EMBASE were searched in July 2015 for studies that considered soft drink intake and risk of mortality, myocardial infarction (MI) or stroke. Pooled risk ratios (RRs) for adverse outcomes were calculated using inverse variance with a random effects model, and heterogeneity was assessed using the I2 statistic. RESULTS: A total of seven prospective cohort studies with 308,420 participants (age range 34-75 years) were included in the review. The pooled results suggest a greater risk of stroke (RR 1.13, 95% CI 1.02-1.24), and MI (RR 1.22, 95% CI 1.14-1.30), but not vascular events with incremental increase in sugar-sweetened beverage (SSB) consumption. With incremental increase in artificially sweetened beverage (ASB) consumption, there was a greater risk of stroke (RR 1.08, 95% CI 1.03-1.14), but not vascular events or MI. In the evaluation of high vs. low SSB, there was a greater risk of MI (RR 1.19, 95% CI 1.09-1.31) but not stroke, vascular events or mortality. For ASB, there was a significantly greater risk of stroke (RR 1.14, 95% CI 1.04-1.26) and vascular events (RR 1.44, 95% CI 1.02-2.03) but not MI or mortality. CONCLUSIONS: Our results suggest an association between consumption of sugar-sweetened and ASBs and cardiovascular risk, although consumption may be a surrogate for adverse health behaviours.
Assuntos
Bebidas Gaseificadas/efeitos adversos , Doenças Cardiovasculares/etiologia , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Comportamento Alimentar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação NutricionalRESUMO
AIMS: To synthesise the evidence relating influenza and influenza-like symptoms to the risks of myocardial infarction (MI), heart failure (HF) and stroke. METHODS: We conducted a systematic review and meta-analysis of the evidence relating influenza and influenza-like symptoms to the risks of MI, HF and stroke. We systematically searched all MEDLINE and EMBASE entries up to August 2014 for studies of influenza vs. the cardiovascular outcomes above. We conducted random effects meta-analysis using inverse variance method for pooled odds ratios (OR) and evaluated statistical heterogeneity using the I(2) statistic. RESULTS: We identified 12 studies with a total of 84,003 participants. The pooled OR for risk of MI vs. influenza (serologically confirmed) was 1.27 (95% CI, confidence interval 0.54-2.95), I(2) = 47%, which was significant for the only study that adjusted for confounders (OR 5.50, 95% CI 1.31-23.13). The pooled OR for risk of MI vs. influenza-like symptoms was 2.17 (95% CI 1.68-2.80), I(2) = 0%, which was significant for both unadjusted (OR 2.23, 95% CI 1.65-3.01, five studies) and adjusted studies (OR 2.01, 95% CI 1.24-3.27, two studies). We found one study that evaluated stroke risk, one study in patients with HF, and one that evaluated mortality from MI - all of these studies suggested increased risks of events with influenza-like symptoms. CONCLUSIONS: There is an association between influenza-like illness and cardiovascular events, but the relationship is less clear with serologically diagnosed influenza. We recommend renewed efforts to apply current clinical guidelines and maximise the uptake of annual influenza immunisation among patients with cardiovascular diseases, to decrease their risks of MI and stroke.
Assuntos
Insuficiência Cardíaca/etiologia , Influenza Humana/complicações , Infarto do Miocárdio/etiologia , Acidente Vascular Cerebral/etiologia , Humanos , Estudos Observacionais como Assunto , Razão de Chances , Fatores de RiscoRESUMO
Heart failure (HF) and diabetes mellitus (DM) commonly co-exist, with a prevalence of DM of up to 40 % in HF patients. Treatment of DM in patients with HF is challenging since many of the contemporary therapies used for the treatment of DM are either contraindicated in HF or are limited in their use due to the high prevalence of co-morbidities such as significant renal dysfunction. This article presents an overview of the physiology of the incretin system and how it can be targeted therapeutically, highlighting implications for the management of patients with DM and HF. Receptors for the incretin glucagon-like peptide-1 (GLP-1) are expressed throughout the cardiovascular system and the myocardium and are up-regulated in HF. GLP-1 therapy improves cardiac function in animal models of HF through augmented glucose uptake in the myocardium mediated through a p38 MAP kinase pathway. Small clinical studies have shown that GLP-1 improves ejection fraction, reduces BNP levels and enhances functional capacity in patients with chronic HF. A number of randomized controlled trials are currently underway to define the utility of targeting the incretin system in HF patients with DM. Incretin-based therapy may represent a novel therapeutic strategy in the treatment of HF patients with diabetes, in particular for their cardioprotective effects independent of those attributable to tight glycemic control.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Incretinas/uso terapêutico , Comorbidade , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Incretinas/metabolismo , Resultado do TratamentoRESUMO
Atrial fibrillation (AF) and heart failure (HF) commonly coexist, and their co-presence is associated with adverse outcomes relating to thromboembolic events, HF progression, hospitalisation and death. Diastolic dysfunction (DD) is also frequently present in patients with HF and is an independent predictor of hospitalisation and mortality. The presence of DD is a strong predictor of incident AF in patients with HF. In this review, we provide mechanistic insight into pathophysiological processes that frequently promote the occurrence of AF, HF and DD and outline the yin-yang relationship between AF, DD and HF. More recently, invasive studies have also shown that asymptomatic paroxysmal atrial fibrillation (PAF) is a common phenomenon in HF patients. We examine complex inter-relationships between PAF, HF and DD and speculate upon the possible clinical influence of undiagnosed PAF in HF patients.
Assuntos
Fibrilação Atrial/fisiopatologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Fibrilação Atrial/complicações , Insuficiência Cardíaca Diastólica/complicações , HumanosRESUMO
The Terumo "five in six" system involves insertion of an extra length, 5 Fr Terumo guide catheter (Heartrail, Terumo) into a standard 6 Fr guide catheter so that the tip protrudes beyond the 6 Fr guide. This system increases backup support and has been used successfully to advance balloon catheters across chronic total occlusions. We describe the use of this system to facilitate extra deep intubation, enabling distal stent delivery beyond proximal points of obstruction that had been unsuccessful using more conventional techniques.
Assuntos
Angioplastia Coronária com Balão/métodos , Cateterismo Cardíaco/instrumentação , Estenose Coronária/terapia , Stents , Idoso , Cateterismo Cardíaco/métodos , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Desenho de Equipamento , Falha de Equipamento , Seguimentos , Humanos , Masculino , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The Asahi sheathless guide catheter system is a hydrophilic catheter with a central dilator that does not require an introducer sheath during transradial percutaneous coronary intervention. Conventional sheath introducers are often 1- to 2F larger than the catheter itself; therefore, this system enables the use of a larger French catheter during procedures than would otherwise be possible using conventional techniques. We describe the use of a 7.5F sheathless guide catheter system with a smaller outer diameter than a conventional 6F introducer sheath in 16 cases performed transradially involving rotablation, crush stent bifurcation lesions, 7F proximal protection, and thrombectomy devices. Such cases would otherwise not always be possible if performed using conventional transradial techniques in patients with smaller radial artery sizes.
Assuntos
Angioplastia Coronária com Balão , Calcinose/terapia , Estenose Coronária/terapia , Artéria Radial , Stents , Adulto , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Angioplastia Coronária com Balão/instrumentação , Angioplastia Coronária com Balão/métodos , Calcinose/diagnóstico por imagem , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Trombectomia/instrumentação , Resultado do TratamentoRESUMO
BACKGROUND: Routine heart failure (HF) monitoring and management is in the community but the natural course of worsening renal function (WRF) and its influence on HF prognosis is unknown. We investigated the influence of routinely monitored renal decline and related comorbidities on imminent hospitalisation and death in the HF community population. METHODS: A nested case-control study within an incident HF cohort (Nâ¯=â¯50,114) with 12-years follow-up. WRF over 6-months before first hospitalisation and 12-months before death was defined by >20% reduction in estimated glomerular filtration rate (eGFR). Additive interactions between chronic kidney disease (CKD) and comorbidities were investigated. RESULTS: Prevalence of CKD (eGFR<60â¯ml/min/1.73m2) in the HF community was 63%, which was associated with an 11% increase in hospitalisation and 17% in mortality. Both risk associations were significantly worse in the presence of diabetes. Compared to HF patients with eGFR,60-89, there was no or minimal increase in risk for mild to moderate CKD (eGFR,30-59) for both outcomes. Adjusted risk estimates for hospitalisation were increased only for severe CKD(eGFR,15-29); Odds Ratio 1.49 (95%CI;1.36,1.62) and renal failure(eGFR,<15); 3.38(2.67,4.29). The relationship between eGFR and mortality was U-shaped; eGFR, ≥90; 1.32(1.17,1.48), eGFR,15-29; 1.68(1.58,1.79) and eGFR,<15; 3.04(2.71,3.41). WRF is common and associated with imminent hospitalisation (1.50;1.37,1.64) and mortality (1.92;1.79,2.06). CONCLUSIONS: In HF, the risk associated with CKD differs between the community and the acute HF setting. In the community setting, moderate CKD confers no risk but severe CKD, WRF or CKD with other comorbidities identifies patients at high risk of imminent hospitalisation and death.
Assuntos
Insuficiência Cardíaca , Insuficiência Renal Crônica , Idoso , Estudos de Casos e Controles , Comorbidade , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Administração dos Cuidados ao Paciente , Prevalência , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Índice de Gravidade de Doença , Reino Unido/epidemiologiaRESUMO
Heart failure (HF) and atrial fibrillation (AF) frequently coexist and each complicates the course of the other. The purpose of this review is to analyse the prognostic impact of AF in patients with HF and assess whether there is an advantage in targeting therapies towards the maintenance of sinus rhythm (SR) in this cohort of patients. The presence of AF in patients with HF has been reported to be independently associated with an increase in mortality in many studies and this increased risk is observed in those with both preserved and impaired LV systolic function. The optimal strategy for targeting AF in patients with HF is unclear but recent randomised controlled studies indicate no significant prognostic advantage associated with a rhythm control strategy as compared to a rate control strategy. A number of small studies have investigated the role of both cardiac resynchronization therapy (CRT) and AF catheter ablation for the maintenance of / conversion to SR in patients with HF with initial promising results although larger randomised controlled studies will need to be performed to define the role of these modalities in the treatment of this cohort and whether preliminary benefits observed in these studies translate to improvements in longer term prognosis. Finally, there has been a focus on modifying the arrhythmogenic atrial substrate and neurohormonal milieu by pharmacological means in order to prevent AF although it remains to be seen whether this approach proves to be efficacious with improvements in clinically relevant outcomes.
Assuntos
Fibrilação Atrial/complicações , Insuficiência Cardíaca/complicações , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/terapia , Humanos , Prognóstico , Fatores de RiscoRESUMO
The presence of thrombus is independently associated with adverse outcomes during percutaneous coronary intervention (PCI), particularly in those cases involving a large thrombus burden such as in saphenous vein grafts (SVGs) or during primary PCI. Mechanical thrombectomy devices are used to reduce the thrombus burden in such high-risk procedures to reduce the risk of distal embolization and slow flow and no-reflow. Here we describe 3 cases of successful use of a stent delivery system with a wide-bore lumen, the "five-in-six" Heartrail catheter, as a thrombectomy device in SVG lesions and primary PCI following failure of conventional simple aspiration thrombectomy catheters.
Assuntos
Angioplastia Coronária com Balão , Catéteres , Trombose Coronária/cirurgia , Trombectomia/instrumentação , Síndrome Coronariana Aguda , Idoso , Cateterismo Cardíaco/métodos , Oclusão Coronária/terapia , Desenho de Equipamento , Humanos , Masculino , Pessoa de Meia-Idade , Veia Safena/transplante , Trombectomia/métodosRESUMO
The actions of arachidonic acid (AA) were investigated in guinea-pig isolated ventricular myocytes. Exposure of myocytes to 10 microM AA reduced the amplitude of contractions and calcium transients accompanying action potentials at a frequency of 1 Hz. AA (10 microM) also reduced the amplitude of calcium currents recorded under voltage-clamp conditions. The suppression of contraction by AA was not prevented by either 10 microM trihydroindomethicin (to inhibit cyclo-oxygenase) or 10 microM ETYA (5,8,11,14-eicosatetraynoic acid, to inhibit AA metabolising enzymes), showing that the actions of AA appeared not to be mediated by these metabolites. The reduction of contraction by 10 microM AA was also not prevented by the protein kinase C inhibitor, Ro31-8220 (1 microM), showing that this pathway appeared not to be required for the observed effect. Direct effects of AA may be involved. A further action of 10 microM AA was to suppress spontaneous electrical activity induced by either the beta-adrenergic agonist isoprenaline or the Na(+) pump inhibitor, ouabain. This effect of AA on spontaneous activity might be associated with the observed reduction of calcium entry through L-type calcium channels, although additional effects of AA on calcium release from the sarcoplasmic reticulum might also be involved. Experimental Physiology (2001) 86.4, 437-449.
Assuntos
Ácido Araquidônico/farmacologia , Fibras Musculares Esqueléticas/fisiologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/citologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Ácido 5,8,11,14-Eicosatetrainoico/farmacologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cardiotônicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Canais de Potássio de Retificação Tardia , Inibidores Enzimáticos/farmacologia , Cobaias , Ventrículos do Coração/citologia , Técnicas In Vitro , Indóis/farmacologia , Indometacina/farmacologia , Isoproterenol/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Ouabaína/farmacologia , Técnicas de Patch-Clamp , Canais de Potássio/metabolismo , Proteína Quinase C/antagonistas & inibidoresRESUMO
The mechanisms which underlie the inotropic actions of phorbol dibutyrate (PDBu), a synthetic compound which can directly activate protein kinase C (PKC), were investigated in guinea-pig isolated ventricular myocytes. Exposure of cells to PDBu (10(-7) M) reduced myocyte contraction amplitude to 46 +/- 3% of control (n = 8; P < 0.05) with an associated shortening in action potential duration (action potential duration at 90% repolarisation (APD90) was reduced to 83 +/- 1% of control; P < 0.05). The negative inotropic actions of PDBu and the shortening in action potential duration were abolished in the presence of a selective PKC inhibitor, Ro31-8220. Calcium transients (constructed from calcium-activated tail currents following interruption of action potentials by voltage clamp to -70 mV) were reduced following exposure to 10(-7) M PDBu by 38 +/- 2% (n = 9, P < 0.05). L-type calcium currents were not significantly altered following exposure to 10(-7) M PDBu (98 +/- 2% of control; P > 0.05). In contrast, delayed rectifier potassium currents (I(K)) were enhanced to 154 +/- 8% of control (n = 7; P < 0.05) by 10(-7) M PDBu. This enhancement of I(K) may contribute to the observed shortening in action potential duration observed following exposure to PDBu under the conditions of our experiments. When the action potential configuration was maintained throughout the experiment by applying a voltage-clamp waveform, 10(-7) M PDBu still reduced contraction amplitude to 57 +/- 3% of control (P < 0.05). Exposure to 10(-7) M PDBu also suppressed spontaneous activity (both spontaneous potential fluctuations induced by the beta-adrenergic agonist isoprenaline (40 nM), and transient inward currents induced by the cardiac glycoside ouabain (1 microM) under voltage clamp). It therefore appears that the reduction in myocyte contraction amplitude induced by exposure to PDBu may result in part through mechanisms independent of action potential shortening, which may include direct actions of protein kinase C on the function of the sarcoplasmic reticulum (SR) calcium store and/or on contractile proteins (though action potential shortening would be expected to cause a further decrease as a consequence of reduced calcium loading of the SR). The reduction of spontaneous activity caused by PDBu may also result from changes in the function of the SR store mediated by protein kinase C.
Assuntos
Cálcio/metabolismo , Cardiotônicos/farmacologia , Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Dibutirato de 12,13-Forbol/farmacologia , Proteína Quinase C/metabolismo , Potenciais de Ação/fisiologia , Animais , Canais de Cálcio Tipo L/metabolismo , Tamanho Celular , Ativação Enzimática , Cobaias/fisiologia , Coração/fisiologia , Indóis/farmacologia , Isoproterenol/farmacologia , Miocárdio/citologia , Miocárdio/metabolismo , Ouabaína/farmacologia , Técnicas de Patch-Clamp , Proteína Quinase C/antagonistas & inibidores , Retículo Sarcoplasmático/metabolismoRESUMO
Detrusor-external sphincter dyssynergia (DSD) is a common cause of bladder outlet obstruction in men with spinal cord injuries, which if left untreated leads ultimately to renal failure. External sphincterotomy is currently the main treatment for DSD. However, obstruction persists in a substantial proportion of cases after this procedure. There is no effective drug treatment for DSD. Nitric oxide is an inhibitory neurotransmitter synthesised by nitric oxide synthase. Both animal and human studies suggest that nitric oxide mediates urethral sphincter relaxation. Nitric-oxide-synthase staining neurons have been identified in very high density in the urethral sphincters of a variety of animals and in human beings. Relaxation of the urethral sphincter is abolished by inhibitors of nitric oxide synthase and enhanced by nitric oxide donors. Mice with targeted deletion of the gene, for neuronal nitric oxide have urethral sphincters that do not relax in response to electrical stimulation. We hypothesise that augmentation of external sphincter nitric oxide could be an effective pharmacological treatment for DSD. Currently available nitric oxide donors such as glyceryl trinitrate or isosorbide mononitrate could be used to deliver nitric oxide to the urethral sphincter. The variable pharmacokinetics of these drugs combined with different modes of delivery (sublingual, buccal, or oral) could be used to achieve both short-term and long-term increases in concentrations of sphincter nitric oxide, thereby resulting in either acute or chronic lowering of urethral pressure. The safety and efficacy of this potential treatment for DSD needs to be established in clinical trials of men with spinal cord injures with DSD.
Assuntos
Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico/fisiologia , Traumatismos da Medula Espinal/complicações , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Animais , Humanos , Camundongos , Doadores de Óxido Nítrico/efeitos adversos , Traumatismos da Medula Espinal/fisiopatologia , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Bexiga Urinaria Neurogênica/fisiopatologiaRESUMO
STUDY DESIGN: Literature review of current treatment options for detrusor-sphincter dyssynergia (DSD) in spinal cord injury. OBJECTIVES: To review the outcomes and complications associated with external sphincterotomy and to summarise the results and complications of alternative treatment options for detrusor-sphincter dyssynergia in spinal cord injury. In addition, we propose a potential alternative future drug treatment for external sphincter dyssynergia based upon recent research on the neuropharmacology of the external urethral sphincter. SETTING: The National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, UK. METHODS: Medline search from 1966 to 2002 using the words 'external sphincterotomy', 'detrusor-sphincter dyssynergia' and 'neurogenic bladder combined with surgery'. RESULTS: While external sphincterotomy is an effective treatment for DSD, a significant number of men following this procedure continue to have high intrarenal pressures, recurrent urinary infection or troublesome autonomic dysreflexia and a worryingly high proportion demonstrate persistently raised leak point pressures, putting them at subsequent risk of renal damage. Alternative treatments for external sphincter dyssynergia include urethral stents and balloon dilatation, both of which are effective. However, over the long term stents can undergo encrustation and there remains a definite risk of stent migration necessitating stent removal or replacement. Balloon dilatation of the external sphincter is associated with a risk of subsequent stricture formation. Intraurethral Botulinum A toxin seems to be effective though there have been no large randomised studies comparing it against placebo. However, it is not a durable treatment option and it has not found a common place in the treatment of DSD. There is now a considerable amount of experimental data from both animal and human studies to suggest that nitric oxide (NO) is an important physiological inhibitory neurotransmitter in the urethral sphincter, mediating relaxation of the external urethral sphincter. The potential role of sphincter NO augmentation for treatment of DSD is discussed. CONCLUSION: External sphincterotomy remains the mainstay of treatment for urodynamically significant detrusor-sphincter dyssynergia, but in recent years a number of effective, alternative treatment options have become available. While at present there is no effective systemic drug treatment, recent research into external sphincter neuropharmacology suggests that systemic or topical augmentation of external sphincter NO may provide an effective method for lowering sphincter pressure.