RESUMEN
Evidence-based medicine (EBM) has a long history, but was revived in the early 1990s by a campaign mounted by a movement that took its name. The EBM movement focused attention on the need for greater objectivity in medical decision-making and led to the Cochrane Collaboration, which provides reviews of evidence on the basis of comparative research. Important limitations of EBM's effect on medicine have also emerged. Failure to acknowledge the limitations of clinical trials and systematic reviews has limited their applicability to individual patients' circumstances. An almost exclusive focus on drugs and devices has left vast areas of health care in an evidence vacuum. An overdependence on commissions for its research may have limited its independence in selecting what it investigates. EBM needs to widen its scope beyond drugs and devices to address many areas that often lack evidence at present, notably, health policy, management, and reforms.
Asunto(s)
Logro , Toma de Decisiones Clínicas/métodos , Medicina Basada en la Evidencia/normas , Salud Pública , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/terapia , HumanosRESUMEN
LVH (left ventricular hypertrophy) is associated with impaired coronary vascular reserve. In the present study, we examined the effect of pressure-overload hypertrophy on vasorelaxant responses of guinea-pig isolated coronary small arteries and compared them with mesenteric small arteries. Pressure-overload was induced by banding the ascending aorta of guinea-pigs. Haemodynamics, and ventricular, atrial and lung weights were measured 168 days after banding. Isolated coronary and mesenteric small arteries were contracted with a thromboxane mimetic (U46619) and relaxation to ACH (acetylcholine), ISO (isoprenaline), FSK (forskolin) and SNP (sodium nitroprusside) was examined. Arterial wall morphology was examined by light microscopy. Aortic banding reduced cardiac output and increased systemic vascular resistance; atrial, ventricular and lung weights were increased. Coronary artery adventitial and medial thickness were increased, but mesenteric arterial wall morphology was unaffected. Coronary artery relaxation to ACH, ISO, FSK and SNP were reduced in banded animals. In contrast, relaxation of mesenteric arteries to ACH, FSK and SNP were unaffected by banding, although ISO-induced relaxation was reduced. A COX (cyclo-oxygenase) inhibitor, indomethacin, had no effect on coronary artery responses to ACH in banded or sham animals, but the differences in relaxation of coronary arteries between banded and sham animals were no longer significant following pre-incubation with the NO inhibitors L-NMMA (N(G)-monomethyl-L-arginine) and oxyhaemoglobin. In conclusion, pressure-overload-induced LVH causes impaired relaxation of small coronary arteries to endothelium-dependent and -independent relaxants. These findings are indicative of alterations in vascular smooth muscle responsiveness to vasodilators. Impairment of coronary arterial vasodilation may contribute to the reduced coronary vascular reserve seen in LVH.
Asunto(s)
Estenosis de la Válvula Aórtica/complicaciones , Vasos Coronarios/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Vasodilatación , Animales , Estenosis de la Válvula Aórtica/fisiopatología , Presión Sanguínea , Gasto Cardíaco , Cobayas , Frecuencia Cardíaca , Hipertrofia Ventricular Izquierda/etiología , Masculino , Arterias Mesentéricas/fisiopatología , Resistencia Vascular , VasodilatadoresRESUMEN
OBJECTIVE: The aims of this study were to: i) investigate the role of angiotensin in mediating changes to myocardial electromechanical properties during the development and regression of left ventricular hypertrophy (LVH) generated by constriction of the thoracic aorta; ii) identify any role of angiotensin-1 receptor blockade on ameliorating changes to these electromechanical properties. METHODS: LVH was induced in guinea-pigs by constricting the ascending aorta (AC groups). After 42+/-3 days, the constriction was either removed or left in place. Following the second operation animals were fed losartan (10 mg x kg(-1) x day(-1)) or saline for 42+/-3 days. Sham-operated animals served as controls. In other groups, LVH was generated by subcutaneous angiotensin II (200 ng x kg(-1) x min(-1)) infusion for 42+/-3 days with or without losartan administration (AT groups), and compared to animals undergoing aortic constriction for a similar period. Electromechanical changes were recorded in isolated left ventricular myocardial preparations. RESULTS: Wet and dry heart-to-body weight ratios (HBR) increased significantly in the AC and AT models compared to control. Losartan prevented the increase of HBR in the AT group. Removal of the constriction allowed LVH to regress to control. The force-frequency relationship was reduced in both models and recovered fully on regression. However, the two models generated different electrophysiological changes: in the AC group, longitudinal conduction velocity was reduced and transverse conduction increased, with a consequent reduction of the anisotropic conduction ratio. On regression recovery was only partial; action potential duration was prolonged and did not recover. In the AT group, electrophysiological changes were limited: only an increase of transverse conduction and a reduction of the anisotropic conduction ratio were observed. Losartan had no effect on HBR or electromechanical variables in the aortic constricted animals, nor did it affect the extent of recovery in animals with regression of LVH. CONCLUSIONS: The electromechanical changes to hypertrophied myocardium are different in these two models of LVH. Moreover, losartan was ineffective in modulating the consequences of hypertrophy induced by constriction of the thoracic aorta.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensina II/fisiología , Corazón/fisiopatología , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/fisiopatología , Losartán/uso terapéutico , Angiotensina II/farmacología , Animales , Aorta Torácica , Constricción , Electrocardiografía/efectos de los fármacos , Cobayas , Masculino , Modelos Animales , Factores de TiempoRESUMEN
Therapeutic reference pricing (TRP) places medicines to treat the same medical condition into groups or 'clusters' with a single common reimbursed price. Underpinning this economic measure is an implicit assumption that the products included in the cluster have an equivalent effect on a typical patient with this disease. 'Truly innovative' products can be exempt from inclusion in the cluster. This increasingly common approach to cost containment allocates products into one of two categories - truly innovative or therapeutically equivalent. This study examines the implications of TRP against the step-wise evolution of drugs for cardiovascular conditions over the past 50 years. It illustrates the complex interactions between advances in understanding of cellular and molecular disease mechanisms, diagnostic techniques, treatment concepts, and the synthesis, testing and commercialisation of products. It confirms the highly unpredictable and incremental nature of the innovation process. Medical progress in terms of improvement in patient outcomes over the long-term depends on the cumulative effect of year after year of painstaking incremental advances. It shows that the parallel processes of advances in scientific knowledge and the industrial 'investment-innovative cycle' involve highly developed sets of complementary capabilities and resources. A framework is developed to assess the impact of TRP upon research and development investment decisions and the development of therapeutic classes. We conclude that a simple categorisation of products as either 'truly innovative' or 'therapeutically equivalent' is inconsistent with the incremental processes of innovation and the resulting differentiated product streams revealed by our analysis. Widespread introduction of TRP would probably have prematurely curtailed development of many incremental innovations that became the preferred 'product of choice' by physicians for some indications and patients in managing the incidence of cardiovascular disease.
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Fármacos Cardiovasculares/economía , Enfermedades Cardiovasculares/tratamiento farmacológico , Costos de los Medicamentos/tendencias , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/economía , Costos y Análisis de Costo/tendencias , Diseño de Fármacos , Industria Farmacéutica/economía , Industria Farmacéutica/tendencias , Humanos , Pautas de la Práctica en Medicina/tendencias , Mecanismo de Reembolso , Investigación/tendencias , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Química Farmacéutica/legislación & jurisprudencia , Países en Desarrollo , Industria Farmacéutica/legislación & jurisprudencia , Preparaciones Farmacéuticas/provisión & distribución , Antirretrovirales/provisión & distribución , Medicamentos Genéricos , Humanos , Patentes como Asunto/legislación & jurisprudencia , Tailandia , Estados UnidosRESUMEN
OBJECTIVE: The aim of this study was to investigate changes following regression of left ventricular hypertrophy (LVH). METHODS: Electrophysiolological changes were recorded in isolated guinea-pig myocardial preparations. LVH was induced by constriction of the thoracic aorta and regression was followed after removal of the constriction. Sham-operated animals served as controls. RESULTS: During 42 days constriction, heart/body weight ratio increased (3.19+/-0.49 vs. 3.85+/-0.83 g kg(-1)) and was accompanied by an increase of cell size. Forty-two days after clip removal, values had returned to control values. LVH increased action potential (AP) duration (mean 112% of control) and decreased conduction velocity (60.4+/-3.3 vs. 45.9+/-4.6 cm(-1)). These changes did not return to control after regression of LVH. The changes to condition velocity were attributed solely to increases of intracellular resistivity. The positive staircase response also decreased with LVH, but did recover upon regression. In isolated whole hearts, no changes to subepicardial action potential duration, QRS complex duration or AP refractory period were observed in LVH or its regression. During low-flow ischaemia AP duration shortened reversibly, the rate of shortening was more rapid in hypertrophied hearts but similar to control in regressed hearts. The incidence of ventricular tachyarrhythmias of fibrillation during low-flow ischaemia was similar in control, hypertrophied and regressed hearts. CONCLUSION: Morphological regression of LVH is not accompanied by reversal of electrophysiological changes measured in isolated preparations, whereas some aspects of contractile function to recover.
Asunto(s)
Hipertrofia Ventricular Izquierda/fisiopatología , Potenciales de Acción/fisiología , Animales , Tamaño de la Célula , Técnicas de Cultivo , Electrofisiología , Cobayas , Hipertrofia Ventricular Izquierda/patología , Masculino , Miocitos Cardíacos/patología , PerfusiónRESUMEN
In order to determine whether morphological changes could account for a previously reported reduction in pulmonary capillary filtration in heart failure, we studied pulmonary morphology in lungs from a guinea-pig chronic heart failure model. Heart failure was induced by banding the ascending aorta with sham operated animals serving as controls; all animals were studied at 158 +/- 6 days post-operation. Following banding, a reduction in aortic flow, increased peripheral vascular resistance and raised left ventricular end diastolic, left atrial and right ventricular pressures together with increased right ventricle to body weight ratio (all p < 0.05) are indicative of established pulmonary hypertension and heart failure. This was associated with an increase in pulmonary septal volume fraction (38.1 +/- 3.1% vs 24.6 +/- 2.3 %, p < 0.01) and reticulin fibre density. There was also evidence of siderophage infiltration and examination of pulmonary ultra structure revealed a significantly thicker alveolar-capillary barrier in heart failure (1278 +/-76 vs 638 +/- 32 nm, p < 0.001), thickening of both the alveolar (89%, p < 0.01) and capillary (69%, p < 0.05) basal laminae with pericyte and collagen in filtration of the alveolar-capillary barrier. We hypothesise that these pulmonary adaptations provide protection from oedema formation, but whilst initially protective, are also likely to confer major long-term disadvantages in chronic heart failure.
Asunto(s)
Insuficiencia Cardíaca/patología , Hipertensión Pulmonar/patología , Pulmón/irrigación sanguínea , Pulmón/patología , Animales , Aorta , Modelos Animales de Enfermedad , Cobayas , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Hipertensión Pulmonar/fisiopatología , Ligadura , Pulmón/ultraestructura , Masculino , Microscopía Electrónica , Factores de TiempoRESUMEN
OBJECTIVE: In patients with aortic valve disease, the presence of left ventricular hypertrophy (LVH) carries a significant risk of adverse cardiovascular events. Regression of hypertrophy after aortic valve replacement (AVR) is associated with a reduction in risk. In general, M-mode echocardiography has been used for quantitative assessment of left ventricular mass (LVM) and regression, but this technique is believed to have limitations from which cardiovascular magnetic resonance (CMR) does not suffer. The objective of this study therefore was to determine whether quantitative assessment of LVM and regression after AVR using the two techniques was comparable. METHODS: Thirty-nine patients with aortic valve disease were studied before and 1 year after AVR. Transthoracic M-mode echocardiography and four different formulae were used to calculate left ventricular mass index (LVMI), and then compared with CMR measurements. RESULTS: Overall, correlation between the techniques for single measurement of LVMI was moderate (r-values from 0.64 to 0.69), with a tendency for overestimation by echocardiography; there was no agreement in degree of regression (r-values from 0.004 to 0.18). The Bland-Altman limits of agreement ranged from 85 to 131% for single measurement of LVMI, and 328-470% for regression. The change in LVMI with CMR was 43+/-28 g/m2, vs. 27 to 54+/-19 to 41 g/m2 using echocardiography. CONCLUSIONS: M-mode echocardiography does not provide reliable quantification of regression of LVH in individuals, and for accurate measurement CMR is superior. The use of CMR in future studies may reduce costs since fewer subjects are needed to accurately detect significant changes in LVMI after AVR.
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Estenosis de la Válvula Aórtica/cirugía , Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Hipertrofia Ventricular Izquierda/cirugía , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Anciano , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/patología , Ecocardiografía , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/patología , Humanos , Hipertrofia Ventricular Izquierda/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Increased extravascular compression and reduced diastolic perfusion time (DPT), rather than vascular remodeling, influence coronary microcirculatory dysfunction in aortic stenosis (AS). However, alterations after aortic valve replacement (AVR) remain unclear. The aim of the present study was to quantify changes in transmural perfusion and coronary vasodilator reserve (CVR), a measure of microcirculatory function, after AVR and determine the relative contribution of left ventricular mass (LVM) regression, change in aortic valve area (AVA), and DPT. METHODS AND RESULTS: Twenty-two patients with AS were studied before and 1 year after AVR using echocardiography to measure AVA, cardiovascular magnetic resonance to assess LVM, and positron emission tomography to quantify resting and hyperemic myocardial blood flow (MBF) and CVR. Regression of LVM occurred in all patients (from 129+/-30 to 94+/-24 g/m2; P<0.0001), and there was a significant reduction in resting MBF and increase in CVR corrected for rate-pressure product after AVR, although these changes displayed marked heterogeneity. Regression of LVM was linearly related to change in resting total LV blood flow but not CVR. Increase in hyperemic MBF and CVR transmurally was directly related to the increase in AVA after AVR. A significant relationship existed between the change in hyperemic DPT (1.0+/-4.7 s/min [range, 6.8 to 9.6]) and change in transmural CVR (y=0.08x+0.18; r=0.44; P=0.04). CONCLUSIONS: Changes in coronary microcirculatory function in patients with AS after AVR are not directly dependent on regression of LVM. Reduced extravascular compression and increased DPT are proposed as the main mechanisms for improvement in MBF and CVR after AVR.
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Estenosis de la Válvula Aórtica/fisiopatología , Circulación Coronaria , Implantación de Prótesis de Válvulas Cardíacas , Microcirculación/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Velocidad del Flujo Sanguíneo , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/fisiopatología , Ecocardiografía , Femenino , Hemodinámica , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Angiografía por Resonancia Magnética , Masculino , Microcirculación/diagnóstico por imagen , Persona de Mediana Edad , Análisis de Regresión , Inducción de Remisión , Tomografía Computarizada de Emisión , Resultado del Tratamiento , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND: QT interval prolongation occurs at rest and during exercise in pathological left ventricular hypertrophy. However, athletes with physiological hypertrophy have normal QT at rest. The aim of this study was to compare the effect of exercise on QT in athletes with echocardiographic left ventricular hypertrophy and normal controls, and explore differences in their response. METHODS: Elite male rowers (n=15) with echocardiographic left ventricular hypertrophy, and normal volunteers (n=15) underwent 15 min of a Bruce protocol treadmill test. Electrocardiograms (ECGs) were recorded during each stage and every minute during recovery for 3 min. QT was measured at each stage. Corrected QT (QTc) was calculated using Bazett's formula. RESULTS: QT at rest was significantly greater than QT after 3 min of recovery in the controls (0.36+/-0.02 vs. 0.32+/-0.04 s; P=0.001) but not in the athletes (0.36+/-0.03 vs. 0.34+/-0.02 s; P=0.05). Regression lines for QT versus heart rate showed a strongly negative correlation in both athletes and controls (y=0.463-0.0013x (r=0.91; P<0.0001) and y=0.461-0.0013x (r=0.93; P<0.0001), respectively), but greater individual homogeneity in the athletes. CONCLUSIONS: training-induced hypertrophy does not affect the heart rate/QT relationship. The more rapid recovery in QT and homogeneity of the heart rate/QT relationship in athletes compared to controls is likely to be a benign effect of myocardial fitness, but it is hypothesised that it may contribute to arrhythmias in the unfit individual after vigorous exertion.
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Electrocardiografía , Prueba de Esfuerzo , Hipertrofia Ventricular Izquierda/diagnóstico , Esfuerzo Físico/fisiología , Deportes/fisiología , Adulto , Estudios de Casos y Controles , Ecocardiografía , Frecuencia Cardíaca , Humanos , Masculino , Resistencia Física , Probabilidad , Valores de Referencia , Medición de RiesgoRESUMEN
OBJECTIVES: To investigate changes in coronary morphology and haemodynamic function during regression of established left ventricular hypertrophy (LVH) following surgical unloading. METHODS: LVH was induced in guinea-pigs by aortic banding and sham operated animals served as controls. We examined the degree of LVH, coronary haemodynamic function and contemporaneous vessel morphology 42 days post-operation. Identically treated animals were debanded and the same parameters measured after 1, 3 and 6 weeks to assess haemodynamic and morphological changes as hypertrophy regressed. RESULTS: Banding resulted in an aortic pressure gradient of 41+/-9 mmHg and increases in heart/body weight ratio (46%), myocyte size (26%) and a doubling of arteriolar wall thickness, all P<0.01. These changes were accompanied by a reduction in coronary reserve (38%) and significantly (P<0.01) decreased maximal response to acetylcholine (70%), sodium nitroprusside (87%), adenosine (70%) and reactive hyperaemia (52%). Surgical debanding normalised the systemic haemodynamics and removed the aortic gradient after 7 days. There was some limited improvement in coronary structure and, to a lesser extent, function despite the continued presence of significant LVH. This had completely regressed to normal levels 23 days after debanding and was accompanied by normalisation of coronary structure and function, although systolic impedance to flow remained significantly increased. After 44 days, debanding resulted in complete cardiac morphological and functional recovery. CONCLUSION: Left ventricular haemodynamic unloading can result in complete normalisation of LVH, coronary morphology and haemodynamic function. Although morphological and functional recovery were closely correlated, recovery of coronary morphology and function slightly preceded that of the myocardium in this aortic banded/debanded model.
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Vasos Coronarios/patología , Hipertrofia Ventricular Izquierda/patología , Acetilcolina , Adenosina , Animales , Relación Dosis-Respuesta a Droga , Electrocardiografía , Cobayas , Hemodinámica , Hipertrofia Ventricular Izquierda/cirugía , Ligadura , Masculino , Modelos Animales , Miocardio/patología , Nitroprusiato , Perfusión , Reoperación , VasodilatadoresRESUMEN
BACKGROUND: Attempts at gene therapy for the pulmonary manifestations of Cystic Fibrosis have relied mainly on airway delivery. However the efficiency of gene transfer and expression in the airway epithelia has not reached therapeutic levels. Access to epithelial cells is not homogenous for a number of reasons and the submucosal glands cannot be reached via the airways. PRESENTATION: We propose to inject gene delivery vectors directly into bronchial arteries combined with pre-delivery of vascular endothelial growth factor to increase vascular endothelial permeability and post-delivery flow reduction by balloon occlusion. Thus it may be possible to reach mucous secreting cells of the bronchial luminal epithelium and the submucosal glands in an increased and homogenous fashion. TESTING: This combination of techniques to the best of our knowledge has not previously been investigated, and may enable us to overcome some of the current limitations to gene therapy for Cystic Fibrosis.
RESUMEN
BACKGROUND: Development of left ventricular hypertrophy in aortic stenosis (AS) is accompanied by coronary microcirculatory dysfunction, demonstrated by an impaired coronary vasodilator reserve (CVR). However, evidence for regional abnormalities in myocardial blood flow (MBF) and the potential mechanisms is limited. The aims of this study were to quantitatively demonstrate differences in subendocardial and subepicardial microcirculation and to investigate the relative contribution of myocyte hypertrophy, hemodynamic load, severity of AS, and coronary perfusion to impairment in microcirculatory function. METHODS AND RESULTS: Twenty patients with isolated moderate to severe AS were studied using echocardiography to assess severity of AS, cardiovascular magnetic resonance to measure left ventricular mass (LVM), and PET to quantify resting and hyperemic (dipyridamole 0.56 mg/kg) MBF and CVR in both the subendocardium and subepicardium. In the patients with most severe AS (n=15), the subendocardial to subepicardial MBF ratio decreased from 1.14+/-7 at rest to 0.92+/-7 during hyperemia (P<0.005), and subendocardial CVR (1.43+/-3) was lower than subepicardial CVR (1.78+/-35; P=0.01). Resting total LV blood flow was linearly related to LVM, whereas CVR was not. Increase of total LV blood flow during hyperemia (mean value, 89.6+/-6%; range, 17% to 233%) was linearly related to aortic valve area. The decrease in CVR was related to severity of AS, increase in hemodynamic load, and reduction in diastolic perfusion time, particularly in the subendocardium. CONCLUSIONS: CVR was more severely impaired in the subendocardium in patients with LVH attributable to severe AS. Severity of impairment was related to aortic valve area, hemodynamic load imposed, and diastolic perfusion rather than to LVM.