Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes.

BACKGROUND AND PURPOSE: The SPARCL trial showed that atorvastatin 80 mg/d reduces the risk of stroke and other cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). We tested the hypothesis that the benefit of treatment varies according to index event stroke subtype. METHODS: Subjects with stroke or TIA without known coronary heart disease were randomized to atorvastatin 80 mg/d or placebo. The SPARCL primary end point was fatal or nonfatal stroke. Secondary end points included major cardiovascular events (MCVE; stroke plus major coronary events). Cox regression models testing for an interaction with treatment assignment were used to explore potential differences in efficacy based on stroke subtype. RESULTS: For subjects randomized to atorvastatin versus placebo, a primary end point occurred in 13.1% versus 18.6% of those classified as having large vessel disease (LVD, 15.8% of 4,731 participants), in 13.1% versus 15.5% of those with small vessel disease (SVD, 29.8%), in 11.2% versus 12.7% of those with ischemic stroke of unknown cause (21.5%), in 7.6% versus 8.8% of those with TIA (30.9%), and in 22.2% versus 8.3% of those with hemorrhagic stroke (HS, 2%) at baseline. There was no difference in the efficacy of treatment for either the primary end point (LVD hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49 to 1.02, TIA HR 0.81, CI 0.57 to 1.17, SVD HR 0.85, CI 0.64 to 1.12, unknown cause HR 0.87, CI 0.61 to 1.24, HS HR 3.24, CI 1.01 to 10.4; P for heterogeneity=0.421), or MCVEs (P for heterogeneity=0.360) based on subtype of the index event. As compared to subjects with LVD strokes, those with SVD had similar MCVE rates (19.2% versus 18.5% over the course of the trial), and similar overall reductions in stroke and MCVEs. CONCLUSIONS: Atorvastatin 80 mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype.

High-dose atorvastatin after stroke or transient ischemic attack.

BACKGROUND: Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack (TIA) remains to be established. METHODS: We randomly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry, had low-density lipoprotein (LDL) cholesterol levels of 100 to 190 mg per deciliter (2.6 to 4.9 mmol per liter), and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. RESULTS: The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. CONCLUSIONS: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke. (ClinicalTrials.gov number, NCT00147602 [ClinicalTrials.gov].).

Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

BACKGROUND AND PURPOSE: The intention-to-treat analysis of data from the placebo-controlled Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial found 80 mg atorvastatin per day reduced the risk of stroke and major coronary events in patients with recent stroke or transient ischemic attack. This benefit was present despite only a 78% net difference in adherence to randomized treatment over the course of the trial. In this exploratory analysis, our aim was to evaluate the benefit and risks associated with achieving a >or=50% low-density lipoprotein cholesterol (LDL-C) reduction from baseline. METHODS: This post hoc analysis was based on 55,045 LDL-C measurements among the 4731 patients enrolled in SPARCL (average, 11.6 measurements per patient) during a mean follow-up of 4.9 years. At each postrandomization LDL-C assessment, percent change in LDL-C from baseline for each patient was classified as no change or increase from baseline (32.7% of measurements), <50% LDL-C reduction (39.4%), or >or=50% reduction (27.9%). RESULTS: Compared with no change or an increase in LDL-C, analysis of time-varying LDL-C change showed that patients with >or=50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P=0.0016), a 33% reduction in ischemic stroke (P=0.0018), no statistically significant increase in hemorrhagic stroke (P=0.8864), and a 37% reduction in major coronary events (P=0.0323). There was no increase in the incidence of myalgia or rhabdomyolysis. Persistent liver enzyme elevations were more frequent in the group with >or=50% LDL-C reduction. CONCLUSIONS: As compared with having no change or an increase in LDL-C, achieving a >or=50% lowering was associated with a greater reduction in the risk of stroke and major coronary events with no increase in brain hemorrhages.

Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure.

Aldosterone classically promotes unidirectional transepithelial sodium transport, thereby regulating blood volume and blood pressure. Recently, both clinical and experimental studies have suggested additional, direct roles for aldosterone in the cardiovascular system. To evaluate aldosterone activation of cardiomyocyte mineralocorticoid receptors, transgenic mice overexpressing 11beta-hydroxysteroid dehydrogenase type 2 in cardiomyocytes were generated using the mouse alpha-myosin heavy chain promoter. This enzyme converts glucocorticoids to receptor-inactive metabolites, allowing aldosterone occupancy of cardiomyocyte mineralocorticoid receptors. Transgenic mice were normotensive but spontaneously developed cardiac hypertrophy, fibrosis, and heart failure and died prematurely on a normal salt diet. Eplerenone, a selective aldosterone blocker, ameliorated this phenotype. These studies confirm the deleterious consequences of inappropriate activation of cardiomyocyte mineralocorticoid receptors by aldosterone and reveal a tonic inhibitory role of glucocorticoids in preventing such outcomes under physiological conditions. In addition, these data support the hypothesis that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure.

Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure.

BACKGROUND: In heart failure (HF), aldosterone has been implicated in the formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling. Eplerenone is a novel selective aldosterone blocker. The present study examined the effects of long-term monotherapy with eplerenone on the progression of LV dysfunction and remodeling in dogs with chronic HF. METHODS AND RESULTS: HF was produced in 14 dogs by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with eplerenone (10 mg/kg twice daily, n=7) or no therapy at all (control, n=7). Hemodynamic measurements were made just before randomization and were repeated at the end of 3 months of therapy. In control dogs, LV end-diastolic and end-systolic volume increased significantly (62+/-4 versus 68+/-4 mL, P<0.001, and 38+/-3 versus 47+/-3 mL, P<0.001, respectively), and EF decreased significantly (38+/-1% versus 31+/-2%, P<0.001). In contrast, end-diastolic volume, end-systolic volume, and EF remained unchanged during the 3 months of treatment in eplerenone-treated dogs. LV end-diastolic wall stress increased significantly in control dogs but decreased significantly in eplerenone-treated dogs. Compared with control, eplerenone was associated with a 28% reduction in cardiomyocyte cross-sectional area, a 37% reduction of volume fraction of reactive interstitial fibrosis, and a 34% reduction of volume fraction of replacement fibrosis. CONCLUSIONS: Our results indicate that long-term therapy with eplerenone prevents progressive LV dysfunction and attenuates LV remodeling in dogs with chronic HF.

Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone.

Mineralocorticoid receptor (MR) antagonism has proven to effectively attenuate the pathophysiological effects of aldosterone in clinical and experimental settings of hypertension and heart failure. MR activates transcription of target genes upon aldosterone binding, and eplerenone selectively binds to MR and blocks aldosterone- mediated activation. In this review, we summarize the preclinical and clinical evidence supporting the beneficial effects of eplerenone (INSPRA), a selective aldosterone blocker, in the treatment of hypertension and heart failure. We also review the current status in understanding the molecular mechanisms of action of the MR and its ligand. In addition, we compare the effects of eplerenone and spironolactone, a nonselective aldosterone blocker, on the transcriptional activity of MR and provide a molecular explanation for the improved side-effect profile of eplerenone compared with spironolactone.

The role of the factor X activation peptide: a deletion mutagenesis approach.

To understand the role of the factor X (fX) activation peptide (AP), a deletion mutagenesis approach was employed. Two single-chain, variant enzymes were generated in which 41 residues were deleted from the AP: fX (des-137-183) and fX(des-137-183;N191A), which lacks a carbohydrate moiety at Asn191 due to an alanine substitution. Deletion of the fX AP did not impact fXa catalytic activity. Activation of the variant zymogens, however, was altered. Neither mutant enzyme was activated by the fX coagulant protein from Russell's viper venom (RVV-X(1)). Activation by factor VIIa (fVIIa) and fVIIa in the presence of cofactor, lipidated tissue factor (TF), occurred at an accelerated rate for both variants as compared to wild-type fX (WTfX). Similar to fVII, the mutants auto-activated in a cofactor-independent manner, which was characterized by a lag period and accelerated dose-dependently by plasma fXa (kcat/Km, 0.046 +/- 0.004 micro M(-1) s(-1)). Both mutants were also found to be activated by fVIIa (0.31 +/- 0.03 micro M(-1) s(-1)), fIXa (0.30 +/- 0.03 micro M(-1) s(-1)), and thrombin (0.00078 +/- 0.00015 micro M(-1) s(-1)). In all cases, the rate of activation was faster for fX(des-137-183;N191A) as compared to fX(des-137-183). We propose that the fX AP and Asn191 carbohydrate serve primarily as negative autoregulation mechanisms to prevent spurious activation of fX and secondarily in cofactor dependence and activator specificity.

Aldosterone target organ protection by eplerenone.

The classical mineralocorticoid effect of aldosterone on unidirectional transepithelial sodium transport in the kidney was long thought to be the predominant effect of this hormone. However, there is convincing evidence for additional extrarenal actions of aldosterone that are mediated via activation of mineralocorticoid receptors (MRs) in the heart, vasculature and brain. It is now postulated that many of the detrimental effects of aldosterone are mediated through MR activation in these nonclassical target organs. The selective aldosterone blocker, eplerenone (Inspra), is under development for human therapeutic use for treatment of hypertension and heart failure post-myocardial infarction (MI). Clinical and preclinical studies have linked elevated aldosterone to hypertension, left ventricular and vascular remodeling, cardiac, renal, and cerebral vascular inflammation and injury, and increased risk of mortality in heart failure patients. Multiple studies in experimental models of hypertension and heart failure demonstrate that selective blockade of aldosterone by eplerenone effectively preserves cardiac function, attenuates maladaptive left ventricular remodeling and tissue and vascular injury in part by reducing vascular inflammation in aldosterone target organs.

Emerging therapies for heart failure.

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.

Lessons learned from a survey of the diagnosis and treatment journeys of postmenopausal women with hypertension.

In this qualitative, experiential study, 300 members of the database of WomenHeart: The National Coalition for Women With Heart Disease completed an online survey about hypertension diagnosis and treatment, patient education, and perceptions of this and related conditions. Based on the findings from the survey, characteristics of the prototypical journey were identified. To the extent to which the surveyed WomenHeart members represent typical experiences, this survey provides insights into common hurdles women encounter in their journey throughout the hypertension diagnosis and treatment process. Results of this study suggest the need for a patient-centric approach to hypertension management and to implement programs with the intention of comprehensively assessing and meeting individual needs. Further studies would be of value to expand on patients' journeys in the management of hypertension and identify the types of products, services, and programming that most effectively support treatment adherence and achievement of optimal blood pressure control.

Progression to type 2 diabetes, healthcare utilization, and cost among pre-diabetic patients with or without comorbid hypertension.

OBJECTIVE: This study examined progression to type 2 diabetes and compared healthcare utilization and costs among patients with pre-diabetes, with or without comorbid hypertension. RESEARCH DESIGN AND METHODS: This study drew from a large national claims database (2003-2008). Patients were ≥18 years of age with a medical claim or lab value indicating the presence of pre-diabetes. The index date was the first pre-diabetes diagnosis (ICD-9 codes 790.21, 790.22, 790.29) or qualifying lab value of fasting plasma glucose or impaired glucose intolerance. All patients had ≥12-month data pre- and post- index date. Multivariate analysis was conducted to identify risk factors affecting progression to type 2 diabetes, and to estimate the impact of hypertension status and diabetes progression on healthcare utilization and cost. RESULTS: 144,410 patients met study criteria, with an average follow-up of 802 (SD 344) days. Among participants, 30.7% progressed to diabetes, with a mean 288 (SD 340) days from pre-diabetes identification to diabetes diagnosis. Compared with patients who did not progress, the total adjusted medical costs for patients who developed diabetes increased by $1429 in 1 year, $2451 in 2 years, and $3621 in 3 years (p < 0.001). Patients with concomitant hypertension were significantly more likely to progress to type 2 diabetes, and had higher total medical costs compared to patients without hypertension ($476 higher in 1 year, $949 in 2 years, $1378 in 3 years). CONCLUSIONS: Patients with pre-diabetes who progressed to type 2 diabetes had higher healthcare utilization and costs compared with patients who did not. The presence of hypertension substantially increased costs and was associated with higher likelihood of diabetes progression. Blood pressure, lifestyle intervention, body mass index, and other factors cannot be examined due to the limitations of the data. Results may not be generalizable to patients with insurance other than commercial or Medicare.

Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

OBJECTIVE: To explore the relative contributions of baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) and lipoproteins on the risk of recurrent stroke or first major cardiovascular event (MCVE) and their potential impact on the benefit of statin treatment. METHODS AND RESULTS: The SPARCL trial randomized 4731 patients with recent stroke or transient ischemic attack (TIA) and no known coronary heart disease and LDL-C between 100 and 190 mg/dL to either atorvastatin 80 mg/d or placebo. Baseline assessment included SBP, DBP and measurements of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and triglyceride levels. After 4.9 years of follow-up, there were 575 primary end points (fatal and nonfatal stroke), including 491 ischemic strokes, and 740 MCVEs (stroke plus myocardial infarction and vascular death). Cox regression models analysis showed a trend (P>0.05 and P<0.10) for higher SBP but not DBP to be associated with an outcome stroke with only SBP associated with MCVE. Only baseline low HDL-C was associated with an outcome stroke. Baseline HDL-C, triglycerides, and LDL/HDL ratio were each associated with MCVEs. There were no interactions between any of these baseline variables and the effect of treatment on outcome strokes. CONCLUSIONS: In patients with recent stroke or TIA and no coronary heart disease, only lower baseline HDL-C predicted the risk of recurrent stroke with HDL-C, triglycerides, and LDL/HDL ratio associated with MCVE. Atorvastatin treatment was similarly effective regardless of baseline lipoprotein levels.

Persistence of atorvastatin and simvastatin among patients with and without prior cardiovascular diseases: a US managed care study.

BACKGROUND: In clinical practice, persistence with statin therapy is poor. While little is known about relative persistence to specific statins, previous studies have observed greater persistence in patients who achieve greater degrees of lipid lowering. Identification of statin therapies which improve patient persistence has the potential to improve the quality of patient care and clinical outcomes. Therefore, we assessed patient persistence with atorvastatin and simvastatin in primary and secondary prevention patients enrolled in managed care. METHODS: New statin users aged > or =18 years, both with and without prior cardiovascular (CV) events within the 12 month pre-treatment period, were identified from a large national database of managed care patients. Patients initiated atorvastatin or simvastatin therapy from January 1, 2003 to September 30, 2005 and were continuously enrolled in a covered plan for at least 12 months before and after initiation of statin therapy. Subanalyses of patients > or =65 years were also conducted. Measures of interest included demographic and clinical characteristics of the study samples and persistence of statin utilization over the 1-year follow-up period. Persistence was defined as the number of days a patient remained on treatment in the first year following their index date, measured from the date of first fill to study end or the date of discontinuation. RESULTS: A total of 129 764 atorvastatin users and 45 558 simvastatin users without prior CV events were included in the study. For those patients with prior CV events, a total of 6888 atorvastatin users and 4443 simvastatin users were included in the study. Median persistence in patients without prior CV events was 50 days longer for patients initiating therapy with atorvastatin than simvastatin (207 vs. 157 days, p<0.0001) and after adjusting for confounding factors, those treated with atorvastatin were 15% less likely to discontinue therapy during the first year than those treated with simvastatin (HR=0.85; 95% CI 0.84, 0.86; p<0.001). In secondary prevention patients median persistence was 85 days longer in atorvastatin patients than simvastatin patients (266 vs. 181 days, p<0.0001) and atorvastatin patients were 22% less likely to discontinue therapy (HR=0.78; 95% CI 0.75, 0.82; p<0.001). Persistence was worse in the elderly patients, but the relative difference between atorvastatin and simvastatin was similar to the overall patient population. CONCLUSIONS: In patients with and without prior CV disease, persistence is generally poor, even worse in the elderly, but significantly better for atorvastatin patients than simvastatin patients (p<0.001). Further studies are required to determine whether this is due to differences in cost, effectiveness, side-effects, or other attributes of the statins. STUDY LIMITATIONS: Differences in persistence could be, in part, due to unmeasured confounders although all available variables were adjusted in multivariate analyses. Additionally, the claims database lacks some clinical data such as lipid levels, limiting assessments of statin efficacy, and does not include any reasons for discontinuation of therapy.

Cardiovascular outcomes among patients newly initiating atorvastatin or simvastatin therapy: a large database analysis of managed care plans in the United States.

BACKGROUND: While the results of randomized clinical trials have indicated that statins improve outcomes in patients without cardiovascular disease (CVD), it remains uncertain whether there are differences in efficacy between statins, particularly in clinical practice, where the public health implications could be substantial. OBJECTIVE: We assessed cardiovascular (CV) outcomes among primary-prevention patients newly initiating therapy with atorvastatin or simvastatin. METHODS: Using claims data from 92 US managed care plans, we identified new statin users without CVD who initiated atorvastatin (10 or 20 mg) or simvastatin (20 or 40 mg) from January 2003 to September 2005 and were continuously enrolled in a covered plan for > or = 12 months before and > or = 1 month after the initiation of statin therapy. The main outcome was the time to the first CV event (hospitalization related to myocardial infarction, angina, or coronary artery disease; stroke; amaurosis fugax; transient ischemic attack; peripheral or central nervous system vascular disease; or revascularization). Persistence with treatment was calculated in terms of the number of days during follow-up that a patient remained on statin treatment, starting from the date of the first prescription fill to the end of the study or the date at which therapy was discontinued. RESULTS: A total of 168,973 patients initiating atorvastatin (mean dose, 13.5 mg) and 50,658 patients initiating simvastatin (mean dose, 28.5 mg) were followed for a median of 1.5 years. Atorvastatin patients were significantly more persistent with treatment than simvastatin patients (median treatment duration, 158 vs 124 days, respectively; P < 0.001). After adjustment for age, sex, type of health plan, payer type, geographic region, calendar year of statin initiation, physician specialty, comorbidities, concomitant therapies, and total direct health care costs in the year before statin initiation, use of atorvastatin was associated with significantly fewer CV events compared with use of simvastatin (hazard ratio = 0.88; 95% CI, 0.83-0.93; P < 0.001). CONCLUSIONS: In these patients without CVD, atorvastatin 10 or 20 mg was associated with a significantly lower risk of CV events compared with simvastatin 20 or 40 mg. Further studies are required to determine whether differences in persistence, achieved low-density lipoprotein cholesterol levels, or other factors contribute to these differences in outcomes.

Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction.

BACKGROUND: Mitogen-activated protein kinases (MAPKs) have emerged as an important pathophysiologic regulator during the development of heart failure (HF). p38 MAPK activity is elevated in cardiac hypertrophy and HF. We used a mouse model of myocardial infarction (MI) to test the hypotheses that (1) inhibition of p38 MAPK activity may improve cardiac function and remodeling after myocardial infarction (MI) and (2) coadministration of a p38 inhibitor (p38i) and an angiotensin-converting enzyme inhibitor (ACEI) may provide only limited further cardioprotection in this model. METHODS AND RESULTS: MI was induced in C57BL/6J mice by ligating the left anterior descending coronary artery and then either left untreated or treated with a p38i (SC-409, 30 mg/kg/day in chow), ACEI (enalapril, 20 mg/kg in drinking water), or p38i plus ACEI for 12 weeks. Echocardiography was performed and systolic blood pressure measured before MI and weekly thereafter. At the end of the study, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA) were examined histologically. We found that p38i significantly increased left ventricular ejection fraction and cardiac output and decreased left ventricular area at diastole, ICF, and MCSA. ACEi and p38i each had similar beneficial effects in this mouse model of HF produced by a large MI. Coadministration of p38i and ACEi did not provide any additional benefit. CONCLUSION: Our data suggest that inhibition of p38 MAPK provides significant cardioprotection in mice with HF post-MI.

Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector.

Transmission by flea bite is a relatively recent adaptation that distinguishes Yersinia pestis, the plague bacillus, from closely related enteric bacteria. Here, a plasmid-encoded phospholipase D (PLD), previously characterized as Yersinia murine toxin (Ymt), was shown to be required for survival of Y. pestis in the midgut of its principal vector, the rat flea Xenopsylla cheopis. Intracellular PLD activity appeared to protect Y. pestis from a cytotoxic digestion product of blood plasma in the flea gut. By enabling colonization of the flea midgut, acquisition of this PLD may have precipitated the transition of Y. pestis to obligate arthropod-borne transmission.

Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.

BACKGROUND: We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker, eplerenone. METHODS: Unnephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and randomized to receive treatment for 28 days: vehicle infusion (control); 0.75 microg/hour aldosterone subcutaneous infusion; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone. Blood pressure and urinary albumin were measured and kidneys were evaluated histologically. Renal injury, inflammation, and fibrosis were assessed by immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Aldosterone/salt induced severe hypertension compared to controls (220 +/- 4 mm Hg vs. 131 +/- 4 mm Hg, P < 0.05), which was partially attenuated by eplerenone (179 +/- 4 mm Hg, P < 0.05). In aldosterone/salt treated rats, renal histopathologic evaluation revealed severe vascular and glomerular sclerosis, fibrinoid necrosis and thrombosis, interstitial leukocyte infiltration, and tubular damage and regeneration. Aldosterone/salt increased circulating osteopontin (925.0 +/- 80.2 ng/mL vs. 53.6 +/- 6.3 ng/mL) and albuminuria (75.8 +/- 10.9 mg/24 hours vs. 13.2 +/- 3.0 mg/24 hours) compared to controls and increased expression of proinflammatory molecules. Treatment with eplerenone reduced systemic osteopontin (58.3 +/- 4.2 ng/mL), albuminuria (41.5 +/- 7.2 mg/24 hours), and proinflammatory gene expression: osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta). CONCLUSION: These findings indicate that aldosterone/salt-induced renal injury and fibrosis has inflammatory components involving macrophage infiltration and cytokine up-regulation. Attenuation of renal damage and inflammation by eplerenone supports the protective effects of aldosterone blockade in hypertensive renal disease.

Aldosterone induces a vascular inflammatory phenotype in the rat heart.

Vascular inflammation was examined as a potential mechanism of aldosterone-mediated myocardial injury in uninephrectomized rats receiving 1% NaCl-0.3% KCl to drink for 1, 2, or 4 wk and 1) vehicle, 2) aldosterone infusion (0.75 microg/h), or 3) aldosterone infusion (0.75 microg/h) plus the selective aldosterone blocker eplerenone (100 mg. kg(-1). day(-1)). Aldosterone induced severe hypertension at 4 wk [systolic blood pressure (SBP), 210 +/- 3 mmHg vs. vehicle, 131 +/- 2 mmHg, P < 0.001], which was partially attenuated by eplerenone (SBP, 180 +/- 7 mmHg; P < 0.001 vs. aldosterone alone and vehicle). No significant increases in myocardial interstitial collagen fraction or hydroxyproline concentration were detected throughout the study. However, histopathological analysis of the heart revealed severe coronary inflammatory lesions, which were characterized by monocyte/macrophage infiltration and resulted in focal ischemic and necrotic changes. The histological evidence of coronary lesions was preceded by and associated with the elevation of cyclooxygenase-2 (up to approximately 4-fold), macrophage chemoattractant protein-1 (up to approximately 4-fold), and osteopontin (up to approximately 13-fold) mRNA expression. Eplerenone attenuated proinflammatory molecule expression in the rat heart and subsequent vascular and myocardial damage. Thus aldosterone and salt treatment in uninephrectomized rats led to severe hypertension and the development of a vascular inflammatory phenotype in the heart, which may represent one mechanism by which aldosterone contributes to myocardial disease.

Role of a selective aldosterone blocker in mice with chronic heart failure.

BACKGROUND: Spironolactone, a nonselective aldosterone blocker, has a cardioprotective effect; however, significant endocrine side effects limit its use. Eplerenone is a new selective aldosterone blocker. We investigated whether eplerenone attenuates cardiac remodeling and improves function in a mouse model of heart failure and whether coadministration of eplerenone and an angiotensin-converting enzyme inhibitor (ACEi) provides better cardioprotection than either agent alone. METHODS AND RESULTS: C57BL/6J mice were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Two weeks later, the mice were either left untreated or treated with (1) eplerenone, (2) ACEi, or (3) eplerenone plus ACEi for 12 weeks. Systolic blood pressure (SBP) was measured and echocardiography performed before MI and weekly thereafter. At the end of the study, interstitial collagen fraction (ICF) and myocyte cross-sectional area (MCSA) were examined histologically. We found that (1) eplerenone significantly improved ejection fraction and cardiac output and decreased left ventricular (LV) systolic area, LV weight, ICF, and MCSA independently of changes in SBP compared with untreated animals; (2) ACEi had similar beneficial effects, accompanied by a significant reduction in SBP; and (3) combined treatment offered limited additional benefit beyond monotherapy. CONCLUSIONS: In mice with MI, eplerenone attenuates progression of heart failure comparably to ACEi, and its effect is independent of BP lowering.