Aerobic Physical Exercise is Essential for Cardiac Autonomic Regulation in Hypertensive Patients Undergoing Chronic Treatment with Renin- Angiotensin System Inhibitors.

BACKGROUND: Hypertension treatment with renin-angiotensin system inhibitors (RASi) presents contradictions about the recovery of damage in cardiovascular autonomic modulation characterized by reduced heart rate variability (HRV) and increased blood pressure variability (BPV). Conversely, the association of RASi with physical training can influence achievements in cardiovascular autonomic modulation. OBJECTIVE: To investigate the effects of aerobic physical training on hemodynamics and cardiovascular autonomic modulation in hypertensive volunteers untreated and treated with RASi. METHODS: A non-randomized controlled trial in which 54 men (≅ 40-60 years old) with a history of hypertension for >2 years were allocated in accordance with their characteristics into three groups: untreated (Control; n=16), treated with type 1 angiotensin II (AT1) receptor blocker (losartan; n=21), and treated with angiotensin-converting enzyme inhibitor (enalapril; n=17). All participants underwent hemodynamic, metabolic, and cardiovascular autonomic evaluation using baroreflex sensitivity (BRS) and spectral analysis of HRV and BPV, before and after 16 weeks of supervised aerobic physical training. RESULTS: The volunteers treated with RASi had lower BPV and HRV, both in the supine position and in the tilt test, with the losartan group having the lowest values. Aerobic physical training increased HRV and BRS in all groups. However, the association of enalapril with physical training appears to be more prominent. CONCLUSION: Long-term treatment with enalapril and losartan may harm the autonomic modulation of HRV and BRS. Aerobic physical training is essential to promote positive adjustments in the autonomic modulation of HRV and BRS in hypertensive patients treated with RASi, especially with enalapril.

Safety of Enalapril in Infants: Data from the Pediatric Heart Network Infant Single Ventricle Trial.

OBJECTIVE: To assess the safety profile of angiotensin-converting enzyme inhibitor therapy in infants with single ventricle. STUDY DESIGN: The Pediatric Heart Network conducted a double-blind trial involving infants with single ventricle physiology randomized to receive enalapril or placebo and followed to 14 months of age. Data including demographics, drug administration, hemodynamic monitoring, laboratory measurements, adverse events, and survival were extracted from the public use data set and compared between the placebo and enalapril-treated groups. RESULTS: The Infant Single Ventricle trial randomized 230 patients, with 115 patients in each group. Initial enalapril dose was 0.10 mg/kg/d and median maximal dose was 0.38 mg/kg/d. There was no significant difference in change in blood pressure at study drug initiation or when resuming study drug after Glenn surgery. The incidence of hyperkalemia and neutropenia did not differ between groups. Renal dysfunction occurred in 3% of the enalapril group and none of the placebo patients, which was not statistically significant. There was a high frequency of serious adverse events in both groups. There was no difference in the frequency of heart transplant or death between groups. CONCLUSIONS: Enalapril did not have sustained hemodynamic effects at initiation or up-titration of drug. Creatinine and potassium were not different between groups, although renal dysfunction occurred more often in the patients on enalapril. Although efficacy of enalapril in neonates with single ventricle has not been demonstrated, the safety profile of angiotensin-converting enzyme inhibitors appears to be low risk in infants and children with significant heart disease.

Facts and reflections on COVID-19 and anti-hypertensives drugs.

Based on some publications that associate SARS-CoV-2 infection with the use of anti-hypertensive drug groups such as angiotensin-converting-enzyme inhibitors (e.g. enalapril) or angiotensin II receptor blockers (e.g. losartan), many patients from South America, Central America or Spain, have stopped or intend to interrupt their treatments with these drugs. Hence, it may exist ominous consequences due to this drop out. For this reason, it is necessary to quickly warn about this situation and the risks associated with it.

Cytotoxic and genotoxic effects of antihypertensives distributed in Brazil by social programs: Are they safe?

Hypertension, a chronic non-transmissible multifactorial condition, it is highly frequent in Brazil, affecting about 32.5% of the population over 25 years of age. It is characterized by the sustained increase in systolic and diastolic blood pressure levels above 140 mmHg and 90 mmHg, respectively. It is the major aggravating factor in cardiovascular complications and the appearance of other comorbidities. Aiming to promote greater adherence to treatment and improve the population's access to basic medicament, in 2004 the Federal Government created the Programa Farmácia Popular do Brasil (PFPB); partnership with private institutions that provides the population with medicament to control hypertension, free of charge or subsidized at up to 90% of the value. The PFPB distributes the anti-hypertensives atenolol, captopril, enalapril, hydrochlorothiazide, losartan and propranolol. In this way, this work aims to evaluate the genotoxic potential of antihypertensives in human lymphocytes and macrophages, since they are widely used drugs and with few studies about their genotoxicological safety. The tests were developed from cell cultures treated with five different antihypertensive concentrations, all based on plasma peaks, evaluating cell viability, DNA damage index and DNA double strand breakdown. The results show that, as the concentration of captopril and enalapril maleate increased, cell viability decreased. In addition, a DNA damage was observed with the use Captopril and Enalapril in the higher concentrations. Hydrochlorothiazide also caused DNA damage in the five doses tested. Regarding the breaking of double strands of DNA, all the compounds showed increased ruptures. This decrease in dsDNA is dose dependent for all compounds tested. The set of results shows that the use although frequent still requires care and greater knowledge. In general, the antihypertensive drugs that proved to be safer in relation to the genetic damage tested were Losartan and Propranolol.

[Symmetrical rib fractures associated with chronic cough. Report of one case]. / Fracturas costales simétricas asociadas a tos.

Cough may be associated with complications such as syncope, urinary incontinence, pneumothorax, and less frequently, pulmonary hernia and costal fractures. Chronic cough is a cause of rib fractures and when they occur it is likely to affect more than one rib. We report a 53 year-old obese male in treatment with enalapril 10 mg for hypertension with a dry cough lasting five months. He consulted for bilateral chest pain and a Chest X ray examination showed symmetrical fractures in the seventh left and right ribs. Enalapril was discontinued, cough and pain subsided in two weeks.

Fracturas costales simétricas asociadas a tos / Symmetrical rib fractures associated with chronic cough: report of one case

Cough may be associated with complications such as syncope, urinary incontinence, pneumothorax, and less frequently, pulmonary hernia and costal fractures. Chronic cough is a cause of rib fractures and when they occur it is likely to affect more than one rib. We report a 53 year-old obese male in treatment with enalapril 10 mg for hypertension with a dry cough lasting five months. He consulted for bilateral chest pain and a Chest X ray examination showed symmetrical fractures in the seventh left and right ribs. Enalapril was discontinued, cough and pain subsided in two weeks.

Angioedema intestinal aislado inducido por enalapril / Isolated intestinal angioedema induced by enalapril

El angioedema inducido por inhibidores de la enzima convertidora de angiotensina es una entidad poco frecuente caracterizada por edema en piel y mucosas, debido al aumento de la permeabilidad vascular provocada por la inhibición de la enzima convertidora y el subsiguiente aumento de la bradiquinina. De manera frecuente cursa con compromiso facial y de mucosas, siendo infrecuente el compromiso intestinal o de vía aérea. El angioedema intestinal puede presentarse asociado a angioedema facial o aislado, siendo este último excepcional. Cursa con episodios recurrentes de dolor, distensión abdominal y diarrea acuosa con recuperación completa en dos o tres días. Si bien es una entidad poco frecuente, el hecho de que esté asociada a fármacos utilizados con frecuencia nos hace incluirla en el diagnóstico diferencial del dolor abdominal recurrente. Presentamos un caso de angioedema intestinal aislado, asociado al uso de enalapril.

Angioedema induced by angiotensin converting enzyme inhibitors is a rare entity characterized by skin and mucosal edema, due to increased vascular permeability caused by inhibition of the converting enzyme and subsequent increase in bradykinin. It frequently presents with facial and mucosal involvement, being uncommon the intestinal or airway compromise. Intestinal angioedema may be associated with facial or isolated angioedema, the latter being exceptional. It is associated with recurrent episodes of pain, abdominal distention and watery diarrhea which complete recovery in two or three days. Although it is a rare entity, the fact that it is associated with frequently used drugs makes us include it in the differential diagnosis of recurrent abdominal pain. We report a case of isolated intestinal angioedema associated with the use of enalapril.

[Isolated intestinal angioedema induced by enalapril]. / Angioedema intestinal aislado inducido por enalapril.

Angioedema induced by angiotensin converting enzyme inhibitors is a rare entity characterized by skin and mucosal edema, due to increased vascular permeability caused by inhibition of the converting enzyme and subsequent increase in bradykinin. It frequently presents with facial and mucosal involvement, being uncommon the intestinal or airway compromise. Intestinal angioedema may be associated with facial or isolated angioedema, the latter being exceptional. It is associated with recurrent episodes of pain, abdominal distention and watery diarrhea which complete recovery in two or three days. Although it is a rare entity, the fact that it is associated with frequently used drugs makes us include it in the differential diagnosis of recurrent abdominal pain. We report a case of isolated intestinal angioedema associated with the use of enalapril.

Additive antiproteinuric effect of enalapril and losartan in children with hemolytic uremic syndrome.

BACKGROUND: Angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers decrease postdiarrheal hemolytic uremic syndrome (D + HUS) sequelar proteinuria. However, proteinuria may persist in some patients. In nephropathies other than D + HUS, an additive antiproteinuric effect with coadministration of both drugs has been observed. METHODS: To assess such an effect in D + HUS, 17 proteinuric children were retrospectively studied. After a median period of 1 year post-acute stage (range 0.5-1.9) patients received enalapril alone for a median of 2.6 years (range 0.33-12.0) at a median dose of 0.4 mg/kg/day (range 0.2-0.56). As proteinuria persisted, losartan was added at a median dose of 1.0 mg/kg/day (range 0.5-1.5) during 2.1 years (range 0.5-5.0). RESULTS: The decrease in proteinuria with enalapril was 58.0 %, which was further reduced to 83.8 % from the initial value after losartan introduction. The percentage of reduction was significantly greater with the association of both drugs (p = 0.0006) compared with the effect of enalapril exclusively (p = 0.023). Serum potassium, glomerular filtration rate, and blood pressure remained unchanged. CONCLUSIONS: Our results suggest that adding losartan to persisting proteinuric D + HUS children already on enalapril is safe and reduces proteinuria more effectively. Whereas this effect is associated with long-term kidney protection, it should be determined by prospective controlled studies.

Losartan and enalapril are comparable in reducing proteinuria in children with Alport syndrome.

BACKGROUND: A previous subgroup analysis of a 12-week, double-blind study demonstrated that losartan significantly lowered proteinuria versus placebo and amlodipine and was well tolerated in children (1-17 years old) with proteinuria secondary to Alport syndrome. The present subgroup analysis of the open-label, extension phase of this study assessed the long-term efficacy and tolerability of losartan versus enalapril. METHODS: Patients who had completed the double-blind study were re-randomized to losartan or enalapril and followed for proteinuria and renal function for up to 3 years. RESULTS: Twenty-seven patients with Alport syndrome were randomized to losartan (0.44-2.23 mg/kg/day; n = 15) or enalapril (0.07-0.72 mg/kg/day; n = 12). The least-squares (LS) mean percent change from week 12 in urinary protein to creatinine ratio (UPr/Cr was +1.1 % in the losartan group versus a further 13.9 % reduction in the enalapril group (GMR [95 % CI] = 1.2 [0.7, 2.0]); the LS mean change from week 12 in estimated glomerular filtration rate (eGFR) was -6.4 ml/min/1.73 m(2) in the losartan group versus -9.1 ml/min/1.73 m(2) in the enalapril group. The adverse event incidence was low and comparable in both treatment groups. CONCLUSIONS: In children with proteinuria secondary to Alport syndrome, losartan maintained proteinuria reduction, and enalapril produced a further proteinuria reduction over the 3-year study period. Both agents were generally well tolerated.

Angioedema por enalapril: caso clínico / Enalapril angioedema: clinical case

La prescripción de inhibidores de la enzima convertidora de angiotensina (IECA), en el manejo de la hipertensión e insuficiencia cardíaca se ha incrementado fuertemente desde su introducción en 1980. Estas drogas son consideradas seguras, pero se sabe que pueden producir angioedema severo como efecto secundarop en el 0.1 a 0.3% de los pacientes tratados. Caso clínico: paciente de sexo masculino de 57 años de edad, con diagnóstico de hipertensión arterial, tratado con Enalapril 20mg/día, desde hacía 7 días. Ingresa por guardia presentando angioedema en zona bipalpebral, bilateral; labio superior e inferior y regiones malares. No representa compromiso respiratorio. Dentro de sus antecedentes niega alergia a medicamentos y/o alimentos. Se indica como tratamiento Hidrocortisona y Difenhindramina (EV), evolucionando favorablemente, por lo que es externado indicándose Prednisona y Fexofenadina (OV). Dentro de las 48 hs. siguientes concurre a control, encontrandosé asintomático. Discusión: El mecanismo por el cual los inhibidores de la angiotensina producen angioedema no es claro pero probablemente sería por una acumulación tisular de bradiquinina. El angioedema generalmente afecta cabeza y cuello, por lo tanto la vía aérea está en riesgo. Ante un paciente con angioedema tratado con IECA, debería considerarse como primera causa a la administración del medicamento ya que la misma puede presentarse a los días, meses e incluso años de comenzado el tratamiento. Conclusión: El desafío para futuras investigaciones es identificar los subgrupos de pacientes con mayor riesgo de presentar angioedema, en quienes el riesgo de recibir terapia con IECA es mayor que el beneficio.

Prescription of angiotensin convertidara inhibitors (ACE) in the management of hypertension and heart failure has increased rapidly since its introduction in 1980. These drugs are considered to be safe, but it is known that can produce severe angioedema as side effect in 0.1 to 0.3% of treated patients. Clinical Case: A 57 years old male patient was admitted to the emergency department because angioedema in the bipalpebral and bilateral areas as well as in the upper and cheek regions. He had a diagnosis of hypertension and had been taking enalapril 20mg/day, for the previous 7 days. There was no respiratory compromise. He denied history of drug and / or food allergies. Hydrocortisone and Difenhindramina (EV) were prescribed with a favourable outcome. The patient was discharged with indications of prednisone and fexofenadine (OV). At a follow-up visit, 48 hours later, he presented no symptoms. Discussion: The mechanism by which inhibitors of angiotensin produced angioedema is unclear but would probably be by a tissue accumulation of bradykinin. Angioedema usually affects the head and neck so the airway is at risk. In patients with angioedema and ACE inhibitors treatment, IECA should be considered as first cause. It can occur days, months and even years of after the beginning of treatment. Conclusion: The challenge for future research is to identify subgroups of patients at increased risk of angioedema, in whom the risk of receiving ACE inhibitor therapy is greater than the benefit.

Angioedema por enalapril: caso clínico / Enalapril angioedema: clinical case

La prescripción de inhibidores de la enzima convertidora de angiotensina (IECA), en el manejo de la hipertensión e insuficiencia cardíaca se ha incrementado fuertemente desde su introducción en 1980. Estas drogas son consideradas seguras, pero se sabe que pueden producir angioedema severo como efecto secundarop en el 0.1 a 0.3% de los pacientes tratados. Caso clínico: paciente de sexo masculino de 57 años de edad, con diagnóstico de hipertensión arterial, tratado con Enalapril 20mg/día, desde hacía 7 días. Ingresa por guardia presentando angioedema en zona bipalpebral, bilateral; labio superior e inferior y regiones malares. No representa compromiso respiratorio. Dentro de sus antecedentes niega alergia a medicamentos y/o alimentos. Se indica como tratamiento Hidrocortisona y Difenhindramina (EV), evolucionando favorablemente, por lo que es externado indicándose Prednisona y Fexofenadina (OV). Dentro de las 48 hs. siguientes concurre a control, encontrandosé asintomático. Discusión: El mecanismo por el cual los inhibidores de la angiotensina producen angioedema no es claro pero probablemente sería por una acumulación tisular de bradiquinina. El angioedema generalmente afecta cabeza y cuello, por lo tanto la vía aérea está en riesgo. Ante un paciente con angioedema tratado con IECA, debería considerarse como primera causa a la administración del medicamento ya que la misma puede presentarse a los días, meses e incluso años de comenzado el tratamiento. Conclusión: El desafío para futuras investigaciones es identificar los subgrupos de pacientes con mayor riesgo de presentar angioedema, en quienes el riesgo de recibir terapia con IECA es mayor que el beneficio.(AU)

Prescription of angiotensin convertidara inhibitors (ACE) in the management of hypertension and heart failure has increased rapidly since its introduction in 1980. These drugs are considered to be safe, but it is known that can produce severe angioedema as side effect in 0.1 to 0.3% of treated patients. Clinical Case: A 57 years old male patient was admitted to the emergency department because angioedema in the bipalpebral and bilateral areas as well as in the upper and cheek regions. He had a diagnosis of hypertension and had been taking enalapril 20mg/day, for the previous 7 days. There was no respiratory compromise. He denied history of drug and / or food allergies. Hydrocortisone and Difenhindramina (EV) were prescribed with a favourable outcome. The patient was discharged with indications of prednisone and fexofenadine (OV). At a follow-up visit, 48 hours later, he presented no symptoms. Discussion: The mechanism by which inhibitors of angiotensin produced angioedema is unclear but would probably be by a tissue accumulation of bradykinin. Angioedema usually affects the head and neck so the airway is at risk. In patients with angioedema and ACE inhibitors treatment, IECA should be considered as first cause. It can occur days, months and even years of after the beginning of treatment. Conclusion: The challenge for future research is to identify subgroups of patients at increased risk of angioedema, in whom the risk of receiving ACE inhibitor therapy is greater than the benefit.(AU)

Terapia com inibidor da ECA com dosagens relativamente altas e risco de agravamento renal na insuficiência cardíaca crônica / ACE-inhibitor therapy at relatively high doses and risk of renal worsening in chronic heart failure

FUNDAMENTO: O efeito renoprotetor dos inibidores da ECA vem sendo questionado no caso de diminuição do volume circulante efetivo, como na insuficiência cardíaca crônica direita ou biventricular. Objetivo: Detectar os preditores clínicos de agravamento renal na população de pacientes com ICC, caracterizado por dois tipos de regime de dosagem de inibidores da ECA. MÉTODOS: De acordo com um desenho de coorte retrospectiva, seguimos dois grupos de pacientes com ICC - tanto direita quanto biventricular -, todos na classe III da NYHA, tratados com inibidores da ECA (enalapril ou lisinopril), e com fração de ejeção do ventrículo esquerdo (FEVE) < 50 por cento, por meio de distinção em sua dosagem de inibidor da ECA: média-baixa (< 10 mg por dia) ou dosagem "alta" (> 10 mg por dia) de enalapril ou lisinopril. A disfunção renal agravada (ARD) foi definida pelo aumento de Cr > 30 por cento com relação ao segmento basal. O modelo de risco proporcional de Cox foi utilizado para identificar os preditores da ARD entre as seguintes variáveis: os inibidores da ECA com "alta" dosagem, idade, FEVE basal, histórico de repetidas terapias intensivas com diuréticos de alça por via intravenosa (diurético intravenoso), diabete, Cr basal, histórico de hipertensão, pressão arterial sistólica < 100 mmHg. RESULTADOS: Cinquenta e sete pacientes foram recrutados, dos quais 15 foram tratados com inibidor da ECA com dosagem "alta". Durante um seguimento médio de 718 dias, a ARD ocorreu em 17 pacientes (29,8 por cento). Apenas o inibidor da ECA com "alta" dosagem (RR: 12,4681 IC: 2,1614 - 71,9239 p = 0,0050) e Cr basal (RR:1,2344 IC: 1,0414 - 1,4632 p = 0,0157) foi demonstrado ser preditor da ARD. Além disso, demonstrou-se que o inibidor da ECA com dosagens "altas" não previu ARD em ICC sem diurético intravenoso e ICC com diabete. CONCLUSÃO: Na ICC de classe III da NYHA, o inibidor da ECA com "altas" dosagens e um maior Cr basal foi preditor da ARD. A nefrotoxicidade relacionada com inibidores da ECA em "altas" dosagens foi aumentada com o diurético intravenoso, ao passo que, em pacientes com ICC com diabete, aquela não foi detectada.

BACKGROUND: Renoprotective effect of ACE-inhibitors has been questioned in case of decreased effective circulating volume, like in right or biventricular chronic heart failure. OBJECTIVE: To detect clinical predictors of renal worsening in CHF patient population characterized by two types of ACE-inhibitor dosing regimens. METHODS: According to a retrospective cohort design, we followed 2 groups of patients with CHF - whether right or biventricular -, all in III NYHA class treated with ACE-inhibitors (enalapril or lisinopril), and with left ventricular ejection fraction (LVEF) < 50 percent, by distinguishing them by ACE-inhibitor dosing: average-low (<10 mg per day) or "high" dose (>10 mg per day) of enalapril or lisinopril. Worsened renal failure (ARD) was defined by Cr increase >30 percent from baseline. Cox proportional hazards model was used to identify the predictors of ARD among the following variables: ACE-inhibitors "high" dose, age, basal LVEF, history of repeated intensive intravenous loop diuretic therapies (IV diur), diabetes, basal Cr, history of hypertension, systolic blood pressure < 100 mm Hg. RESULTS: 57 patients were recruited, of whom 15 were treated with ACE-inhibitor "high" dose. During a mean follow-up of 718 days, ARD occurred in 17 (29.8 percent) patients. Only ACE-inhibitor "high" dose (HR: 12.4681 C.I.: 2.1614-71.9239 p=0.0050) and basal Cr (HR: 1.2344 C.I.: 1.0414-1.4632 p=0.0157) were shown to predict ARD. Moreover, ACE-inhibitor "high" doses were shown to fail to predict ARD in both CHF without IV diur and CHF with diabetes. CONCLUSION: In III NYHA class CHF, ACE-inhibitor "high" doses and a higher basal Cr predicted ARD. Nephrotoxicity related to ACE-inhibitor "high" doses was increased by IV diur, whereas it was not detected in CHF patients with diabetes.

Pênfigo vegetante induzido por uso de enalapril / Pemphigus vegetans induced by use of enalapril

Pênfigo Vegetante foi primeiramente descrito como uma variante do pênfigo vulgar, em 1876, por Neumann. Em 1889, Hallopeau descreveu um paciente com pústulas e placas vegetantes, e sugeriu ser uma variante do Pênfigo Vegetante de Neumann. Ambos os tipos de pênfigo vegetante são caracterizados pelo desenvolvimento de placas vegetantes, especialmente, em dobras (axila, inguinal, perianal). Os autores apresentam e discutem um caso de Pênfigo Vegetante com uma clínica incomum, com ausência de acometimento de mucosas e áreas de flexão, em paciente idosa, associado ao uso de enalapril como possível desencadeador. Diagnóstico clínico e histológico sugestivos de Pênfigo Vegetante tipo Hallopeau.

Pemphigus Vegetans was first described as a variant of Pemphigus Vulgaris in 1876 by Neumann. In 1889, Hallopeau described a patient with pustules and vegetating plaques, suggesting that it would be a variant of Pemphigus Vegetans of Neumann. Both types of Pemphigus Vegetans are characterized by the development of vegetating plaques especially on skin folds (axillae, groin, perianal region). The authors present and discuss a case of Pemphigus Vegetans with an unusual clinical presentation lacking involvement of mucous membrane and flexor surfaces in an elderly female patient, associated with the use of enalapril as possible trigger factor. Clinical and histological diagnosis were suggestive of Pemphigus Vegetans of the Hallopeau type.

ACE-inhibitor therapy at relatively high doses and risk of renal worsening in chronic heart failure.

BACKGROUND: Renoprotective effect of ACE-inhibitors has been questioned in case of decreased effective circulating volume, like in right or biventricular chronic heart failure. OBJECTIVE: To detect clinical predictors of renal worsening in CHF patient population characterized by two types of ACE-inhibitor dosing regimens. METHODS: According to a retrospective cohort design, we followed 2 groups of patients with CHF - whether right or biventricular -, all in III NYHA class treated with ACE-inhibitors (enalapril or lisinopril), and with left ventricular ejection fraction (LVEF) < 50%, by distinguishing them by ACE-inhibitor dosing: average-low (<10 mg per day) or "high" dose (>10 mg per day) of enalapril or lisinopril. Worsened renal failure (ARD) was defined by Cr increase >30% from baseline. Cox proportional hazards model was used to identify the predictors of ARD among the following variables: ACE-inhibitors "high" dose, age, basal LVEF, history of repeated intensive intravenous loop diuretic therapies (IV diur), diabetes, basal Cr, history of hypertension, systolic blood pressure < 100 mm Hg. RESULTS: 57 patients were recruited, of whom 15 were treated with ACE-inhibitor "high" dose. During a mean follow-up of 718 days, ARD occurred in 17 (29.8%) patients. Only ACE-inhibitor "high" dose (HR: 12.4681 C.I.: 2.1614-71.9239 p=0.0050) and basal Cr (HR: 1.2344 C.I.: 1.0414-1.4632 p=0.0157) were shown to predict ARD. Moreover, ACE-inhibitor "high" doses were shown to fail to predict ARD in both CHF without IV diur and CHF with diabetes. CONCLUSION: In III NYHA class CHF, ACE-inhibitor "high" doses and a higher basal Cr predicted ARD. Nephrotoxicity related to ACE-inhibitor "high" doses was increased by IV diur, whereas it was not detected in CHF patients with diabetes.