Oral Angiotensin-converting Enzyme Inhibitor Research Articles

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril

Pelvic radiation therapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large genome-wide association study in patients with prostate cancer it was previously reported that SNPs tagging AGT, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria, identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a preclinical study to determine whether RAS modulation protected the bladder against RT injury. C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30 Gy or 3 fractions of 8 Gy (8 Gy×3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, as well as an assessment of systemic changes in inflammatory-mediated circulating immune cells. SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not at 4 weeks, compared with nonirradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (P=.0428) and negatively correlated with number of voids (P=.028), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles and the monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, which was also prevented by captopril. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury but larger confirmatory studies are needed.

Prevention of Radiation-Induced Bladder Injury: A Murine Study Using Captopril

<h3>Purpose/Objective(s)</h3> Pelvic radiotherapy (RT) can cause debilitating bladder toxicities but few clinical interventions exist to prevent injury or alleviate symptoms. From a large GWAS in prostate cancer patients it was previously reported that SNPs tagging <i>AGT</i>, part of the renin-angiotensin system (RAS), correlated with patient-reported late hematuria identifying a potential targetable pathway to prevent RT-induced bladder injury. To investigate this association, we performed a pre-clinical study to determine if RAS modulation protected the bladder against RT injury. <h3>Materials/Methods</h3> C57BL/6 male mice were treated with an oral angiotensin converting enzyme inhibitor (ACEi: 0.3g/L captopril) 5 days before focal bladder X-irradiation with either single dose (SD) 30Gy or 3 fractions of 8Gy (8Gyx3 in 5 days). RT was delivered using XStrahl SARRP Muriplan CT-image-guidance with parallel-opposed lateral beams. ACEi was maintained for 20 weeks post RT. Bladder toxicity was assessed using assays to identify local injury that included urinalysis, functional micturition, bladder-released exosomes, and histopathology, and also an assessment of systemic changes in inflammatory-mediated circulating immune cells. <h3>Results</h3> SD and fractionated RT increased urinary frequency and reduced the volume of individual voids at >14 weeks, but not 4 weeks, compared with non-irradiated animals. Urothelial layer width was positively correlated with mean volume of individual voids (p=0.0063) and negatively correlated with number of voids (p=0.0213), relating urothelial thinning to changes in RT-mediated bladder dysfunction. These chronic RT-induced changes in micturition patterns were prevented by captopril treatment. Focal bladder irradiation significantly increased the mean particle count of urine extracellular vesicles. The monocyte and neutrophil chemokines CCL2 and MIP-2, and the proportions of circulating inflammatory-mediated neutrophils and monocytes, increased after irradiation and these events were also prevented by captopril treatment. Exploratory transcriptomic analysis of bladder tissue implicated inflammatory and erythropoietic pathways. <h3>Conclusion</h3> This study demonstrated that systemic modulation of the RAS protected against and alleviated RT-induced late bladder injury.

Case Report: An Unusual Case of Nutcracker Syndrome and Literature Review

BackgroundHematuria is one of the common complaints of patients with kidney disease and often occurs concurrently with proteinuria. Hematuria caused by nutcracker syndrome (NCS) is relatively common, while hematuria caused by type I von Willebrand disease (VWD) is less common.Case PresentationA 12-year-old boy was admitted to our ward due to sudden gross hematuria that had lasted for 4 days. After admission, his gross hematuria lasted for 24 days without remission and was combined with nephrotic-range proteinuria. A series of blood biochemical and urine tests, as well as renal ultrasound, lower abdominal CT angiography, cystoscopy, kidney biopsy, and genetic testing, were completed, and he was eventually diagnosed with NCS combined with type 1 VWD. After nutritional support, oral angiotensin-converting enzyme inhibitor (ACEI), and plasma infusion treatment, gross hematuria and microhematuria disappeared, proteinuria turned negative, and there was no recurrence during the 10 months of follow-up.ConclusionsNCS and/or VWD may exist in patients with hematuria, and bleeding disorders such as VWD should generally be on the list of suspected diagnoses in patients with hematuria.

Association of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists use with risk of atrial fibrillation after pacemaker implantation among very old patients

It remains unknown whether and to what extend the angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can play a role in the development of atrial fibrillation (AF) after pacemaker implantation in very old patients. Therefore, we aimed to investigate the association between oral ACEIs or ARBs and the risk of developing AF in very old patients after pacemaker implantation. Patients above 80 years old with pacemaker implantation and without baseline history of AF were included and their real-world information about ACEIs or ARBs use was extracted from electronic medical records. New AF cases were confirmed via the records of outpatient visits. The multivariable Cox proportional-hazards model was used to evaluate the associations between oral ACEIs or ARBs and risk of AF after pacemaker implantation. Among a total of 388 identified patients aged 80 to 98 years, 118 used ACEIs, 174 had ARBs therapy, and 115 AF were identified after pacemaker implantation during a median follow-up time of 3.1 years. After adjustment for potential confounders, patients with daily use of ARBs had a relatively lower risk of AF after pacemaker implantation (HR: 0.627, 95% CI: 0.425, 0.926; P = 0.019) compared with those non-users, whereas ACEIs therapy didn't show a significant relation with AF risk (HR: 1.335, 95% CI: 0.894, 1.995; P = 0.157). In conclusion, for very old patients with a permanent pacemaker, daily use of oral ARBs was associated with a relative lower risk of AF after pacemaker implantation, however, daily use of ACEIs was not related with AF risk.

Endogenous CCN5 Participates in Angiotensin II/TGF-β1 Networking of Cardiac Fibrosis in High Angiotensin II-Induced Hypertensive Heart Failure

Aberrant activation of angiotensin II (Ang II) accelerates hypertensive heart failure (HF); this has drawn worldwide attention. The complex Ang II/transforming growth factor (TGF)-β1 networking consists of central mechanisms underlying pro-fibrotic effects; however, this networking still remains unclear. Cellular communication network 5 (CCN5), known as secreted matricellular protein, mediates anti-fibrotic activity by inhibiting fibroblast-to-myofibroblast transition and the TGF-β1 signaling pathway. We hypothesized that endogenous CCN5 plays an essential role in TGF-β1/Ang II networking-induced cardiac fibrosis (CF), which accelerates the development of hypertensive HF. This study aimed to investigate the potential role of CCN5 in TGF-β1/Ang II networking-induced CF. Our clinical retrospective study demonstrated that serum CCN5 decreased in hypertensive patients, but significantly increased in hypertensive patients taking oral angiotensin-converting enzyme inhibitor (ACEI). A negative association was observed between CCN5 and Ang II in grade 2and 3 hypertensive patients receiving ACEI treatment. We further created an experimental model of high Ang II-induced hypertensive HF. CCN5 was downregulated in the spontaneously hypertensive rats (SHRs) and increased via the inhibition of Ang II production by ACEI. This CCN5 downregulation may activate the TGF-β1 signaling pathway, which promotes direct deposition of the extracellular matrix (ECM) and fibroblast-to-myofibroblast transition via activated Smad-3. Double immunofluorescence staining of CCN5 and cell markers of cardiac tissue cell types suggested that CCN5 was mainly expressed in the cardiac fibroblasts. Isolated cardiac fibroblasts were exposed to Ang II and transfected with small interfering RNA targeting CCN5. The expression of TGF-β1 together with Col Ia and Col IIIa was further promoted, and alpha-smooth muscle actin (α-SMA) was strongly expressed in the cardiac fibroblasts stimulated with Ang II and siRNA. In our study, we confirmed the anti-fibrotic ability of endogenous CCN5 in high Ang II-induced hypertensive HF. Elevated Ang II levels may decrease CCN5 expression, which subsequently activates TGF-β1 and finally promotes the direct deposition of the ECM and fibroblast-to-myofibroblast transition via Smad-3 activation. CCN5 may serve as a potential biomarker for estimating CF in hypertensive patients. A novel therapeutic target should be developed for stimulating endogenous CCN5 production.

Membranoproliferative glomerulonephritis related to a streptococcal infection in a girl with IgA deficiency: a case report

BackgroundIgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN.Case presentationThe patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued.ConclusionsWe report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.

Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: A randomized controlled trial

Homocysteine levels are elevated in patients with type 1 diabetes mellitus (T1DM) and could induce renal injury. B vitamins have an important role in preventing microvascular complications of diabetes. We performed a randomized-controlled trial of oral supplementation with vitamin B complex as an adjuvant therapy for nephropathy in pediatric T1DM patients and assessed its relation to homocysteine and cystatin C as a marker of nephropathy. This trial included 80 T1DM patients with microalbuminuria, despite oral angiotensin-converting enzyme inhibitors, aged 12-18 years with at least 5 years disease duration and HbA1c ≤8.5%. Patients were randomly assigned into two groups; intervention group which received oral vitamin B complex (B1, B6 and B12) once daily and placebo group. Both groups were followed-up for 12 weeks with assessment of plasma homocysteine, HbA1c, urinary albumin excretion (UAE) and cystatin C. Both groups were well-matched in baseline clinical and laboratory parameters. Baseline homocysteine levels were elevated in both groups compared with reference control values. After 12 weeks, supplementation with vitamin B complex for the intervention group resulted in a significant decrease of homocysteine, fasting blood glucose, HbA1c, triglycerides, total cholesterol, UAE and cystatin C compared with baseline levels (p<0.001) and with placebo group (p<0.001). No adverse reactions were reported. Baseline cystatin C was negatively correlated to vitamin B12 (r=-0.77, p=0.001). Vitamin B complex improved glycemic control and renal function through decreasing homocysteine and could be a safe and effective strategy for treatment of early stage nephropathy in pediatric T1DM. This trial was registered at ClinicalTrials.gov (NCT03594240).

The Effectiveness of a Comprehensive Wellness Assessment on Medication Adherence in a Medicare Advantage Plan Diabetic Population.

The issue of medication nonadherence has generated significant interest because of its complexity from both cost and outcomes perspectives. Of the 3.2 billion prescriptions written annually in the United States, estimates indicate that half are not taken as prescribed, especially among patients with asymptomatic chronic conditions. The objective of this study was to assess whether a comprehensive wellness assessment (CWA) program helps improve medication adherence for oral diabetic medications, statins, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACE/ARBs) in a Medicare Advantage (MA) plan diabetic population. The Centers for Medicare & Medicaid Services includes these medications among its triple-weighted measures.The researchers used a retrospective panel study employing administrative claims data and member month-level enrollment data for members who were newly diagnosed with diabetes since 2010, allowing for up to 5 years of follow-up. The treatment variable of interest was whether the enrollee had undergone a CWA in the 12 months prior to the study. Results for the full sample show that a CWA visit in the prior 12 months is significantly associated with increased adherence to statin medication (incidence rate ratio [IRR]: 1.022, t-test: 2.51) and oral diabetes medication (IRR: 1.032, t-test: 3.00), but it is not significantly associated with adherence to ACE/ARB medication (IRR: 1.009, t-test: 1.09). Results vary considerably in subsamples stratified by dual Medicare and Medicaid eligibility status, presence of certain chronic conditions, and age. CWAs are most beneficial when targeted toward dual-eligible members or members younger than 65. On the basis of these findings, improving medication adherence by targeting CWA visits to certain MA member subcategories may be more cost-effective than using CWAs for the full MA membership.

The effect of 12 weeks carnosine supplementation on renal functional integrity and oxidative stress in pediatric patients with diabetic nephropathy: a randomized placebo-controlled trial.

Oxidative stress is a significant contributor to the pathogenesis of diabetic nephropathy. Carnosine is a natural radical oxygen species scavenger. We investigated the effect of carnosine as an adjuvant therapy on urinary albumin excretion (UAE), the tubular damage marker alpha 1-microglobulin (A1M), and oxidative stress in pediatric patients with type 1 diabetes and nephropathy. This randomized placebo-controlled trial included 90 patients with diabetic nephropathy, despite oral angiotensin-converting enzyme inhibitors (ACE-Is), who were randomly assigned to receive either 12 weeks of carnosine 1 g/day (n = 45), or matching placebo (n = 45). Both groups were followed-up with assessment of hemoglobin A1c (HbA1c), UAE, A1M, total antioxidant capacity (TAC) and malondialdhyde (MDA). Baseline clinical and laboratory parameters were consistent between carnosine and placebo groups (P > .05). After 12 weeks, carnosine treatment resulted in significant decrease of HbA1c (8.2 ± 2.1% vs 7.4 ± 1.3%), UAE (91.7 vs 38.5 mg/g creatinine), A1M (16.5 ± 6.8 mg/L vs 9.3 ± 6.6 mg/L), MDA levels (25.5 ± 8.1 vs 18.2 ± 7.7 nmol/mL) while TAC levels were increased compared with baseline levels (P < .001) and compared with placebo (P < .001). No adverse reactions due to carnosine supplementation were reported. Baseline TAC was inversely correlated to HbA1c (r = -0.58, P = .04) and A1M (r = -0.682, P = .015) among carnosine group. Oral supplementation with L-Carnosine for 12 weeks resulted in a significant improvement of oxidative stress, glycemic control and renal function. Thus, carnosine could be a safe and effective strategy for treatment of pediatric patients with diabetic nephropathy.

The Significance of Angiotensin Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Use in Sudden Cardiac Death

Objectives: To investigate the relationship between the use of angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and hyperkalemia in patients diagnosed with sudden cardiac death. Methods: We examined oral ACE inhibitor or ARB use among cardiopulmonary arrest patients brought by ambulance to our emergency room during a 5-year period from January 2012 to December 2016. The cause of death was determined to be sudden cardiac death, despite temporary return of spontaneous circulation after starting cardiopulmonary resuscitation. Subjects were dichotomized into 2 groups, those taking and those not taking an ACE inhibitor or ARB. Variables determined retrospectively included serum potassium, estimated glomerular filtration rate as an index of kidney function and time from cardiopulmonary arrest to return of spontaneous circulation. The Mann-Whitney U-test was used to compare continuous data, and the chi-square test to compare categorical data between groups. The results are expressed as the median plus range. Statistical significance was assumed at p < 0.05. Results: Thirty-five patients met the inclusion criteria. The mean age was 77.1 years (range, 35 - 93 years), and there were 26 males and 9 females. Eleven subjects were ACE inhibitor or ARB users, and 24 were non-users. The serum potassium level was significantly higher in users than non-users (median, 6.2 mEq/L (range, 4.5 - 10.0) vs. 5.2 mEq/L (range, 3.6 - 8.3); p = 0.001). The estimated glomerular filtration rate was significantly lower in users than non-users (median, 25.1 mL/min/1.73 m2 (range, 4.6 - 60.3) vs. 46.9 mL/min/1.73 m2 (range, 19.8 - 97.1); p = 0.009). There was no significant difference in time from cardiopulmonary arrest to return of spontaneous circulation between the 2 groups (median, 24 minutes (range, 3 - 111) vs. 29 minutes (range, 10 - 54); p = 0.355). Conclusion: It is possible that hyperkalemia induced by ACE inhibitor or ARB use is a cause of sudden cardiac death, especially in patients with chronic kidney disease.

Oral Enoximone as an Alternative to Protracted Intravenous Medication in Severe Pediatric Myocardial Failure.

Phosphodiesterase 3 inhibitors have been used successfully in pediatric patients with acute or chronic myocardial dysfunction over the last two decades. Their protracted continuous intravenous administration is associated with risk of infectious and thromboembolic complications. Weaning intravenous medication and starting oral angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers can be challenging. We reviewed retrospectively hospital records of 48 patients receiving oral enoximone treatment in a single tertiary pediatric cardiac center between November 2005 and April 2014. Failure to wean from intravenous milrinone infusion and/or intolerance of ACE inhibitors and/or beta-blockers was indications for oral enoximone treatment. Age of the patients ranged between 0.5 and 191months (median 7.5months) at the time of starting enoximone treatment. There were 14 patients (29%) with left ventricular dysfunction due to myocarditis or dilated cardiomyopathy and 34 patients (71%) with myocardial dysfunction complicating congenital heart disease. Fifteen (44%) of these 34 patients had left ventricular dysfunction, 13 (38%) right ventricular dysfunction, and in 6 (18%) both ventricles were failing. Duration of oral enoximone treatment was between 3days and 34months (median of 2.3months). Myocardial functional recovery allowed for weaning of enoximone treatment in 15 patients (31%) after 6days-15months (median 5 months). No adverse hemodynamic effects were noted. Blood stained gastric aspirates encountered in two patients resolved with concomitant milk administration. Based on our limited experience, oral enoximone is a well-tolerated and promising alternative to intravenous medication and/or other commonly used oral medications in selected pediatric patients with chronic heart failure.

Effective treatment of severe hypertensive crisis in 2-year-old child with neuroblastoma

We describe a case of a 2-year-old boy with neuroblastoma and high catecholamine levels which developed a severe hypertensive crisis. An oral propranolol and oral angiotensin-converting enzyme inhibitor were used with a mild short transient benefit. However, an intravenous labetalol and oral doxazosin used for over 3 weeks resulted in successful blood pressure control. This report highlights the prolonged use of α and β-adrenergic antagonist therapy in children with neuroblastoma with refractory catecholamine-induced hypertension.

RAAS inhibition and mortality in hypertension

The renin-angiotensin-aldosterone system (RAAS) regulates the body's hemodynamic equilibrium, circulating volume, and electrolyte balance, and is a key therapeutic target in hypertension, the world's leading cause of premature mortality. Hypertensive disorders are strongly linked with an overactive RAAS, and RAAS inhibitors, like angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are routinely used to treat high blood pressure (BP). BP reduction is one of the main goals of current European hypertension guidelines. Oral ACE inhibitors, the oldest category of RAAS inhibitor, were commercially released over 30 years ago in the early 1980s, over a decade before the first ARBs became available. The introduction of ACE inhibitors heralded major changes in the way hypertension and cardiovascular disease were treated. Although the decision of the medical community to replace older ACE inhibitors with more modern ARBs in the 1990s was debatable, it did nevertheless allow scientists to learn more about the angiotensin receptors involved in RAAS stimulation. This and much else of value have been discovered since RAAS inhibitors first became available, but some surprising gaps in our knowledge exist. Until recently, the effect of RAAS inhibition on mortality in hypertension was unknown. This question was recently addressed by a meta-analysis of randomized controlled trials in populations who received contemporary antihypertensive medication. The results of this meta-analysis have helped elucidate the long-term consequences of treatment with RAAS inhibitors on mortality in hypertension. This article will consider the differences between RAAS inhibitors in terms of pharmacological and clinical effects and analyze the impact of the main types of RAAS inhibitor, ACE inhibitors and ARBs, on mortality reduction in hypertensive patients with reference to this latest meta-analysis.

Angiotensin converting enzyme inhibitor as an additive treatment after successful balloon dilation of a critical pulmonary valve stenosis

A 2 days old, 2.7 kg heavy baby boy with critical pulmonary stenosis, underwent successful balloon dilation. After the uneventful procedure, he remained oxygen dependent. The baby was given oral angiotensin converting enzyme inhibitor (ACE inhibitor), instead of an infusion of alpha blocker. Within few hours, in the afternoon of the same day after administration of ACE Inhibitor, the baby could be weaned off oxygen, maintaining on room air, oxygen saturation between 87% and 92%. At follow-up, two months later, his saturation was 99% on room air. We believe that some neonates with critical pulmonary valve stenosis who remain oxygen dependent despite successful balloon dilation, could benefit from such management.

ＡＣＥ阻害剤による口腔底および顎下部の晩発性血管浮腫例

Angioedema, occurring in the pharynx and induced by Angiotensin-Converting Enzyme inhibitor (ACEi), is life-threatening and requires emergency treatment. A 69-year old woman referred for recurrent oral edema and neck swelling had been taking oral ACEi due to hypertension for over 5 years. She had no history of food allergy or marked family history. Examination showed soft diffuse bilateral oral floor swelling with normal-color mucosa. She did not report dyspnea, dysphagia, or pain. Blood tests showed normal levels of C3, C4, CH50, and C1 inhibitor function. Although most ACEi-associated angioedema occurs within the first week of administration, we diagnosed angioedema due to ACEi based on laboratory results. Once ACEi administration was stopped, oral floor swelling disappeared. It is thus important in angioedema treatment to check oral medication.

Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney

PET imaging has been recently introduced for investigating the type 1 angiotensin II receptor (AT(1)R) in vivo. The goal of the present study was to investigate the effects of acute and chronic exposure to angiotensin converting enzyme inhibitors (ACEI) on the AT(1)R in the dog kidney. Animals were imaged at baseline, after acute intravenous ACEI treatment and after a chronic 2-week exposure to an oral ACEI. Control animals were imaged at identical time points in the absence of ACEI treatment. In vivo AT(1)R binding expressed by K (i) was increased in the renal cortex by chronic ACEI treatment (p < 0.05). In vitro measurements of AT(1)R density (B (max)) also revealed significant increases in AT(1)R in isolated glomeruli (p < 0.05). Plasma renin activity was increased, but angiotensin II (Ang II) and the Ang II/Ang I ratio showed a weak correlation with chronic ACEI treatment, consistent with an Ang II escape phenomenon. This study reveals, for the first time, that chronic ACEI treatment increases AT(1)R binding in vivo in the dog renal cortex.

Hemolytic Anemia

Captopril was the first oral angiotensin-converting enzyme (ACE) inhibitor available and, as such, has been extensively studied and in clinical use for many years. Several studies have defined captopril's efficacy in the treatment of congestive heart failure (CHF) as well as determined its safety profile. The most common adverse hematologic reactions associated with captopril use include neutropenia and agranulocytosis. This paper describes an uncommon and a potentially serious hematologic side effect associated with captopril-hemolytic anemia.

Preventive drug use in patients with a history of nonfatal myocardial infarction during 12-year follow-up in The Netherlands: A retrospective analysis

Background: Myocardial infarction (MI) is a common cause of death in developed countries. Long-term preventive pharmacotherapy has been shown to decrease mortality and morbidity after MI. Based on a literature search, studies of these therapies to date have estimated the use of monotherapy, whereas many patients are prescribed combination therapy. Thus, assessment of long-term combination drug use after MI is timely. Objective: The aim of this study was to assess the use of oral antithrombotics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, hydroxymethyl-glutaryl coenzyme A reductase inhibitors (“statins”), and their combinations after MI at discharge and during 12-year follow-up. Methods: This community-based, retrospective data analysis was conducted at Utrecht University, Utrecht, The Netherlands. Data from patients aged ≥18 years at hospital admission who experienced nonfatal acute MI between 1991 and 2000 and had a duration of follow-up ≥30 days were included in the analysis. Data were retrieved from the Pharmo Record Linkage System database, which links pharmacies' dispensation records to hospitals' discharge records on an individual patient level, allowing the investigator to observe individual patients' medication use over time. Primary outcome measures were the use of pre ventive medicines (oral antithrombotics, β-blockers, ACE inhibitors, and statins) at discharge, overall use, and persistence during 12-year follow-up. Results: Of 330,000 patients in the database, 4007 were included in the analysis (2828 men, 1179 women; mean [SD] age, 63.5 [12.5] years). Use at discharge and overall use of oral antithrombotics and statins increased significantly between 1991 and 2000, whereas use of β-blockers and ACE inhibitors increased mainly in patients discharged in the latter years of the follow-up period. Therapy with any combination of drugs increased strikingly from 1991 to 2000, from 47% to 90%. At 1 year after discharge, 32% of patients had discontinued their first-prescribed combination treatments. At 5 years after discharge, this rate increased to 57%, suggesting a low rate of persistence Conclusions: Based on the results of this retrospectivedata analysis, the use of MI-preventive drug treatment at and after discharge increased significantly in this population in The Netherlands during the 1990s. Combination therapy increased strikingly. However, persistence with combination therapy was low.

Post-thrombolysis intracerebral hemorrhage: Data from the Spanish Register ARIAM*

Our objective was to investigate the predisposing factors in patients with acute myocardial infarction (AMI) treated with thrombolysis and complicated by intracranial hemorrhage (ICH), as well as the factors associated with death for patients whose conditions were complicated by ICH. A retrospective study. An intensive care/critical care unit. All patients with AMI listed in the Spanish ARIAM register. None. The study period was from June 1996 to December 2003. The follow-up period was limited to the time spent in the intensive care unit/coronary care unit. Associations with the development of ICH were studied by univariate analysis. Another univariate analysis was used to evaluate the differences between patients affected by AMI complicated by ICH who died and those who survived. Two multivariate analyses were also used: one to evaluate the factors related to the development of ICH and the other to evaluate the factors associated with the death of patients with ICH. A total of 17,111 patients with AMI were included in the study. ICH occurred in 151 (0.9%) of these patients during their stay in the intensive care unit/coronary care unit. The multivariate analysis showed that the variables associated with ICH development were smoking (odds ratio [OR], 0.684; 95% confidence interval [CI], 0.478-0.979); oral b-blockers (OR, 0.488; CI, 0.337-0.706); angiotensin-converting enzyme (ACE) inhibitors (OR, 0.480; CI, 0.340-0.678); arterial hypertension (OR, 4.900; CI, 2.758-8.705); age of 55-64 yrs (OR, 2.253; CI, 1.117-4.546); age of 65-74 yrs (OR, 4.240; CI, 2.276-7.901); age of 75-84 yrs (OR, 4.450; CI, 2.319-8.539); and age of >84 yrs (OR, 2.997; CI, 1.039-8.647). The mortality rate among patients with ICH was 48.3%, vs. 8.3% among patients without ICH. The multivariate study showed that the mortality rate among patients with ICH was associated with age (OR, 1.086; CI, 1.033-1.143), arterial hypertension cardiovascular risk factor (OR, 2.773; CI, 1.216-6.324), and the need for mechanical ventilation (OR, 4.324; CI, 1.665-11.230) or cardiopulmonary resuscitation (OR, 12.258; CI, 1.268-118.523). However, the administration of b-blockers (OR, 0.369; CI, 0.136-0.997) or ACE inhibitors (OR, 0.367; CI, 0.149-0.902) was associated with a reduction in the mortality rate. Factors associated with the development of ICH in our population were age and arterial hypertension, whereas smoking and the administration of b-blockers or ACE inhibitors were associated with a reduction in incidence. Among patients with AMI complicated by ICH, mortality was associated with age, arterial hypertension, cardiopulmonary resuscitation, and the use of mechanical ventilation, whereas the administration of oral b-blockers and ACE inhibitors could be associated with a reduction in mortality.

Cardiac adrenomedullin gene expression and peptide accumulation after acute myocardial infarction in rats.

Plasma adrenomedullin (AM) has been shown to increase in the early phase of acute myocardial infarction (MI). However, little information is available regarding cardiac AM synthesis after MI. Accordingly, we examined the time course of ventricular AM production and potential stimulation of AM in the infarcted and noninfarcted regions in MI rats produced by coronary artery ligation. Compared with sham-operated rats, the ventricular AM peptide level 6 h after MI increased 1.5-fold in the infarcted region and 1.7-fold in the noninfarcted region in association with increased left ventricular end-diastolic pressure (EDP). Northern blot analysis also showed marked induction of AM gene expression in the infarcted region (11-fold) and the noninfarcted region (6-fold) 6 h after MI. The AM peptide level in the infarcted region reached its peak (2. 6-fold) 1 wk postinfarction and thereafter decreased to normal. In the noninfarcted region, however, the AM level remained elevated for at least 4 wk. Immunohistochemical studies demonstrated that intense immunostaining for AM was limited to myocytes in both the infarcted and noninfarcted regions. Interestingly, the AM level in the noninfarcted region correlated positively with infarct size (r = 0. 40, P < 0.01) and EDP (r = 0.52, P < 0.001). An oral angiotensin-converting enzyme inhibitor suppressed the overproduction of AM 1 wk postinfarction in association with decreases in EDP and mean arterial pressure. In summary, cardiac AM synthesis was rapidly induced in both the infarcted and noninfarcted regions after MI. The subsequent ventricular AM in the two regions demonstrated different time-concentration curves during 4 wk after MI. AM may be synthesized predominantly by cardiac myocytes, but not by fibroblasts, at least in part, in association with increased ventricular load after MI.