RESUMEN
We describe the case of a 45-year-old male smoker who presented with an acute anterior wall myocardial infarction and a platelet count on admission of 1030000/mm3. Emergent coronary angiography revealead left anterior wall akinesia caused by a spontaneously resolved thrombosis of the left anterior descending artery with residual stenosis. Primary percutaneous coronary angioplasty and stenting were performed. Postangioplasty course was uneventful. He was diagnosed with essential thrombocythemia based on the findings of marked thrombocytosis of 1,030,000/mm3, splenomegaly and numerous clumping giant megakaryocytes on bone marrow biopsy. In addition to standard therapy with aspirin, heparin, betablocking agent, ACE-inhibitor and statine he received additional anti-platelet therapy with Clopidogrel. Cytoreductive therapy was not necessary.
Asunto(s)
Angioplastia Coronaria con Balón , Enfermedad Coronaria/terapia , Infarto del Miocardio/etiología , Stents , Trombocitemia Esencial/complicaciones , Ticlopidina/análogos & derivados , Examen de la Médula Ósea , Clopidogrel , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/tratamiento farmacológico , Estenosis Coronaria/diagnóstico , Estenosis Coronaria/diagnóstico por imagen , Trombosis Coronaria/diagnóstico , Trombosis Coronaria/diagnóstico por imagen , Diagnóstico Diferencial , Electrocardiografía , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Recuento de Plaquetas , Factores de Riesgo , Fumar/efectos adversos , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/tratamiento farmacológico , Ticlopidina/uso terapéuticoRESUMEN
Recent advances in the recognition and the treatment of acute coronary syndromes (ACS) have lead to an improvement in patient survival and definition of newer guidelines. Current strategies for the treatment of patients with non-ST-elevation ACS include anti-ischemic and antiplatelet medications. While aspirin, beta-blockers, heparin and nitrates are still common practice, the advent of newer anticoagulants (low molecular weight heparins) and antiplatelet agents (glycoprotein llb/IIIa inhibitors and thienopyridines like ticlopidin and clopidogrel) and, possibly, aggressive lipid lowering with statins have added significant benefits to the treatment options with a better prognosis for these patients. Moreover, aggressive medical strategies seem to be justified not only in high-risk patients but also in those that undergo an early invasive approach.
Asunto(s)
Angina Inestable/tratamiento farmacológico , Electrocardiografía , Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/efectos adversos , Angina Inestable/diagnóstico , Angina Inestable/mortalidad , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/efectos adversos , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Electrocardiografía/efectos de los fármacos , Humanos , Morfina/administración & dosificación , Morfina/efectos adversos , Nitroglicerina/administración & dosificación , Nitroglicerina/efectos adversos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/efectos adversos , Tasa de SupervivenciaRESUMEN
A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET(A)/ET(B)-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET(A) receptor only.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Sulfonamidas/uso terapéutico , Bosentán , Enfermedad Crónica , Ensayos Clínicos como Asunto , Endotelina-1/fisiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/fisiología , Humanos , Receptores de Endotelina/fisiología , Sulfonamidas/efectos adversosRESUMEN
Natriuretic peptides play an important role in water and salt homeostasis and in the regulation of the cardiovascular system. In recent years, exogenous administration of natriuretic peptides has primarily been used to improve our understanding of the role of natriuretic peptides. Also, it became evident that natriuretic peptides may be used therapeutically. Because of their peptide character, they cannot be administered orally and, therefore, may be used for short-term intravenous therapy only. In recent years, inhibitors of neutral endopeptidase, which degrades natriuretic peptides to inactive metabolites, have been investigated. This review focuses on the potential benefits of increasing natriuretic peptide levels, either through exogenous administration or inhibiting the degradation of endogenous natriuretic peptides.
Asunto(s)
Factor Natriurético Atrial/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Péptido Natriurético Encefálico/uso terapéutico , Factor Natriurético Atrial/sangre , Enfermedades Cardiovasculares/sangre , Humanos , Péptido Natriurético Encefálico/sangre , Inhibidores de Proteasas/uso terapéuticoRESUMEN
BACKGROUND: There is evidence that elevated post-prandial lipoproteins adversely affect progression and outcome of cardiovascular disease. Traditional risk factors are associated with impaired endothelium-mediated vasodilatation. However, studies regarding the relationship between post-prandial lipaemia and endothelial function are divergent. METHODS: Twelve healthy non-smokers were included in this study. Before and after intake of a lipid cocktail rich in dairy fat, we tested endothelial-dependent (acetylcholine 0.8-160 mg/min per 100 ml forearm tissue) and -independent (sodium nitroprussid 0.6 microgram/min) vascular function in the forearm vascular bed with plethysmography. Moreover, we tested the effect of 1-NMMA, a competitive inhibitor of the NO synthetase, on base-line flow. Extent of post-prandial lipaemia was assessed with the increases in triglycerides and retinyl-palmitate, a marker for intestinally derived lipoproteins. RESULTS: Baseline flow was higher after the test meal than during fasting (preprandial 6.5 +/- 0.5 ml/min* 100 ml tissue, post-prandial 8.0 +/- 0.5, p = 0.03), but similar after 1-NMMA (p = 0.85). Before and after intake of the test meal, there was no significant difference in acetylcholine-induced endothelium-dependent vasodilatation (repeated measurement ANOVA, p = 0.22). At the highest acetylcholine dose, forearm flow was very similar (fasting 18.4 +/- 1.9, post-prandial 17.9 +/- 1.9, p = 0.75). At maximum acetylcholine dose, there was a weak inverse but non-significant correlation between forearm flow and post-prandial triglyceridaemia (r = -0.38, p = 0.23) and intestinally derived lipoproteins (chylomicrons r = -0.29, p = 0.35, chylomicron remnants r = -0.15, p = 0.63). However, at the lowest acetylcholine dose there was a suggestion for a positive correlation between change in flow and post-prandial lipaemia (triglyceridaemia, r = 0.53, p = 0.07; chylomicrons, r = 0.41, p = 0.18 and remnants, r = 0.51, p = 0.09). Endothelium-independent vasodilatation in response to sodium nitroprusside did not significantly change (p = 0.23). CONCLUSION: Our results suggest that among healthy men post-prandial lipaemia is not associated with a notable impairment of endothelium-mediated vascular function in forearm resistance vessels.
Asunto(s)
Endotelio Vascular/fisiopatología , Periodo Posprandial/fisiología , Vasodilatación/fisiología , Adulto , Diterpenos , Humanos , Masculino , Pletismografía , Valores de Referencia , Ésteres de Retinilo , Factores de Riesgo , Triglicéridos/sangre , Vitamina A/análogos & derivados , Vitamina A/sangreRESUMEN
OBJECTIVE: The dihydropyridine calcium antagonist isradipine has anti-atherosclerotic effects in animals and improves endothelium-mediated nitric oxide (NO)-dependent vasodilation in vitro. As improved endothelial function may be beneficial we investigated its effects in patients with a high likelihood of endothelial dysfunction. DESIGN: Thirty patients (two female, age 55.4 +/- 10.5 years) with known coronary artery disease and elevated (> 6 mmol/l) total cholesterol (cholesterol: mean 6.7 +/- 0.78 mmol/l) or a cholesterol/high density lipoproteins (HDL) ratio of > 5 not on lipid lowering therapy, participated in the study. Endothelial vasodilator function was assessed before and after double-blind, randomized administration of isradipine 5 mg/day or placebo for 3 months. METHODS: Endothelial function was assessed as forearm blood flow (FBF, venous occlusion plethysmography) responses to graded brachial artery infusions of acetylcholine (Ach), to the NO-synthase blocker NG-monomethyl-L-arginine (L-NMMA) and to the endothelium-independent vasodilator sodium nitroprusside (SNP). Blood pressure was measured either directly from the brachial arterial or by sphygmomanometer during clinic visits. RESULTS: Blood pressure was unchanged in both groups after 3 months (isradipine: 88.8 versus 92.1 mmHg; placebo: 81.0 versus 82.5 mmHg; NS) but cholesterol levels decreased similarly in both groups (isradipine: 6.7 versus 6.1 mmol/l, NS; placebo: 6.6 versus 5.9 mmol/l, P< 0.05). The vasodilator response to SNP and the decrease in FBF in response to blockade of NO synthesis by L-NMMA were unchanged in both groups. However, isradipine, but not placebo, enhanced the NO-dependent vasodilator response to Ach (P < 0.05). CONCLUSION: Isradipine improves acetylcholine-mediated vasodilation in hypercholesterolemic patients independent of changes in lipids or blood pressure.
Asunto(s)
Presión Sanguínea , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/fisiopatología , Endotelio Vascular/fisiología , Hipercolesterolemia/complicaciones , Isradipino/uso terapéutico , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/uso terapéutico , Anciano , Presión Sanguínea/efectos de los fármacos , Colesterol/sangre , Enfermedad Coronaria/tratamiento farmacológico , Método Doble Ciego , Antebrazo/irrigación sanguínea , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
A role of the potent and long-acting vasoconstrictor peptide endothelin-1 in the pathophysiology of chronic human heart failure has been postulated based on indirect evidence such as elevated plasma endothelin-1 levels, their correlation with the degree of hemodynamic impairment, and their predictive value for patient survival. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity to directly evaluate its pathophysiologic role and assess its potential role as a new approach to heart failure therapy. This review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure, and analyzes the clinical results obtained thus far in patients during acute intravenous, and more prolonged, oral administration of endothelin-1-receptor antagonists.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/tratamiento farmacológico , Receptores de Endotelina/uso terapéutico , Enfermedad Crónica , HumanosRESUMEN
BACKGROUND: Prevention of distal embolisation during percutaneous coronary revascularisation may be necessary to reduce postinterventional morbidity and mortality. METHODS AND RESULTS: We employed a newly developed emboli containment and retrieval system in native coronary arteries during percutaneous coronary angioplasty and stenting in 39 selected patients (mean age 58.9 +/- 10.1 years, 11 females) presenting with acute (n = 22; 8 LAD, 3 LCX, 11 RCA), subacute (n = 7; 2 LAD, 2 LCX, 3 RCA) or chronic (n = 6; 2 LAD, 4 RCA) total or subtotal occlusion of an infarct-related vessel, or with severe stenosis and symptoms of unstable angina (n = 4; 2 LAD, 2 RCA). Protection device-assisted angioplasty with stent implantation was uneventful in all patients with good angiographic results and normal postprocedural flow. Intermittent aggravation of anginal pain during inflation of the occlusive balloon (from 2.5 to a maximum of 25 minutes cumulative inflation time) was observed in 19 of the 36 conscious patients (7 with acute, 7 with subacute and 3 with chronic occlusion, and 2 with unstable angina), but caused neither interruption of distal occlusion nor haemodynamic instability. In 31 patients the aspirates contained visible debris. Histological analysis showed particles up to 12 mm in size, consisting of necrotic core, inflammatory cells, cholesterol debris, and old and fresh thrombi. In 8 patients the aspirated particles were too small to allow microscopic diagnosis or debris was absent. CONCLUSIONS: This preliminary report demonstrates the feasibility of using a protection device in native coronary arteries to prevent distal embolisation of particulate matter that is mobilised during percutaneous interventions. To the extent that this material contributes to the mechanisms of distal embolisation, noreflow and infarction, this device may help to reduce such complications. Appropriately designed trials are required to assess the clinical benefit of this system.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Angioplastia Coronaria con Balón/métodos , Enfermedad Coronaria/terapia , Embolia/prevención & control , Stents , Adulto , Anciano , Angina de Pecho/fisiopatología , Angina Inestable/fisiopatología , Enfermedad Coronaria/patología , Femenino , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Necrosis , Stents/efectos adversosRESUMEN
Endothelin (ET)-1 is a potent vasoconstrictor with growth promoting and mitogenic properties associated with various cardiovascular diseases (CVD) and has been found to be an important protagonist in congestive heart failure (CHF). The introduction of ET-1 receptor antagonists into the arena of clinical research has amplified our understanding of the ET system: the first human trials with acute and chronic inhibition of the ET system have shown promising results and confirm the findings from experimental models. The availability of oral compounds such as bosentan has raised the hope that these novel drugs might become a new therapeutic class of agents for the treatment of CVD and, in particular, of CHF. The question, however, remains whether the beneficial effects observed so far in patients with CHF go beyond simple hemodynamic improvements and whether these compounds improve long-term survival in these patients.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Endotelina-1/fisiología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Sulfonamidas/uso terapéutico , Bosentán , Hemodinámica/efectos de los fármacos , Humanos , Vasoconstricción/fisiologíaRESUMEN
Endothelin-1 (ET-1) regulates vascular tone in congestive heart failure and modulates renal function. Its role in patients with normal left ventricular (LV) function and its renal effects are unclear. Cardiac and renal hemodynamics were studied in 24 patients with normal LV function and coronary arteries after single-dose, double-blind, randomized administration of TAK-044 (25, 50, or 100 mg, i.v.), an ET(A/B)-receptor antagonist, or placebo. Hemodynamics were monitored using Swan-Ganz and arterial catheters, and ET levels were measured. Renal function was assessed by clearance techniques. In the absence of a dose-response relation, TAK-044 patients were analyzed as a single group. Most hemodynamic effects occurred during the first 4 h. TAK-044 reduced mean arterial (-9.3 mm Hg, p < 0.001), pulmonary (-1.8 mm Hg, p = 0.01), and pulmonary capillary wedge pressure (-1.6 mm Hg, p < 0.001) between 30 min and 4 h. Mean reduction in systemic vascular resistance was 279 dyne/s/cm2 (p < 0.001), whereas heart rate increased 6.1 beats/min (p < 0.001) and cardiac index by 0.37 L/m2 (p = 0.01). Stroke volume index, right atrial pressure, and pulmonary vascular resistance did not change. TAK-044 increased renal plasma flow in proportion to the increase in cardiac output (+119 ml/min, 4 h after TAK-044; p < 0.05) and ET-1 levels (2.5-fold; p < 0.05). No serious side effects were noted. In patients with normal cardiac function, ET-receptor blockade causes vasodilation and reduces systemic but not pulmonary vascular resistance and increases cardiac index and renal plasma flow.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , Pulmón/efectos de los fármacos , Péptidos Cíclicos/farmacología , Función Ventricular Izquierda , Anciano , Método Doble Ciego , Endotelina-1/sangre , Femenino , Humanos , Riñón/fisiología , Pulmón/fisiología , Masculino , Persona de Mediana Edad , Receptor de Endotelina A , Receptor de Endotelina B , Renina/sangreRESUMEN
We studied acute (day 1) and long-term (day 14) effects of endothelin (ET) receptor blockade with the mixed ET(A/B) antagonist bosentan (1 g twice daily; n = 18) or placebo (n = 12) on plasma angiotensin II and aldosterone in 30 patients with symptomatic chronic heart failure taking angiotensin-converting enzyme inhibitors, diuretics, and digoxin. Hormones were determined before and 3 hours after morning doses of diuretics and digoxin and the double-blind study drug, respectively, on days 1 and 14. On day 1, angiotensin II increased from 16.1+/-17.9 to 27.6+/-5.6 ng/L (p <0.05) with bosentan and similarly with placebo (15.5+/-9.3 and 36.0+/-49.1 ng/L, p = 0.06) after the morning dose of diuretics and digoxin. Aldosterone tended to increase from 322+/-239 to 362+/-254 pmol/L (bosentan) and from 271+/-70 to 297+/-136 pmol/L (placebo). On day 14, before drug intake, angiotensin II was unchanged compared with day 1 in both groups. However, aldosterone was lower than on day 1 with bosentan (213+/-124 vs. 322+/-239 pmol/L, p<0.05) and remained below baseline values 3 hours after drug intake, whereas it was unchanged with placebo. Thus, short-term ET(A/B) receptor antagonism decreases basal aldosterone secretion independently of angiotensin II, suggesting that ET participates in the regulation of aldosterone in patients already treated with angiotensin-converting enzyme inhibitors and diuretics.
Asunto(s)
Aldosterona/metabolismo , Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina , Endotelinas/fisiología , Insuficiencia Cardíaca/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Aldosterona/sangre , Angiotensina II/sangre , Bosentán , Método Doble Ciego , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Cardiac allograft vasculopathy after heart transplantation leads to an accelerated form of atherosclerosis with marked and often diffuse vessel wall changes that limit long-term survival. Previous studies showed contradictory results relating vessel wall changes to endothelial vasodilator response. METHODS: A total of 30 cardiac transplant recipients were studied 3, 12, and 24 months after heart transplantation. Coronary angiography was performed at rest, during supine bicycle ergometry, and after 1.6 mg sublingual nitroglycerin. Coronary cross-sectional area (biplane coronary angiography) and coronary artery wall changes (intravascular ultrasound) were assessed and extent of intimal changes correlated to vasodilator responses to nitroglycerine and bicycle ergometry. RESULTS: Intravascular ultrasound showed significant intimal thickening in 43, 64, and 58% of patients at 3, 12, and 24 months. Intimal thickening 3 months after transplantation was related to donor age (r=0.70, P<0.01) but did not predict progression of disease that manifested itself angiographically as a decrease in coronary cross-sectional area at 12 and 24 months (P<0.005) and significant coronary stenosis in 12% of patients after 24 months. Endothelium-independent vasodilatation after nitroglycerin (33+/-15, 44+/-20, and 43+/-24%) was normal. Endothelium-dependent, flow-induced vasodilatation during exercise was decreased (14+/-11, 18+/-14, and 16+/-17%) but did not correlate to intimal changes assessed by ultrasound. CONCLUSIONS: The study confirms the high incidence of intimal thickening after heart transplantation as assessed by intravascular ultrasound. Impaired exercise-induced vasodilatation suggests diminished bioavailability of endothelium-derived nitric oxide to physiological stimulation but the lack of relationship between coronary wall changes and this functional impairment suggests intermittent and presumably reversible endothelial injury in graft atherosclerosis.
Asunto(s)
Trasplante de Corazón , Complicaciones Posoperatorias , Enfermedades Vasculares/epidemiología , Enfermedades Vasculares/etiología , Adolescente , Adulto , Anciano , Angiografía Coronaria , Vasos Coronarios/diagnóstico por imagen , Progresión de la Enfermedad , Femenino , Hemodinámica , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Suiza , Túnica Íntima/diagnóstico por imagen , Ultrasonografía Intervencional , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/fisiopatologíaRESUMEN
Coronary artery stenting has definitely been proven to improve results of percutaneous revascularisation in a large number of patients. Stenting reduces restenosis in large vessels above 3 mm diameter. Stenting has not solved the problem of restenosis but in spite of the inevitable in-stent restenosis due to neointimal proliferation seems to yield better long-term results than conventional PTCA. Adjunctive pharmacological treatment with aspirin and clopidogrel in combination with improved stent deployment techniques has reduced the incidence of subacute stent thrombosis. GP IIb/IIIa inhibition is a promising mean for the reduction of procedure related ischaemic events and complications not only with stent implantation but also with conventional PTCA. Other new devices may further influence the treatment choices of stenting versus conventional PTCA in the future. Novel approaches such as brachytherapy and molecular genetic approaches to reduce in-stent restenosis are currently being investigated but to date no conclusions can be drawn as to their future place in clinical practice. From a mechanistic standpoint it seems obvious to give all our efforts to protect patients with coronary atherosclerosis from loss of myocardium either with coronary artery bypass grafting or percutaneous revascularisation. As both approaches are palliative in nature, it may be useful to attempt percutaneous revascularisation in patients amenable to this therapy and thus obviate or delay the need for definitive revascularisation by coronary artery bypass grafting. At the end of this discussion we would like to remind that medical therapy for coronary artery disease is of utmost importance as all revascularisation procedures do not influence the underlying disease. Besides symptomatic relief of angina, treatment of heart failure, and other beneficial strategies to improve endothelial function, medical therapy with lipid lowering compounds together with risk factor control offers the possibility to delay progression of coronary artery disease.
Asunto(s)
Angioplastia Coronaria con Balón , Enfermedad Coronaria/terapia , Stents , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/cirugía , Angiopatías Diabéticas/terapia , Humanos , Revascularización Miocárdica , Recurrencia , Stents/efectos adversosRESUMEN
OBJECTIVE: The use of cyclosporine A after organ transplantation is associated with a high incidence of hypertension, but the underlying mechanisms for this process are not clear. We investigated the effects of blockade of basal release of endothelial nitric oxide and the effects of endothelium-independent and -dependent vasodilators and vasoconstrictors in patients treated with cyclosporine A after heart transplantation. DESIGN: We measured blood pressure and forearm blood flow responses to brachial artery infusions of NG-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine, norepinephrine and vasodilating and vasoconstricting doses of endothelin-1 in eight patients early (< 3 months) and in 11 patients late (> 18 months) after transplantation. RESULTS: Diastolic blood pressure was higher late after transplantation, but calculated forearm vascular resistance was lower (P < 0.01). Thus, increased forearm vascular resistance does not contribute to the increase in blood pressure. The vasoconstrictor response to L-NMMA was similar in both groups but a reduced endothelium-dependent vasodilator response to acetylcholine was seen late after transplantation. However, impaired smooth muscle responsiveness to nitric oxide may have contributed to this finding, since the response to sodium nitroprusside tended to be reduced. Vasoconstrictor responses to norepinephrine and endothelin-1 were comparable but no vasodilation was seen with low doses of endothelin-1 late compared with early after transplantation (P < 0.05). CONCLUSIONS: The findings in the forearm circulation question the concept of generalized increases in vasoconstrictor responses or a disturbance of tonic, basal release nitric oxide in the pathogenesis of cyclosporine-A-induced hypertension. Although the forearm vasodilator responses to the stimulation of endothelial nitric oxide production and release by acetylcholine, and to low doses of endothelin-1, were impaired, these findings could be explained by the increase in blood pressure rather than cyclosporine A itself.
Asunto(s)
Arteria Braquial/fisiopatología , Ciclosporina/uso terapéutico , Trasplante de Corazón , Hipertensión/fisiopatología , Músculo Liso Vascular/fisiopatología , Presión Sanguínea , Arteria Braquial/efectos de los fármacos , Ciclosporina/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Estudios de Seguimiento , Antebrazo/irrigación sanguínea , Rechazo de Injerto/prevención & control , Humanos , Hipertensión/inducido químicamente , Inyecciones Intraarteriales , Masculino , Persona de Mediana Edad , Pronóstico , Vasoconstrictores/administración & dosificación , Vasodilatadores/administración & dosificación , omega-N-Metilarginina/administración & dosificaciónRESUMEN
Congestive heart failure is a complex disease that results from pumping failure of the cardiac muscle and adaptational processes of the cardiovascular system to correct for the reduced blood supply to the organism. It is associated with increased vasoconstriction and impaired vasodilation in response to physical activity. The elevated vasoconstrictor tone is caused by the activation of compensatory mechanisms including the sympathetic nervous system and stimulation of the release of neurohormones like angiotensin II, catecholamines, and vasopressin. Furthermore, the vascular endothelium is importantly involved in the regulation of vascular tone as it releases a variety of vasoactive substances that act locally and systemically. In congestive heart failure, there is a marked imbalance between the diminished release or the increased inactivation of vasodilators on the one hand, ie, nitric oxide, and the elevated production, release, or reduced inactivation of vasoconstrictors such as endothelin-1 on the other hand. In addition to its very potent vasoconstrictor effects, endothelin-1 possesses antinatriuretic and mitogenic properties that are a common feature of substances that are involved in development of the deleterious consequences that render congestive heart failure a lethal disease. The spectrum of action of the endothelin system and the advent of specific antagonists for its receptors have made this system a very interesting target for clinical research and possibly for future therapeutic approaches.
Asunto(s)
Endotelina-1/fisiología , Insuficiencia Cardíaca/fisiopatología , Animales , Humanos , Receptores de Endotelina/fisiología , Resistencia Vascular/fisiologíaRESUMEN
BACKGROUND: The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown. METHODS AND RESULTS: Thirty-six men (mean age+/-SD, 55+/-8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4+/-4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (-24.2% [-28.1% to -20.3%]) and pulmonary (-19.9% [-28.4% to -11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15. 2% [10.8% to 19.6%]) and systemic (-9.3% [-12.3% to -6.4%]) and pulmonary (-9.7% [-16.3% to -3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged. CONCLUSIONS: Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Insuficiencia Cardíaca/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Administración Oral , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bosentán , Enfermedad Crónica , Método Doble Ciego , Quimioterapia Combinada , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptor de Endotelina A , Sulfonamidas/administración & dosificación , Resultado del TratamientoRESUMEN
Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 micrograms/kg) or placebo, i.v., over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 +/- 3.7% (+/- SE; P < 0.0005) and the stroke volume index by 21 +/- 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 +/- 4.4% (P < 0.0002), right atrial pressure by 33 +/- 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 +/- 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.