Advances in Medical Treatment of Primary Aldosteronism / 中国医学科学杂志(英文版)

Primary aldosteronism (PA) is the most common form of secondary hypertension, with its main manifestations including hypertension and hypokalemia. Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation, stroke, and myocardial infarction. The past decade has witnessed the rapid advances in the genetics of PA, which has shed new light on PA treatment. While surgery is the first choice for unilateral diseases, bilateral lesions can be treated with mineralocorticoid receptor antagonists (MRAs). The next-generation non-steroidal MRAs are under investigations. New medications including calcium channel blockers, macrophage antibiotics, and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

Research progress on the cardiorenal protection of non-steroid mineralocorticoid receptor antagonists in patients with chronic kidney disease / 生理学报

Mineralocorticoid receptor antagonists not only are used as a diuretics to treat essential hypertension, but also protect the heart and kidney by inhibiting inflammation and fibrosis. Since the discovery of spironolactone, the first generation of mineralocorticoid receptor antagonist, two types of non-steroid mineralocorticoid receptor antagonists (finerenone and esaxerenone) approved for clinical use have been developed, which have the advantages of high affinity, high selectivity and balanced distribution in heart and kidney, and can be used in clinic as a cardiorenal protective drug. In this paper, the development history of mineralocorticoid receptor antagonists was reviewed, and the pathophysiological mechanism of inflammation and fibrosis caused by mineralocorticoid receptors and the similarities and differences of different generations of mineralocorticoid receptor antagonists were analyzed. In particular, the phase III clinical research evidence of finerenone and esaxerenone was discussed. This paper also reviews the research progress of cardiorenal protection of non-steroid mineralocorticoid receptor antagonists in patients with chronic kidney disease.

Antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica / Mineralocorticoid receptor antagonists in chronic central serous chorioretinopathy

INTRODUCCIÓN: La coriorretinopatía central serosa consiste en la filtración de fluido desde la coroides y su acumulación en el espacio subretinal. Su forma crónica se asocia a pérdida visual permanente. Los antagonistas de mineralocorticoides son una alternativa de tratamiento para esta patología, aunque no existe evidencia clara sobre su efectividad. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron 22 estudios primarios, de los cuales, cuatro corresponden a ensayos aleatorizados. Concluimos que el uso de antagonistas de mineralocorticoides en coriorretinopatía central serosa crónica probablemente resulta en poca o nula diferencia en la agudeza visual corregida. No es posible establecer con claridad si su uso disminuye el grosor del fluido subretinal, debido a que la certeza de la evidencia ha sido evaluada como muy baja. Además, esta intervención podría resultar en poca o nula diferencia en la aparición de efectos adversos, pero la certeza de la evidencia es baja.

INTRODUCTION: Central serous chorioretinopathy consists of the leakage of fluid from the choroid and its accumulation into the subretinal space. Its chronic form is associated with permanent vision loss. Mineralocorticoid receptor antagonists are an alternative treatment for this condition, although there is no clear evidence about their effectiveness. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including 22 studies overall and four of them are randomized trials. We concluded that in chronic central serous chorioretinopathy, mineralocorticoid receptor antagonists probably make little or no difference to best-corrected visual acuity. We are uncertain whether this intervention reduces subretinal fluid height because the certainty of the evidence is very low. Furthermore, this intervention may make little or no difference in terms of adverse effects, but the certainty of the evidence is low.

Effect of spironolactone on the progression of coronary calcification in peritoneal dialysis patients: a pilot study / Efeito da espironolactona na progressão da calcificação coronariana em pacientes em diálise peritoneal: um estudo piloto

ABSTRACT Introduction: There is evidence that aldosterone plays a role in the pathogenesis of vascular calcification. The aim of this study was to evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, on the progression of coronary calcification (CC) in peritoneal dialysis patients and to identify the factors involved in this progression. Methods: Thirty-three patients with a coronary calcium score (CCS) ≥ 30, detected through multi-detector computed tomography (MDCT) and expressed in Agatston units, were randomly assigned to a group receiving 25mg spironolactone per day for 12 months (spironolactone group) and a control group not receiving this drug. The primary outcome was a percentage change in CCS from baseline to end of the study (relative progression), when a further MDCT was conducted. Patients who had progression of CC were compared with those who did not progress. Results: Sixteen patients, seven in the spironolactone group and nine in the control group, concluded the study. The relative progression of the CCS was similar in both groups, 17.2% and 27.5% in the spironolactone and control groups respectively. Fifty-seven percent of the treated patients and 67% of those in the control group presented progression in the CC scores (p = 0.697). Progressor patients differed from non-progressors because they presented higher levels of calcium and low-density lipoprotein cholesterol and lower levels of albumin. Conclusion: In peritoneal dialysis patients, spironolactone did not attenuate the progression of CC. However, large-scale studies are needed to confirm this observation. Disorders of mineral metabolism and dyslipidemia are involved in the progression of CC.

RESUMO Introdução: Existem evidências de que a aldosterona exerça um papel na patogênese da calcificação vascular. O objetivo deste estudo foi avaliar o efeito da espironolactona, um antagonista do receptor mineralocorticoide, na progressão da calcificação coronariana (CC) de pacientes em diálise peritoneal, e identificar os fatores envolvidos nessa progressão. Métodos: Trinta e três pacientes com escore de cálcio coronariano (ECC) ≥ 30, detectado por tomografia computadorizada com múltiplos detectores (TCMD) e expresso em unidades de Agatston, foram randomizados para um grupo que recebeu 25 mg de espironolactona por dia durante 12 meses (grupo espironolactona) e um grupo controle que não recebeu este medicamento. O desfecho primário foi a mudança percentual do ECC do início para o final do estudo (progressão relativa), quando uma nova TCMD foi realizada. Os pacientes que tiveram progressão de CC foram comparados com aqueles que não progrediram. Resultados: Dezesseis pacientes, sete no grupo espironolactona e nove no grupo controle, concluíram o estudo. A progressão relativa do ECC foi semelhante nos dois grupos, 17,2% e 27,5% nos grupos espironolactona e controle, respectivamente. Cinquenta e sete por cento dos pacientes tratados e 67% daqueles no grupo controle apresentaram progressão nos escores de CC (p = 0,697). Os pacientes progressores diferiram dos não progressores porque apresentaram níveis séricos mais elevados de cálcio e LDL-colesterol e menores níveis de albumina. Conclusão: Em pacientes em diálise peritoneal, a espironolactona não atenuou a progressão da CC. No entanto, estudos em grande escala são necessários para confirmar essa observação. Distúrbios do metabolismo mineral e dislipidemia estão envolvidos na progressão da CC.

Diagnosis and management of primary aldosteronism

ABSTRACT Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.

Hipertensión arterial secundaria en el hiperaldosteronismo primario / Secondary blood hypertension in primary hyperaldosteronism

El hiperaldosteronismo primario es una de las formas de hipertensión arterial secundaria de etiología endocrina potencialmente curable. Fue descrita por primera vez por Jerome Conn en 1955. Se caracteriza por la producción inapropiadamente elevada de aldosterona con relativa autonomía del sistema renina-angiotensina. Su diagnóstico se sospecha en pacientes con hipertensión arterial con o sin hipokaliemia y se confirma con la elevación del índice aldosterona/ actividad de renina plasmática. El tratamiento de elección es el quirúrgico, pero el empleo de agentes antagonistas de mineralocorticoides puede ser otra alternativa terapéutica, previa a la cirugía, o cuando esta no sea posible(AU)

Primary hyperaldosteronism is one of the potentially curable secondary blood hypertension forms of endocrine etiology. This disease was firstly described by Jerome Conn in 1955 and characterized by high production of aldosterone with relative autonomy of the renin-angiotensin system. This disease may be suspected in patients with blood hypertension with or without hypokalemia and confirmed with the increase of aldosteron/plasma rennin activity index. The treatment of choice is surgery, but the use of antagonist agents of mineralocorticoids can be another therapeutic alternative before the surgery or when this procedure is not possible(AU)

Betabloqueantes e inhibidores del sistema renina-angiotensina-aldosterona en el síndrome coronario agudo / Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system in acute coronary syndrome

Los betabloqueantes y los inhibidores de la enzima convertidora de angiotensina / antagonistas de los receptores de angiotensina II (I-ECA/ARA II) son medicamentos esenciales en el manejo del síndrome coronario agudo (SCA) con un efecto beneficioso en la sobrevida, aditivo al obtenido con otros fármacos, como aspirina y estatinas, reduciendo la morbi-mortalidad temprana y tardía en pacientes revascularizados o no. Los pacientes pos IAM con fracción de eyección del ventrículo izquierdo (FEVI) < 40% e insuficiencia cardíaca o diabetes, se pueden beneficiar del tratamiento con antagonistas de los receptores mineralocorticoides si se aplican en forma temprana.

Aplicaciones y proyecciones de los antagonistas del receptor de mineralocorticoides en el tratamiento de patologías cardiovasculares / Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage

In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up.

Efecto de los antagonistas de aldosterona en nefropatía diabética: revisión sistemática de la literatura / Systematic review of the effect of aldosterone antagonists on urinary albumin excretion in diabetic nephropathy

The beneficial effect angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) for diabetic nephropathy can be hampered by the phenomenon of aldosterone escape. Aldosterone antagonists such as espironolactone or epleronone could potentiate the effects of ACEI and ARA and avoid the later problem. We performed a systematic search of the literature on the effects of aldosterone antagonists on diabetic nephropathy. We searched for clinical trials and follow up studies measuring the effects of aldosterone antagonists on urinary albumin excretion among patients with diabetic nephropathy. We retrieved 1345 papers on the subject and 10 were selected for analysis. Among these, spironolactone was more effective than comparing drugs to achieve a reduction in urinary albumin excretion of approximately 30 to 40 percent. On the other hand epleronone was not superior to comparing drugs. All studies reported a modest reduction in glomerular filtration rate and an increase in serum potassium levels. In conclusion, spironolactone in doses of 25 to 100 mg/day reduces urinary albumin excretion but reduces also glomerular filtration rate and increases serum potassium levels.

Efecto de la administración de espironolactona sobre la pérdida de podocitos y la progresión de la nefropatía diabética experimental / Effects of spironolactone administration on the podocytes loss and progression of experimental diabetic nephropathy

Objetivos. Evaluar el efecto de espironolactona (SPL) sobre la pérdida de los podocitos durante la progresión de la nefropatía diabética (ND) experimental. Materiales y métodos. Aleatoriamente un grupo de ratas macho Holtzman recibieron estreptozotocina (grupo diabético) o citrato buffer (grupo control). Las ratas diabéticas fueron tratadas con SPL (50 mg/kg/día). El área glomerular y la celularidad fueron evaluadas por métodos histomorfométricos. La lesión y pérdida de podocitos fue evaluada por la expresión de desmina y Wt-1, respectivamente. La expresión génica del TGF-β1 se evaluó mediante RT-PCR. Resultados. Los niveles de glucosa, el área glomerular, la expansión mesangial y el contenido de colágeno se incrementaron significativamente en las ratas diabéticas. La administración de SPL previno estos cambios sin modificar los niveles de glucosa. La inmunotinción para Wt-1 se redujo significativamente, mientras que la inmunotinción para desmina se incrementó drásticamente en las ratas diabéticas. El tratamiento con SPL previno el incremento de expresión de desmina y la pérdida de expresión de Wt-1. Asimismo, la administración de SPL previno el incremento de la expresión del mRNA del TGF-β1 en las ratas diabéticas. Conclusiones. El tratamiento con SPL, a través de efectos glucosa independientes, atenúa la perdida de podocitos y la progresión de los cambios morfológicos de la ND. Los presentes resultados sugieren que estos efectos son mediados, al menos en parte, por la inhibición de la la expresión del mRNA del TGF-β1.

Objectives. Evaluate the effect of spironolactone (SPL) on the loss of podocytes during the progression of experimental diabetic nephropathy (DN). Materials and methods. A group of male Holtzman rats randomly received streptozotocin (diabetic group) or a buffer citrate (control group). Diabetic rats were treated with SPL (50 mg/kg/day). The glomerular area and the cellularity were evaluated by histomorphometric methods. The injury and loss of podocytes was assessed by desmin expression and Wt-1, respectively. The gene expression of TGF-β1 was assessed by RT-PCR. Results. Glucose levels, the glomerular area, the mesangial expansion and collagen content increased significantly in diabetic rats. The administration of SPL prevented these changes without changing glucose levels. Immunostain for Wt-1 decreased significantly while immunostain for desmin increased dramatically in diabetic rats. Treatment with SPL prevented the increase of desmin expression and the loss of Wt-1 expression. Furthermore, the administration of SPL prevented the increase of TGF-β1 mRNA expression in diabetic rats. Conclusions. Treatment with SPL, through independent glucose effects, reduces the loss of podocytes and the progression of DN morphological changes. These results suggest that these effects are mediated, at least in part, by the inhibition of TGF-β1 mRNA expression.

Atenuação da remodelação ventricular após infarto agudo do miocárdio / Attenuation of ventricular remodeling after myocardial acute infarction

Após o infarto agudo do miocárdio podem ocorrer complexas alterações da arquitetura ventricular, envolvendo tanto a região infartada como a região não infartada. Há alguns anos, essas alterações passaram a ser designadas como remodelação ventricular pós-infarto. Do ponto de vista clínico, a remodelação está associada ao pior prognóstico após a oclusão coronária. Assim, a remodelação predispõe o coração infartado à ruptura ventricular e é o substrato fisiopatológico para a posterior formação do aneurisma ventricular. Cronicamente, a remodelação está associada com maior prevalência de arritmias malignas, principalmente a taquicardia ventricular sustentada e a fibrilação ventricular. O aspecto mais relevante da remodelação pós-infarto, no entanto, é que esse processo desempenha papel fundamental na fisiopatologia da disfunção ventricular. Aspecto a ser considerado refere-se ao fato de que a evolução do processo de remodelação pode ser modificado por meio de diversas intervenções terapêuticas. Entre as estratégias para atenuar a remodelação ventricular destacam-se: terapia de reperfusão, inibidores da enzima conversora da angiotensina e antagonistas da angiotensina II, betabloqueadores, antagonistas da aldosterona e dispositivos de assistência circulatória.

After acute myocardial infarction (AMI), complex changes in ventricular architecture may occur involving the infarcted and the non-infarcted region. This set of adaptations, which includes changes in the composition, mass, volume and geometry of the heart, is known as myocardial remodeling. In relation to clinical significance, the intensity of the ventricular remodeling process is directly associated with worse prognosis, due to the higher incidence of aneurysm formation, ventricular rupture and arrhythmia, and is also associated with the progression of ventricular dysfunction. A relevant aspect to be considered is that a number of strategies have been employed to prevent or mitigate the process of ventricular remodeling following AMI, for instance: reperfusion therapy, angiotensin converting enzyme inhibitors and angiotensin II antagonists, beta-adrenergic receptor blockade, aldosterone antagonists, and left ventricular assist devices.

Espironolactona melhora a vasodilatação fluxo mediada em indivíduos com síndrome metabólica / Espironolactone improves flow-mediated vasodilatation in subjects with the metabolic syndrome

INTRODUÇÃO: O papel da aldosterona na fisiopatologia da disfunção endotelial relacionada à síndrome metabólica (SM) tem sido objeto de estudos. OBJETIVO: Avaliar o bloqueio da aldosterona sobre a vasodilatação fluxo mediada (VDFM) e sobre parâmetros renais e metabólicos em indivíduos com SM. MÉTODOS: Dezenove indivíduos com SM foram submetidos a exame clínico; exames complementares: glicose, insulina, lipidograma, depuração da creatinina, microalbuminúria e a monitorização ambulatorial da pressão arterial (MAPA) e análise da VDFM antes e após 16 semanas do uso de espironolactona. RESULTADOS: Após o tratamento, observou-se aumento da VDFM, de 7,6 ± 5,63 por cento para 15,0 ± 6,10 por cento (p < 0,001), com redução não significante da pressão sistólica e diastólica (142,2 ± 16,37 mmHg para 138,8 ± 16,67 mmHg e 84,3 ± 10,91 mmHg para 82,7 ± 9,90 mmHg, respectivamente). O colesterol HDL (High-density lipoprotein - lipoproteína de alta densidade) aumento de modo significante, a microalbuminúria apresentou tendência à redução, enquanto a depuração da creatinina não variou significativamente com o tratamento. CONCLUSÃO: O bloqueio da aldosterona em pacientes com SM melhorou a VDFM, sem induzir alterações no perfil metabólico e em parâmetros renais.

INTRODUCTION: The role of aldosterone in the pathophysiology of the metabolic syndrome (MS)-related endothelial dysfunction has been the subject of recent research. OBJECTIVE: To evaluate the effects of aldosterone blockade on flow-mediated vasodilation (FMD) and on renal and metabolic parameters of patients with the MS. METHODS: 19 MS subjects underwent clinical examination, laboratory work-up (serum lipid profile, glucose and insulin; creatinine clearance; microalbuminuria investigation), ambulatory blood pressure monitoring (ABPM), and FMD analysis before and after 16 weeks of aldosterone blockade with spironolactone. RESULTS: After the treatment period, FMD increased from 7.6 ± 5.63 percent to 15.0 ± 6.10 percent (p < 0.001), associated with a non-significant decrease of blood pressure (from 142.2 ± 16.37 mmHg to 138.8 ± 16.67 mmHg, and from 84.3 ± 10.91 mmHg to 82.7 ± 9.90 mmHg, respectively). HDL-cholesterol significantly increased, microalbuminuria showed a decreasing trend and creatinine clearance did not change after treatment. CONCLUSION: Aldosterone blockade in patients with the MS improved FMD without interfering with metabolic and renal parameters.

Effects of spironolactone in spontaneously hypertensive adult rats subjected to high salt intake

OBJECTIVE: To evaluate the effect of spironolactone on ventricular stiffness in spontaneously hypertensive adult rats subjected to high salt intake. INTRODUCTION: High salt intake leads to cardiac hypertrophy, collagen accumulation and diastolic dysfunction. These effects are partially mediated by cardiac activation of the renin-angiotensin-aldosterone system. METHODS: Male spontaneously hypertensive rats (SHRs, 32 weeks) received drinking water (SHR), a 1 percent NaCl solution (SHR-Salt), or a 1 percent NaCl solution with a daily subcutaneous injection of spironolactone (80 mg.kg-1) (SHRSalt- S). Age-matched normotensive Wistar rats were used as a control. Eight weeks later, the animals were anesthetized and catheterized to evaluate left ventricular and arterial blood pressure. After cardiac arrest, a doublelumen catheter was inserted into the left ventricle through the aorta to obtain in situ left ventricular pressurevolume curves. RESULTS: The blood pressures of all the SHR groups were similar to each other but were different from the normotensive controls (Wistar = 109±2; SHR = 118±2; SHR-Salt = 117±2; SHR-Salt-S = 116±2 mmHg; P<0.05). The cardiac hypertrophy observed in the SHR was enhanced by salt overload and abated by spironolactone (Wistar = 2.90±0.06; SHR = 3.44±0.07; SHR-Salt = 3.68±0.07; SHR-Salt-S = 3.46±0.05 mg/g; P<0.05). Myocardial relaxation, as evaluated by left ventricular dP/dt, was impaired by salt overload and improved by spironolactone (Wistar = -3698±92; SHR = -3729±125; SHR-Salt = -3342±80; SHR-Salt-S = -3647±104 mmHg/s; P<0.05). Ventricular stiffness was not altered by salt overload, but spironolactone treatment reduced the ventricular stiffness to levels observed in the normotensive controls (Wistar = 1.40±0.04; SHR = 1.60±0.05; SHR-Salt = 1.67±0.12; SHR-Salt- S = 1.45±0.03 mmHg/ml; P<0.05). CONCLUSION: Spironolactone reduces left ventricular hypertrophy secondary to high salt intake and ventricular stiffness in adult SHRs.

Hiperpotassemia na vigência de espironolactona em pacientes com insuficiência cardíaca descompensada / Hyperkalemia during spironolactone use in patients with decompensated heart failure

FUNDAMENTO: A incidência de hiperpotassemia relacionada à espironolactona é baixa na insuficiência cardíaca estável, entretanto não foi estudada durante a descompensação. OBJETIVO: Avaliar a influência da espironolactona na insuficiência cardíaca descompensada sobre o potássio sérico. MÉTODOS: Em um estudo de coorte, selecionamos pacientes hospitalizados por descompensação da insuficiência cardíaca, FEVE < 0,45 e potássio sérico entre 3,5 e 5,5 mEq/l. Os pacientes foram divididos segundo o uso da espironolactona (grupo E) ou não (grupo C). O desfecho foi aumento do potássio (> 6,0 mEq/l) e uso de poliestireno de cálcio. Realizou-se a análise multivariada pela regressão logística, e p < 0,05 foi considerado significante. RESULTADOS: Foram estudados 186 pacientes (grupo E: 56; grupo C: 130), FEVE 0,25, idade 55,5 anos e 65,2 por cento de homens. A incidência de hiperpotassemia foi de 10,7 por cento no grupo E e de 5,4 por cento no grupo C (p = 0,862). A análise multivariada mostrou que a uréia sérica > 60,5 mg/dl, durante a internação, apresenta risco relativo de 9,6 (IC 95 por cento 8,03 - 11,20; p = 0,005) para a ocorrência de hiperpotassemia. CONCLUSÃO: A incidência de hiperpotassemia foi duas vezes maior com espironolactona, mas não estatisticamente significante. Elevação da uréia foi associada à hiperpotassemia. Estudos randomizados são necessários para esclarecer o assunto.

BACKGROUND: The incidence of hyperkalemia related to spironolactone use is low in stable heart failure; however, it has not been studied during decompensation. OBJECTIVE: To evaluate the influence of spironolactone on serum potassium in decompensated heart failure (HF). METHODS: In a cohort study, patients that had been hospitalized due to decompensated HF, with left ventricular ejection fraction (LVEF) < 0.45 and serum potassium between 3.5 and 5.5 mEq/l were selected. The patients were divided according to spironolactone use (Group S) or no use (Group C). The outcome was potassium increase (> 6.0 mEq/l) and the use of calcium polystyrene. A multivariate analysis through logistic regression was carried out and values of p < 0.05 were considered significant. RESULTS: A total of 186 patients (group S: 56; group C: 130) were studied; LVEF of 0.25, aged 55.5 years and 65.2 percent of them males. The incidence of hyperkalemia was 10.7 percent in group S and 5.4 percent in group C (p = 0.862). The multivariate analysis showed that serum urea > 60.5 mg/dl during the hospitalization presents a relative risk of 9.6 (95 percentCI 8.03 - 11.20; p = 0.005) for the occurrence of hyperkalemia. CONCLUSION: The incidence of hyperkalemia was two-fold higher with spironolactone use, but it was not statistically significant. The increase in urea levels was associated to the hyperkalemia. Randomized studies are necessary to clarify this issue.

Influência da terapia com espironolactona sobre níveis sangüíneos de tiamina em pacientes com insuficiência cardíaca / Influence of spironolactone therapy on thiamine blood levels in patients with heart failure

FUNDAMENTO: Estudos do manejo não-farmacológico da insuficiência cardíaca (IC) têm sido muito escassos. A importância de micronutrientes como tiamina há muito é conhecida, uma vez que sua deficiência está associada com o desenvolvimento de IC de alto débito. OBJETIVO: Nós estudamos a relação entre adicionar à inibição da ECA uma supressão adicional da aldosterona com espironolactona e níveis sangüíneos de tiamina (pmol/ml). MÉTODOS: Um total de 22 pacientes (pc) com IC (classes III/IV da NYHA) foi dividido em dois grupos [grupo I - espironolactona 25mg/dia (n=11) e grupo II - sem espironolactona (n=11)]. Determinamos os níveis de tiamina pelo uso da atividade da transcetolase eritrocitária. Os grupos foram comparados com relação à ingesta alimentar, demografia, doses de furosemida e níveis sangüíneos de tiamina, usando os testes de Mann-Whitney e t de Student. Analisamos as proporções com testes de qui-quadrado e de Kruskal-Wallis para associarmos a tiamina com fatores demográficos e usamos as doses de furosemida como variáveis dependentes. RESULTADOS: Os grupos I e II eram similares em relação à ingesta alimentar, doses diárias de furosemida (110,9±30,2 e 105,5±26,9 mg, respectivamente; p>0,05), demografia (etiologia, idade, hipertensão, diabete, tabagismo, abuso de álcool, dislipidemia e tratamento adjuvante da IC com drogas). Os pacientes do grupo I mostraram níveis de tiamina significativamente superiores, comparados com aqueles do grupo II (277,2±89,8 e 154,7±35,7, respectivamente) (p<0,001). Nenhuma das variáveis dependentes citadas acima estava associada com a tiamina. CONCLUSÃO: Em uma coorte de pacientes ambulatoriais com IC tratados com alta dose de diuréticos de alça, o uso de espironolactona está associado com níveis sangüíneos superiores de tiamina. A importância deste achado ainda deverá ser estabelecida por estudos futuros com desenho prospectivo e amostras maiores.

BACKGROUND: The nonpharmacological management of heart failure (HF) has been understudied. The importance of micronutrients such as thiamine has long been known since its deficiency is associated with the development of high-output HF. OBJECTIVE: We studied the relationship between adding to ACE inhibition further aldosterone suppression with spironolactone and thiamine blood levels (pmol/ml). METHODS: A total of 22 patients (pts) with HF (NYHA III/IV) were divided in two groups [group I-spironolactone 25mg/qd (n=11) and group II - no spironolactone (n=11)]. Thiamine levels were determined using the erythrocyte transketolase activity. The groups were compared regarding food intake, demographics, furosemide doses and thiamine blood levels using Mann-Whitney and student's T-test. The proportions were analyzed with Chi-square and Kruskal-Wallis tests to associate thiamine with demographics and furosemide doses as dependent variables. RESULTS: Group I and II were similar regarding food intake, daily furosemide doses (110.9±30.2 and 105.5±26.9 mg, respectively; p>0.05), demographics (etiology, age, hypertension, diabetes, smoking, alcohol abuse, dyslipidemia and adjuvant drug HF treatment). Pts in group I showed significantly higher thiamine levels when compared to pts in group II (277.2±89.8 and 154.7±35.7, respectively) (p<0.001). None of the dependent variables cited above were associated with thiamine. CONCLUSION: In a cohort of ambulatory HF patients on high dose of loop diuretics, the use of spironolactone is associated with higher thiamine blood levels. The significance of this finding remains to be established by future studies with prospective design and larger sample sizes.

Hipertensión arterial resistente: [revisión] / Resistant hypertension: [review]

Resistant hypertension, defined as a persistent blood pressure over 140/90 mmHg despite the use of three antihypertensive drugs including a diuretic, is unusual. The diagnosis requires ruling out initially pseudoresistance and a lack of compliance with treatment. Ambulatory blood pressure recording allow the recognition of white coat hypertension. When there is a clinical or laboratory suspicion, secondary causes of hypertension should be discarded. Excessive salt intake, the presence of concomitant diseases such as diabetes mellitus, chronic renal disease, obesity, and psychiatric conditions such as panic attacks, anxiety and depression, should also be sought. The presence of target organ damage requires a more aggressive treatment of hypertension. Recent clinical studies indicate that the administration of aldosterone antagonists as a fourth therapeutic line provides significant additional blood pressure reduction, when added to previous antihypertensive regimens in subjects with resistant hypertension. The possible blood pressure lowering effects of prolonged electrical activation of carotid baroreceptors is under investigation.

Blockade of renin-angiotensin-aldosterone system in kidney and heart disease: how much do we need?

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in both cardiac and renal injury. Inhibition of RAAS with either an angiotensin converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) provides both cardiac and renal protection, which is independent and additive to the benefit obtained from lowering blood pressure (BP). The combination of an ACE-I and an ARB should be used only for proteinuric renal disease and not for BP reduction. Patients with proteinuria >1 g/day despite optimal BP control with maximal dose of ACE-I or ARB monotherapy may benefit from a combination therapy. Inhibition of aldosterone with spironolactone or eplerenone provides survival advantage in patients with low LV ejection fraction and may also have antiproteinuric effects. Until further information is available, the routine combined use of all three inhibitors of the RAAS cannot be recommended.

Spironolactone effects on myocardium changes induced by thyroid hormone in rats / Efeitos da espironolactona sobre as alterações miocárdicas induzidas pelo hormônio tireoideano em ratos

FUNDAMENTO: Estudar o papel do sistema renina-angiotensina-aldosterona na hipertrofia miocárdica induzida pelo hormônio tireoideano, utilizando-se a espironolactona. OBJETIVO: Analisar as alterações morfológicas no miocárdio induzidas pelo hormônio tireoideano e os efeitos da espironolactona nesse processo. MÉTODOS: Foram estudados 40 ratos Wistar, divididos em quatro grupos, que receberam: veículo utilizado para a diluição do hormônio tireoideano (C); levotiroxina sódica (50 µg/rato/dia) (H); espironolactona (0,3 mg/kg/dia) (E) e hormônio tireoideano + espironolactona (HE), nas mesmas doses citadas, durante 28 dias consecutivos. Todos os animais foram submetidos a pesagem, coleta de sangue para dosagens hormonais e realização de ECG no início e no final do experimento. Ao final do período de estudo, os animais foram sacrificados para determinação do peso do ventrículo esquerdo (VE) e obtenção de cortes de VE para análise morfológica. RESULTADOS: Houve aumento dos níveis de T3 no plasma, perda de peso corporal e aumento da freqüência cardíaca nos animais que receberam o hormônio. O peso do VE foi maior nos grupos H e HE. A análise histométrica mostrou maiores diâmetros dos miócitos no grupo H, com os valores decrescentes nos grupos HE, E e C, sendo as diferenças estatisticamente significantes entre todos os grupos. A espironolactona associada ao hormônio tireoideano (HT) diminuiu em 14,6 por cento a hipertrofia transversal dos miócitos. CONCLUSÃO: Em ratos tratados com hormônio tireoideano ocorre hipertrofia cardíaca com aumento do peso do VE e do diâmetro do miócito. A associação de espironolactona ao hormônio tireoideano previne parcialmente essa hipertrofia por mecanismos ainda desconhecidos.

BACKGROUND: To study the possible role of aldosterone on thyroid hormone-induced myocardium hypertrophy, using spironolactone. OBJECTIVE: To evaluate morphological changes in the myocardium induced by thyroid hormone and the possible effects of spironolactone use on these alterations. METHODS: Forty Wistar rats were studied. The animals were allocated to four groups and were given: the vehicle used for dilution of the thyroid hormone (C); sodium levothyroxin at 50 µg/rat/day (H); spironolactone, 0.3 mg/kg/day (S); or thyroid hormone plus spironolactone (HS), at the same doses mentioned above, for 28 consecutive days. All the animals were weighed, had blood drawn for hormonal measurements and underwent ECG at the start and the end of the experiment. At the end of experiment all animals were euthanized, the weight of the left ventricle (LV) was determined and LV slices were obtained for morphological analysis. RESULTS: There was an increase in T3 levels, decrease of body weight and higher heart rate in the animals from group H. The LV weight was significantly higher in the H e HS groups. The histometric analyses that measured the diameter of the myocytes showed higher values in group H and a progressive decrease in groups HS, S and C, with a significant difference among all the groups. The addition of spironolactone decreased the transversal myocyte hypertrophy by 14.6 percent. CONCLUSION: Rats treated with thyroid hormone present cardiac hypertrophy with increased LV weight and greater myocyte diameter. Spironolactone, when associated with thyroid hormone, can partially prevent this hypertrophy through mechanisms that are yet to be determined.