RESUMO
Extracorporeal assist systems for respiratory and circulatory failure are increasingly used in intensive care medicine. Important technical innovations over the past years have resulted in improved biocompatibility and, consequently, reduced complication rates. Extracorporeal membrane oxygenation (ECMO) technology experienced a surge of use during the influenza A (H1N1) pandemic, but transport of unstable patients with life-threatening ARDS is still hazardous. We describe the first successful application of a newly developed, compact and easily portable ECMO device in a patient with severe ARDS due to influenza A (H1N1). Support with the miniaturized ECMO resulted in immediate improvement of gas exchange and a highly protective ventilation. Inspiratory pressure was decreased from 40 to 29 cmH(2)O and tidal volume per kilogram of predicted bodyweight could be reduced from 6.5 to 3.3 mL. Small and efficient heart-lung assist systems will become a tool of growing importance in intensive care medicine, both for profound respiratory and cardiac failure in the future. The reduced weight and compact design of the device greatly facilitates transport and handling of unstable patients on ECMO.
Assuntos
Oxigenação por Membrana Extracorpórea , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/terapia , Miniaturização , Síndrome do Desconforto Respiratório/terapia , Transporte de Pacientes/métodos , Adulto , Oxigenação por Membrana Extracorpórea/instrumentação , Oxigenação por Membrana Extracorpórea/métodos , Feminino , Humanos , Influenza Humana/epidemiologia , Pandemias , Síndrome do Desconforto Respiratório/epidemiologiaRESUMO
Respiratory acidosis can become a serious problem during protective ventilation of severe lung failure. A pumpless arteriovenous interventional lung assist (iLA) for extracorporeal carbon dioxide removal has been used increasingly to control critical respiratory situations. The present study sought to evaluate the factors determining the efficacy of iLA and calculate its contribution to gas exchange. In a cohort of 96 patients with severe acute respiratory distress syndrome, haemodynamic parameters, oxygen consumption and carbon dioxide production as well as gas transfer through the iLA were analysed. The measurements demonstrated a significant dependency of blood flow via the iLA device on cannula size (mean+/-sd 1.59+/-0.52 L x min(-1) for 15 French (Fr), 1.94+/-0.35 L x min(-1) for 17 Fr, and 2.22 +/-0.45 L x min(-1) for 19 Fr) and on mean arterial pressure. Oxygen transfer capacity averaged 41.7+/-20.8 mL x min(-1), carbon dioxide removal was 148.0+/-63.4 mL x min(-1). Within two hours of iLA treatment, arterial oxygen partial pressure/inspired oxygen fraction ratio increased significantly and a fast improvement in arterial carbon dioxide partial pressure and pH was observed. Interventional lung assist eliminates approximately 50% of calculated total carbon dioxide production with rapid normalisation of respiratory acidosis. Despite limited contribution to oxygen transfer it may allow a more protective ventilation in severe respiratory failure.
Assuntos
Oxigenação por Membrana Extracorpórea/instrumentação , Pulmão/patologia , Respiração Artificial/instrumentação , Síndrome do Desconforto Respiratório/fisiopatologia , Acidose Respiratória , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Concentração de Íons de Hidrogênio , Oxigênio/química , Consumo de Oxigênio , Pressão , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/terapia , RiscoRESUMO
A 15-year-old girl with a history of Kawasaki disease was admitted to our nephrological department due to acute renal failure. Despite antibiotic therapy because of fever and the symptoms of a pharyngitis in the last few days, the girl showed persisting fever and developed arthralgias, an exanthema and a rising serum creatinine as well as anuria. A wide variety of differential diagnoses has to be thought of because of the history of the Kawasaki disease (symptoms like fever, pharyngitis, exanthema and arthralgia), i.e. hemolytic-uremic syndrome, vasculitis, ascending infection, postinfection glomerulonephritis. In consideration of etiologically unclear "rapidly progressive renal failure" with anuria and thrombocytopenia an immediate renal biopsy was done and revealed a severe drug induced acute interstitial nephritis. Due to this diagnosis we treated the patient with corticosteroids. Within 4 weeks serum creatinine declined to 1.8 mg/dl but did not normalize.
Assuntos
Injúria Renal Aguda/complicações , Exantema/complicações , Injúria Renal Aguda/etiologia , Adolescente , Corticosteroides/uso terapêutico , Antibacterianos/efeitos adversos , Anuria/complicações , Anuria/etiologia , Creatinina/sangue , Diagnóstico Diferencial , Exantema/etiologia , Exantema/patologia , Feminino , Humanos , Síndrome de Linfonodos Mucocutâneos/complicações , Nefrite Intersticial/complicações , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/etiologiaRESUMO
INTRODUCTION: There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up. METHODS: We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study's nested case control component. RESULTS: At study inclusion in cases and controls, respectively, mean age was 67.3 +/- 8.2 and 58.1 +/- 11.2 years and duration of diabetes mellitus was 15.6 +/- 9.6 (at dialysis initiation) and 11.0 +/- 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 +/- 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had microor macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 +/- 21.0 to 82.5 +/- 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline. DISCUSSION: GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.
Assuntos
Albuminúria/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/terapia , Fatores Etários , Idoso , Albuminúria/epidemiologia , Albuminúria/mortalidade , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Estudos de Casos e Controles , Comorbidade , Creatinina/urina , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/genética , Progressão da Doença , Quimioterapia Combinada , Feminino , Seguimentos , Predisposição Genética para Doença/genética , Alemanha/epidemiologia , Humanos , Masculino , Diálise Renal , Fatores Sexuais , Inquéritos e Questionários , Taxa de SobrevidaRESUMO
BACKGROUND: The renin-angiotensin system plays an important part in the pathogenesis of congestive heart failure (CHF). This study evaluated the effect of an angiotensin II type 1 receptor antagonist on exercise tolerance and symptoms of CHF. METHODS AND RESULTS: In this multicenter, double-blind, parallel-group study, 844 patients with CHF were randomized to 12 weeks' treatment with placebo (n=211) or candesartan cilexetil 4 mg (n=208), 8 mg (n=212), or 16 mg (n=213) after a 4-week placebo run-in period. Changes in exercise time, Dyspnea Fatigue Index score, NYHA functional class, and cardiothoracic ratio were determined. Candesartan cilexetil produced a dose-related improvement in exercise time. For the intention-to-treat population, the increase produced by candesartan cilexetil 16 mg was significantly greater than that produced by placebo (47.2 versus 30.8 seconds, P=0.0463). All doses of candesartan cilexetil significantly improved the Dyspnea Fatigue Index score relative to placebo. NYHA class improved more frequently in the candesartan cilexetil groups; the differences relative to placebo were not significant. The decrease in cardiothoracic ratio with candesartan 4 to 16 mg was small but statistically significant compared with placebo (all P<0.05). In all candesartan cilexetil groups, plasma renin activity and angiotensin II levels increased from baseline and aldosterone levels decreased in the 8- and 16-mg treatment groups. Candesartan cilexetil was well tolerated at all doses. CONCLUSIONS: In summary, treatment with candesartan cilexetil demonstrated significant improvements in exercise tolerance, cardiothoracic ratio, and symptoms and signs of CHF and was well tolerated.
Assuntos
Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensina II/sangue , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacologia , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Interações Medicamentosas , Dispneia/tratamento farmacológico , Dispneia/etiologia , Teste de Esforço , Fadiga/tratamento farmacológico , Fadiga/etiologia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipotensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Renina/sangue , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Cardiac growth and function may be modulated in part by trophic effects of neurohormones. Specifically, aldosterone has been shown to stimulate the growth of cardiac myocytes and the accumulation of cardiac extracellular matrix proteins. Moreover, a variant of the aldosterone synthase gene (a cytosine/thymidine exchange at position -344 in the transcriptional regulatory region) has been associated with enlargement and disturbed filling of the left ventricle (LV) in a small sample of young white adults. The aim of the present study was to reinvestigate the implications of aldosterone synthase -344C/T allele status for serum aldosterone levels, blood pressure, and LV structure and function in large population-based samples. METHODS AND RESULTS: Individuals who participated in the echocardiographic substudy of the third MONICA (MONitoring trends and determinants in CArdiovascular disease) survey (n=1445) or in the second follow-up of the first MONICA survey (n=562) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for aldosterone synthase -344C/T allele status. In both surveys, the distribution of sex, age, arterial blood pressure, and body mass index was homogeneous in the aldosterone synthase genotype groups. Echocardiographic LV wall thicknesses, dimensions, and mass indexes were not significantly associated with a specific aldosterone synthase genotype. Likewise, no association was detectable with echocardiographic measures of LV systolic or diastolic function. Data were consistent in both samples and not materially different in subgroups defined by age, sex, or intake of antihypertensive medication. Finally, no significant association was observed for aldosterone synthase allele status and serum aldosterone levels in the group of 562 individuals. CONCLUSIONS: The data are not in favor of a significant contribution of the C/T exchange at position -344 in the aldosterone synthase transcriptional regulatory region to the variability of serum aldosterone levels, blood pressure, or cardiac size or function as found in 2 white population-based samples.
Assuntos
Citocromo P-450 CYP11B2/genética , Hipertrofia Ventricular Esquerda/etiologia , Polimorfismo Genético , Adulto , Idoso , Aldosterona/sangue , Ecocardiografia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: The present retrospective analysis of data derived from a population-based study examined the relationship between intake of beta-receptor antagonists and plasma concentrations of the cardiac natriuretic peptides and their second messenger. BACKGROUND: Beta-receptor antagonists are widely used for treatment of cardiovascular disease. In addition to direct effects on heart rate and cardiac contractility, recent evidence suggests that beta-receptor antagonists may also modulate the cross talk between the sympathetic nervous system and the cardiac natriuretic peptide system. METHODS: Plasma concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their second messenger cyclic guanosine monophosphate (cGMP) were assessed in addition to anthropometric, hemodynamic and echocardiographic parameters in a population-based sample (n = 672), of which 80 subjects used beta-receptor antagonists. RESULTS: Compared to subjects without medication, subjects receiving beta-receptor antagonists were characterized by substantially elevated ANP, BNP and cGMP plasma concentrations (plus 32%, 89% and 18%, respectively, p < 0.01 each). Analysis of subgroups revealed that this effect was highly consistent and present even in the absence of hypertension, left atrial enlargement, left ventricular hypertrophy or left ventricular dysfunction. The most prominent increase was observed in a subgroup with increased left ventricular mass index. By multivariate analysis, a statistically significant and independent association between beta-receptor antagonism and ANP, BNP and cGMP concentrations was confirmed. Such an association could not be demonstrated for other antihypertensive agents such as angiotensin-converting enzyme inhibitors or diuretics. CONCLUSIONS: Beta-receptor antagonists appear to augment plasma ANP, BNP and cGMP concentrations. The current observation suggests an important contribution of the cardiac natriuretic peptide system to the therapeutic mechanism of beta-receptor antagonists.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Fator Natriurético Atrial/sangue , Coração/efeitos dos fármacos , Peptídeo Natriurético Encefálico/sangue , Idoso , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Estudos Retrospectivos , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
OBJECTIVES: The study evaluated the contribution of familial predisposition to the risk of left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular hypertrophy is a multifactorial condition that serves as an important predictor of cardiovascular mortality. At present it is unclear whether familial predisposition contributes to the manifestation of LVH. Thus, we determined whether siblings of subjects with LVH are at increased risk to present with an elevation of LV mass or an abnormal LV geometry. METHODS: Echocardiographic and anthropometric measurements were performed in 2,293 individuals who participated in the echocardiographic substudies of population-based MONICA Augsburg surveys. In addition, a total of 319 siblings of survey participants with echocardiographic evidence of LVH were evaluated. The risk of these siblings to present with LVH or abnormal LV geometry was estimated by comparison with 636 subjects matched for gender and age that were selected from the entire echocardiography study base. RESULTS: Blood pressure, body mass index, age, and gender (i.e., known determinants of LV mass) were comparable in LVH-siblings and the matched comparison group. However, septal and posterior wall thicknesses, relative wall thickness as well as LV mass index were significantly elevated in LVH-siblings (p < 0.001, each) whereas LV dimensions did not differ. Likewise, the prevalence of LVH was raised in LVH-siblings, as was the relative risk of LVH after adjustment for confounders (p < 0.05). More specifically, LVH-siblings displayed increased prevalences of concentric remodeling and concentric LVH (p < 0.05) but not of eccentric LVH. CONCLUSIONS: Familial predisposition appears to contribute to increased LV wall thickness, to the development of LV hypertrophy and abnormal LV geometry.
Assuntos
Predisposição Genética para Doença/genética , Hipertrofia Ventricular Esquerda/genética , Adulto , Idoso , Índice de Massa Corporal , Volume Cardíaco/genética , Ecocardiografia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Remodelação Ventricular/genéticaRESUMO
OBJECTIVES: We investigated the relationship between body size, body composition and left ventricular mass (LVM) in adults, and assessed the impact of different indexations of LVM on its associations with gender, adiposity and blood pressure. BACKGROUND: The best way to normalize LVM for body size to appropriately distinguish physiologic adaptation from morbid heart morphology was discussed. METHODS: We undertook a community survey of 653 men and 718 women, aged 25 to 74 years. Lean body mass (LBM) was determined by bioelectric impedance analyses and LVM was assessed by two-dimensional guided M-mode echocardiography. RESULTS: After traditional indexations to body height, body height2.7, or body surface area, men had higher LVM than women (p < 0.001). These gender differences disappeared (p > 0.05) when LVM was indexed to LBM. The type of indexation also modified the strength of the association between adiposity and LVM. The estimated impact of body fat on LVM indexed to LBM was less than half that obtained with traditional indexations. In contrast, the magnitude of the associations of blood pressure with LVM was entirely independent of the type of indexation. CONCLUSIONS: This study showed the prominent influence of body composition on adult heart size. Indexation for LBM removed gender differences for LVM and reduced the impact of adiposity, but left the effects of blood pressure unchanged. We suggest that this approach be used for clinical and research applications.
Assuntos
Composição Corporal , Constituição Corporal , Índice de Massa Corporal , Ventrículos do Coração/anatomia & histologia , Adaptação Fisiológica , Tecido Adiposo/anatomia & histologia , Adulto , Idoso , Pressão Sanguínea , Estatura , Superfície Corporal , Peso Corporal , Ecocardiografia , Impedância Elétrica , Feminino , Coração/anatomia & histologia , Cardiopatias/etiologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/anatomia & histologia , Fatores SexuaisRESUMO
The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors.
Assuntos
Circulação Sanguínea/efeitos dos fármacos , Endotelinas/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Endotelinas/genética , HumanosRESUMO
In normal hearts, endothelin-1 (ET-1) has been shown to initiate myocyte growth and to modulate cardiac function. However, regulation of the various components of the system and the functional effects of ET-1 in established left ventricular hypertrophy (LVH) are less clear. We thus studied ET-1, ET(A) receptor, and endothelin converting enzyme (ECE-1) mRNA regulation as well as the effects of ET-1 on coronary resistance, LV contractility and relaxation in hypertrophied rat hearts. Cardiac pressure overload, secondary to banding of the ascending aorta, resulted in a transient increase of cardiac ET-1 and ET(A) receptor mRNAs that reached a maximum at 2 days (+75% and +40%, respectively, P<0.05, each). ET-1 mRNA levels reached a second peak at 84 days of pressure overload (+60%, P<0.05), at the later time point in conjunction with elevated ECE-1 mRNA levels (+20%, P<0.05). The functional implications of ET-1 were examined in a study of isolated perfused hearts. Both hearts with established LVH and sham control hearts responded to ET-1 perfusion (10(-1)] to 10(-9) M) with an increase of coronary perfusion pressure (CPP; +85+/-15 and +75+/-8 mm Hg; P<0.001 each) and a slight decrease of LV systolic pressure (LVP; -12+/-9 and -9+/-7 mm Hg; P = NS). In contrast, ET-1 increased LV end-diastolic pressure (LVEDP) only in LVH hearts (+22+/-7 mm Hg, P<0.05 versus baseline and +20+/-7 mm Hg, P<0.05 versus sham). Direct stimulation of protein kinase C mimicked the effects of ET-1, whereas inhibition of this kinase or the Na+ -H+ exchanger blunted the effects of ET-1 on CPP, LVP, and LVEDP. Interestingly, coadministration of the vasodilator and the nitric oxide (NO) donor nitroglycerin not only prevented the increase of CPP and LVEDP, but also uncovered a slight positive inotropic effect of ET-1 in LVH hearts. Thus, the cardiac expression of ET-1, ET(A), and ECE-1 mRNAs displays a distinct pattern during early and advanced cardiac pressure overload. Furthermore, ET-1 mediates a slight depression of systolic, and a profound depression of diastolic, functional parameters in hearts with established LVH, effects that appear to be secondary to ET-1-related coronary vasoconstriction. The data suggest a functional role of the endothelin system in hearts with established pressure overload hypertrophy.
Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Endotelina-1/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Receptores de Endotelina/metabolismo , Amilorida/farmacologia , Animais , Doenças da Aorta/complicações , Pressão Sanguínea/fisiologia , Enzimas Conversoras de Endotelina , Inibidores Enzimáticos/farmacologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Técnicas In Vitro , Masculino , Metaloendopeptidases , Miocárdio/metabolismo , Nitroglicerina/farmacologia , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Receptor de Endotelina A , Estaurosporina/farmacologiaRESUMO
INTRODUCTION: We studied the effect of HMG-CoA-reductase inhibitor (= CSE-I) treatment on mortality in a population of hemodialysis patients with diabetic nephropathy due to type 2 diabetes. Since the efficacy of CSE-I in dialysis patients is discussed controversially, we tested the hypothesis that only patients with LDL-cholesterol > 100 mg/dl benefit from CSE-I. METHODS: We enrolled all 445 prevalent chronic hemodialysis patients with end-stage diabetic nephropathy from 30 centres in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. Fasting lipid profiles prior to dialysis session and a complete clinical phenotype were determined at inclusion. We formed 2 patient groups (serum LDL > vs. < or = 100 mg/dl). Only CSE-I were used as lipid lowering therapy in our cohort. 122 Patients were on CSE-I therapy during the study. All cause mortality (ACM) was the primary end point. Survival analysis was performed by Kaplan Meier and multivariate Cox regression analysis. RESULTS: Multivariate regression analysis and Kaplan Meier survival analysis showed a decrease in risk for ACM for patients on CSE-I therapy, irrespective of lipid status (multivariate hazard ratio (= HR) 0.58; p = 0.049; ACM 72.1% (no CSE-I) vs. 59.7% (+ CSE-I); mean survival 2.37 +/- 0.08 years (no CSE-I) vs. 2.77 +/- 0.12 years (+ CSE-I), p = 0.003). In patients with LDL > 100 mg/dl, statin treatment was also associated with reduced ACM: 48.0% (+ CSE-I) vs. 70.1% (no CSE-I), (multivariate HR 0.28, CI 95% 0.11 - 0.75, p = 0.01), but not in patients with LDL < or = 100 mg/dl (HR 0.84, CI 95% 0.41 - 1.72 p = 0.63). CONCLUSION: Our data indicates that hemodialysis patients with type 2 diabetic nephropathy may benefit from statin therapy irrespective of baseline LDL-cholesterol level. Patients with LDL > 100 mg/dl benefit most when treated with CSE-I.
Assuntos
Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/mortalidade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , LDL-Colesterol/sangue , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Prospectivos , Diálise Renal , Fatores de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: The role of interaction of polymorphisms in the Renin-Angiotensin-System (RAS) with angiotensin converting enzyme (ACE) or angiotensin receptor (AGTR1) inhibitors (RAS inhibitors) is unknown, as is the role of such therapy in end stage renal disease (ESRD) patients. METHODS: We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective survival analysis until December 2003. Blood pressure and medication was recorded at inclusion. We determined survival specific for allelic variants of the ACE (insertion/deletion), Angiotensinogen (M235T) and AGTR1 (A1166C) genes. The effect of therapy with RAS inhibitors at study inclusion was determined for the allelic variants of each gene. The primary end point was all cause mortality (ACM). RESULTS: For all polymorphisms, and for therapy with RAS inhibitors there was no significant effect on survival in the complete collective (n = 445), though there was an insignificant trend for improved survival in patients on AGTR1 antagonists. Increased ACM risk was associated with treatment with RAS inhibitors only in patients homozygous for the wild type AGTR1 1166A allele (HR 1.65, p = 0.01). For all other polymorphisms, therapy with RAS inhibitors had no significant effect on ACM, irrespective of genotype. Similar results were obtained in patients with systolic ventricular dysfunction. CONCLUSION: Our data do not show a survival advantage for type 2 diabetes hemodialysis patients receiving RAS inhibiting therapy. In addition, our data indicate that allelic variation in RAS genes and pharmacogenetic interaction with RAS inhibition does not affect mortality risk in diabetic hemodialysis patients.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Variação Genética , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/genética , Idoso , Alelos , Angiotensinogênio/genética , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Peptidil Dipeptidase A/genética , Estudos Prospectivos , Diálise Renal , Taxa de Sobrevida , Resultado do TratamentoRESUMO
STUDY OBJECTIVE: The aim of the study was to develop a new animal model of pulmonary arterial hypertension allowing direct measurement of pulmonary artery pressure in conscious chronically instrumented rats. DESIGN: Pulmonary artery pressure was measured via a pulmonary artery catheter, and cardiac output by thermodilution with a thermistor probe in the aortic arch, allowing determination of stroke volume and total pulmonary arterial resistance. Pulmonary hypertension was induced by fractionated injections of latex microspheres into pulmonary circulation, causing an increase in mean pulmonary pressure of 13.7 mm Hg (p less than 0.001). To test the regulatory influence of the renin system on the pulmonary vascular bed, one group of rats received an intravenous bolus injection of the angiotensin converting enzyme inhibitor teprotide 1 mg x kg-1 24 h after pulmonary embolism. The effect of general barbiturate anaesthesia was also investigated. SUBJECTS: Experimental animals were male Wistar rats, 300-350 g weight. They were studied in groups of 6-8. MAIN RESULTS: Following pulmonary embolism there was no significant difference in haemodynamic variables between control and teprotide treated rats. General anaesthesia caused an 11% fall in mean pulmonary artery pressure (p less than 0.01) and a 32% decrease in cardiac index (p less than 0.01). CONCLUSIONS: (1) The renin-angiotensin system has no important role in the regulation of pulmonary resistance vessels 24 h after pulmonary embolism; (2) the negative inotropic effect of anaesthesia has major implications for interpretation of results obtained in animals under general anaesthesia; and (3) the results emphasise the need to study haemodynamic variables in conscious chronically instrumented, fully recovered, animals.
Assuntos
Anestesia Geral , Modelos Cardiovasculares , Embolia Pulmonar/fisiopatologia , Animais , Pressão Sanguínea , Débito Cardíaco , Hipertensão Pulmonar/fisiopatologia , Masculino , Artéria Pulmonar , Ratos , Ratos Endogâmicos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Teprotida/farmacologia , Fatores de Tempo , Resistência VascularRESUMO
STUDY OBJECTIVE: The aim was to test the hypothesis that endothelium dependent vasomotor control is impaired in heart failure. DESIGN AND SUBJECTS: The haemodynamic effects of NG-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthesis, were studied in five dogs with and without pacing induced heart failure. MAIN RESULTS: In healthy dogs, NNA increased total peripheral resistance and arterial pressure, decreasing cardiac output and heart rate. These effects were partially reversed by L-arginine. In dogs with heart failure, NNA did not change any haemodynamic variable. However, L-arginine decreased total peripheral resistance. CONCLUSIONS: These findings support a physiological role for endothelium derived nitric oxide in control of vascular resistance and are in agreement with the hypothesis that endothelium dependent vasomotion may be impaired in heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Óxido Nítrico/metabolismo , Vasoconstrição/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Estimulação Cardíaca Artificial , Cães , Endotélio Vascular/fisiopatologia , Insuficiência Cardíaca/etiologia , Hemodinâmica/efeitos dos fármacos , NitroargininaRESUMO
OBJECTIVE: The aim was to investigate the interrelation between pulsatile components (assessed by determination of aortic input impedance) and neurohormonal activation in chronic congestive heart failure. METHODS: Aortic input impedance, plasma noradrenaline, renin, atrial natriuretic factor, and arginine vasopressin were measured in 20 patients with mild to moderate chronic congestive heart failure (coronary artery disease n = 12, idiopathic dilated cardiomyopathy n = 8). RESULTS: Cardiac index [2.2(SEM 0.3) litre.min-1.m-2] and left ventricular ejection fraction [38(4)%] were reduced, and pulmonary wedge pressure was increased [21(2) mmHg]. Plasma concentrations of noradrenaline [462(62) pg.ml-1], renin [12(4) ng AI.ml.h-1], atrial natriuretic factor [408(64) pg.ml-1], and--to a slight degree--arginine vasopressin [1.1(0.3) pg.ml-1] were increased. Characteristic impedance Zc [80(6) dyne.s.cm-5) and relative oscillatory aortic input pressure power [10(1)%]--both reflecting the pulsatile components of left ventricular afterload--were within the normal range. There was no significant correlation between these variables and the degree of neurohormonal activation (r values: -0.05 to -0.35). CONCLUSIONS: The data show that in patients with mild to moderate chronic congestive heart failure there is no interrelationship between the degree of neurohormonal activation and pulsatile components of left ventricular afterload. This may indicate that in these stages of heart failure there are no trophic effects of stimulated neurohormonal systems on the physical properties of the great arteries.
Assuntos
Aorta/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hormônios/metabolismo , Resistência Vascular/fisiologia , Idoso , Doença Crônica , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The aim of the present study was to investigate the functional regulation of the myocardial postreceptor adenylyl cyclase (AC) system in compensated left ventricular hypertrophy (LVH) and the effect of long-term angiotensin converting enzyme (ACE) inhibition. METHODS: Pressure overload LVH was induced in rats by supravalvular aortic banding for 12 weeks. At 12 weeks left ventricular function and inner diameters were analyzed by echocardiography of anesthetized animals, and responsiveness to forskolin (systolic developed pressure) was determined in isolated perfused hearts. Functional activities of AC and the stimulatory G protein Gs were measured as well as mRNA expression (quantitative slot blot analyses) of AC type V, isoforms of Gs alpha and Gi alpha 2. G protein alpha-subunits were also quantified by immunoblotting. Rats were treated with ramipril (Ram, 10 mg/kg per day p.o.) during weeks 7 to 12 to induce regression of LVH or with vehicle (Veh, tap water). RESULTS: Pressure overload induced severe LVH (3.2 +/- 0.09 g/kg in Veh vs. 1.8 +/- 0.03 in sham; P < 0.05) which was significantly reduced by ramipril (2.7 +/- 0.09; P < 0.05 vs. Veh). In-vivo left ventricular function and diameters were unchanged in LVH. In contrast, in hearts with LVH, responsiveness of left ventricles to forskolin was attenuated and basal, GTP gamma S and forskolin as well as manganese chloride-stimulated adenylyl cyclase activity was significantly downregulated by approximately 40% (basal 20.8 +/- 1.9 pmol cAMP/mg per min vs. 34.0 +/- 2.2 in sham; P < 0.01). However, no significant changes of AC type V mRNA were found in hypertrophied left ventricles. Functional activity of the stimulatory G protein Gs was reduced in LVH (48 +/- 7 pmol cAMP/mg per min in Veh vs. 68 +/- 3 in sham), whereas mRNA expression of long and short Gs alpha-isoforms was not altered and that of Gi alpha 2 was only slightly increased in ramipril-treated animals. Western analysis showed no significant differences of Gs alpha or Gi alpha 2 subunits. Long-term blockade of the renin-angiotensin system had no effect on the activity of the adenylyl cyclase system. CONCLUSIONS: Functional desensitization of adenylyl cyclase and stimulatory G protein occurred in rat adaptive LVH prior to the onset of severe left ventricular dysfunction which was not restored by ACE-inhibitor treatment. The desensitization seems not to be mediated by significant changes of mRNA expression of AC type V or abundance of regulatory G proteins.
Assuntos
Adenilil Ciclases/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Ramipril/uso terapêutico , Adenilil Ciclases/genética , Animais , Western Blotting , Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVES: Growth hormone (GH) causes cardiomyocyte hypertrophy without development of fibrosis in the normal rat heart. The aim of this study was to evaluate the effects of GH on cardiac remodeling following experimental myocardial infarction (MI). METHODS: Following ligation of the left coronary artery or sham operation, rats were randomized to receive 2 IU GH/kg/day or vehicle for four weeks (n = 140). Extracellular matrix proteins were assessed in the non-infarcted myocardium of the posterior wall using immunohistochemistry and automatic image analysis. In addition, cardiomyocyte size was measured. RESULTS: Compared to sham, vehicle-treated rats with moderate (20-40%) and large (> 40%) infarct size showed left ventricular (LV)-dilatation, reduced fractional shortening as well as increases in LV end-diastolic and right atrial pressures, LV/body weight (BW) ratio and LV posterior wall thickness. Compared to vehicle-treated MI-rats, treatment with GH considerably increased fractional shortening and attenuated LV-dilatation. Vehicle-treated MI-rats displayed progressive increases in cardiomyocyte width and deposition of collagen I, compared to sham rats. Treatment with GH nearly doubled the increase in cardiomyocyte width and reduced collagen I accumulation by 50%. CONCLUSIONS: Our study demonstrates that GH, given early after large MI, elicits a unique pattern of structural effects characterized by enhanced cardiomyocyte hypertrophy and reduced adaptive fibrosis. This attenuation of pathological remodeling translates into a significant improvement in systolic and diastolic LV-function.
Assuntos
Proteínas da Matriz Extracelular/metabolismo , Hormônio do Crescimento/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Cardiomegalia/fisiopatologia , Tamanho Celular/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Imuno-Histoquímica , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
OBJECTIVE: A polymorphism at position 825(C-->T) of the G protein beta3 (GNB3) gene was found to be associated with enhanced transmembrane signalling as well as with an increased prevalence of arterial hypertension. The aim of the present study was to further investigate the association of the GNB3 C825T allele status with arterial hypertension in a large population-based sample and its association with specific end organ damage, i.e. myocardial infarction (MI). METHODS: Individuals from a population-based sample (n=2052) and patients suffering from premature MI (age at first MI < or = 60 years, n = 606) were studied by questionnaire as well as by physical examination and biochemical analyses. RESULTS: In the population-based sample, the prevalence of arterial hypertension (blood pressure > or = 160/95 mmHg and/or antihypertensive medication) was higher in individuals with the TT genotype (41.8%) as compared to heterozygote individuals (36.6%) or those with the CC genotype (32.75%) (P = 0.02). This association was predominantly found in men. Moreover, men without antihypertensive medication carrying the TT genotype showed higher diastolic blood pressure than those carrying the CC genotype (86.5 vs. 83.7 mmHg, P = 0.04). However, the genotype distribution and the allele frequencies were similar in both, the population-based and the MI patient sample. Furthermore, neither the age at the time of MI nor the location of the MI were related to the genotype distribution. Similarly, gender and age stratified analyses did not show any association of the GNB3 genotype and MI. CONCLUSIONS: In male individuals from a large population-based sample, the T allele of the GNB3 polymorphism was associated with arterial hypertension. However, the effects of the GNB3 825T allele on blood pressure were small and did not translate to a clinically relevant increase of risk for MI.
Assuntos
Proteínas de Ligação ao GTP/genética , Hipertensão/genética , Polimorfismo Genético , Anti-Hipertensivos/uso terapêutico , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Humanos , Hipertensão/tratamento farmacológico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , RiscoRESUMO
OBJECTIVE: Activation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) is considered a hallmark of myocardial remodeling. To determine magnitude and relative proportion of activation during the progression to heart failure, we assessed ANP and BNP gene expression in atrial and left ventricular (LV) tissue in a newly developed model of progressive rapid ventricular pacing-induced heart failure in rabbits. METHODS: Six animals underwent progressive pacing with incremental rates (330 beats per min (bpm) to 380 bpm over 30 days), resulting in congestive heart failure (CHF). Five animals underwent pacing at 330 bpm for 10 days only (early LV dysfunction, ELVD) and five additional animals served as control group (CTRL). RESULTS: ELVD was characterized by decreased mean arterial pressure (P=0.05 vs. CTRL) as well as significantly impaired LV function (LV fractional shortening (FS) P<0.01 vs. CTRL) and dilatation (P<0.01 vs. CTRL). CHF was characterized by further decreased mean arterial pressure (P<0.01 vs. ELVD), further impaired LV function (FS P<0.03 vs. ELVD) and dilatation (P<0.01 vs. CTRL). In control animals, significant ANP expression was observed only in atrial tissue (P<0.02 vs. BNP) while BNP expression was ubiquitous but marginal (LV P<0.05 vs. ANP). In ELVD, activation of ANP (atria and LV P<0.05 vs. CTRL) and BNP (atria P<0.05 vs. CTRL, LV n.s.) was observed. In CHF, LV-BNP increased further markedly (P<0.01 vs. CTRL, P<0.05 vs. ELVD) while atrial ANP and BNP expression as well as LV ANP expression remained unchanged (all P=n.s. vs. ELVD). CONCLUSION: The current studies demonstrate differential activation of atrial and LV ANP and BNP under normal conditions and during the progression to heart failure and provide a molecular basis for the superiority of BNP as marker of LV dysfunction and CHF.