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Hypertension. 2008;52:271-278
Published online before print June 16, 2008, doi: 10.1161/HYPERTENSIONAHA.107.109314
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(Hypertension. 2008;52:271.)
© 2008 American Heart Association, Inc.

Original Articles

History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure

Bertram Pitt; Ali Ahmed; Thomas E. Love; Henry Krum; Jose Nicolau; José S. Cardoso; Alexander Parkhomenko; Michael Aschermann; Ramon Corbalán; Henry Solomon; Harry Shi; Faiez Zannad

From the University of Michigan Health System (B.P.), Ann Arbor; School of Medicine (A.A.), University of Alabama at Birmingham, and Veterans Affairs Medical Center, Birmingham, Ala; School of Medicine, Case Western Reserve University (T.E.L.), Cleveland, Ohio; Department of Epidemiology and Preventive Medicine (H.K.), Monash University, Prahan, Australia; Heart Institute (InCOR) (J.N.), University of São Paulo Medical School, São Paulo, Brazil; Departamento de Engenharia Electrotécnica e de Computadores (J.S.C.), Faculdade de Engenharia, Universidade do Porto, Porto, Portugal; Emergency Cardiology Department (A.P.), National Institute of Cardiology, Kiev, Ukraine; Interni Klinika (M.A.), Cardiovascular Center, Prague, Czech Republic; Departamento de Enfermedades Cardiovasculares (R.C.), Hospital Clínico y Facultad de Medicina, Pontifica Universidad Catolica de Chile, Santiago, Chile; Pfizer Inc (H. Solomon, H. Shi), New York, NY; and the Clinical Investigation Center (F.Z.), INSERM-CHU de Nancy Hopital Jeanne d'Arc, Dommartin-les Toul, France.

Correspondence to Bertram Pitt, University of Michigan, 1500 E Medical Center Dr, 3910 Taubman Center, Ann Arbor, MI 48109-0366. E-mail bpitt{at}med.umich.edu


*    Abstract
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In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (n=6632), eplerenone-associated reduction in all-cause mortality was significantly greater in those with a history of hypertension (Hx-HTN). There were 4007 patients with Hx-HTN (eplerenone: n=1983) and 2625 patients without Hx-HTN (eplerenone: n=1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx-HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx-HTN, all-cause mortality occurred in 18% of patients treated with placebo (rate, 1430/10 000 person-years) and 14% of patients treated with eplerenone (rate, 1058/10 000 person-years) during 2350 and 2457 years of follow-up, respectively (hazard ratio [HR]: 0.71; 95% CI: 0.59 to 0.85; P<0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients (3029/10 000 person-years) and 28% of eplerenone-treated patients (2438/10 000 person-years) with Hx-HTN (HR: 0.82; 95% CI: 0.72 to 0.94; P=0.003). In patients without Hx-HTN, eplerenone reduced heart failure hospitalization (HR: 73; 95% CI: 0.55 to 0.97; P=0.028) but had no effect on mortality (HR: 0.91; 95% CI: 0.72 to 1.15; P=0.435) or on the composite end point (HR: 0.91; 95% CI: 0.76 to 1.10; P=0.331). Eplerenone should, therefore, be prescribed to all of the post–acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx-HTN.


Key Words: eplerenone • hypertension • myocardial infarction • heart failure • morbidity • mortality


*    Introduction
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In the Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), eplerenone, a selective aldosterone blocker, significantly reduced all-cause mortality and the coprimary combined end points of cardiovascular (CV) hospitalization or CV mortality.1 A subgroup analysis of the EPHESUS suggested that the effect of eplerenone on all-cause mortality was greater in patients with a history of hypertension (Hx-HTN) than in those without Hx-HTN (P for interaction=0.05).1 However, there was no significant difference between these groups for eplerenone on the coprimary combined end points of CV hospitalization or CV mortality. To gain further insight into this relationship, we examined the effects of eplerenone on mortality and morbidity in a propensity score–matched cohort of patients with and without Hx-HTN.


*    Methods
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Study Design and Patients
EPHESUS was a multicenter, international, randomized, double-blind, placebo-controlled clinical trial of eplerenone.1 Briefly, 6632 patients with acute myocardial infarction (AMI) complicated by low (≤40%) left ventricular ejection fraction (LVEF) and symptomatic heart failure (HF) were randomly assigned within 3 to 14 days of their AMI to receive eplerenone 25 mg/d titrated to 50 mg/d (n=3319) or matching placebo (n=3313). Patients were receiving standard medical therapy, including an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (87%) and a β-blocker. Patients were followed for up to 2.5 years, with a mean follow-up of 16 months. Patients in the placebo and eplerenone groups were receiving a mean dose of 43.5 mg and 42.6 mg per day, respectively. Exclusion criteria included the use of potassium-sparing diuretics, a serum creatinine concentration >2.5 mg/dL (220 µmol/L), and a serum potassium concentration >5.0 mEq/L (mmol/L). Of the EPHESUS participants, 4007 patients had a history of hypertension (Hx-HTN), and 2625 had no Hx-HTN at the time of enrollment. Of the 4007 patients with Hx-HTN, 2024 (50.5%) were in the placebo group, and 1983 (49.5%) were in the eplerenone group. Of the 2625 patients without Hx-HTN, 1289 (49.1%) were in the placebo group, and 1336 (50.9%) were in the eplerenone group.

The 2 primary end points of the EPHESUS, all-cause mortality and the combined end point of CV hospitalization or CV mortality, were also the primary end points for this analysis. Major secondary end points from EPHESUS, such as CV mortality, which included mortality because of AMI, HF, stroke, and sudden cardiac death (SCD), as well as hospitalization because of AMI and HF, were also studied. The cause of death or the primary diagnosis leading to hospitalization was adjudicated by a blinded EPHESUS critical events committee.

Statistical Analysis
Because the balance achieved by randomization in the main trial may have been lost in the groups with and without Hx-HTN, propensity scores for the receipt of eplerenone were used to assemble a balanced cohort. The propensity score for the receipt of eplerenone for a patient is defined as the conditional probability of receiving eplerenone given that patient’s measured covariates.2–6 Propensity scores were calculated separately for each of the 4007 and 2625 patients with and without Hx-HTN, respectively, using a nonparsimonious multivariable logistic regression model, incorporating the 36 baseline covariates (Table 1). Patients receiving eplerenone and placebo were matched based on their propensity to receive eplerenone. In all, 1838 pairs of patients with Hx-HTN and 1176 pairs of patients without Hx-HTN were matched. Absolute standardized differences were estimated to assess residual balance after matching.6,7


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  		Table 1. Baseline Patient Characteristics of Propensity Score–Matched Patients

We used Kaplan–Meier plots and matched Cox regression analysis to estimate the effect of eplerenone in patients with and without Hx-HTN. We used multivariable Cox regression analyses in the prematch cohort, separately adjusting for the raw propensity scores. All of the analyses were based on intent to treat. All of the statistical tests were evaluated using 2-tailed 95% CIs.

Because the sample size of matched patients with Hx-HTN (n=3676) was larger than matched patients without Hx-HTN (n=2352), we conducted a sensitivity analysis by repeating our analysis in a smaller group of patients with Hx-HTN. In addition, we conducted a sensitivity analysis to determine the potential effects of an unmeasured covariate that may potentially invalidate our main conclusions.6,8,9


*    Results
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Study Patients
Baseline characteristics of patients with and without Hx-HTN are presented in Table 1. In both groups with and without Hx-HTN, the distribution of all of the measured baseline covariates was balanced, and there were no statistically significant differences between treatment groups.

Eplerenone and All-Cause Mortality
During a median follow-up of 16 months, 596 matched patients with Hx-HTN (16.2%) and 336 matched patients without Hx-HTN (14.3%) died of all causes. Among patients with Hx-HTN, all-cause mortality occurred in 18% of the placebo group and 14% of the eplerenone group (hazard ratio [HR]: 0.71; 95% CI: 0.59 to 0.85; P<0.0001; Figure 1A and Table 2). Among patients without Hx-HTN, all-cause mortality occurred in 14.4% of the placebo group and 14.2% of the eplerenone group (HR: 0.91; 95% CI: 0.72 to 1.15; P=0.435; Figure 1B and Table 2).


Figure 1
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  		Figure 1. Kaplan–Meier plots for all-cause mortality in patients (A) with and (B) without Hx-HTN.


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  		Table 2. Effects of Eplerenone on Primary and Secondary End Points

Eplerenone and CV Hospitalization or CV Mortality
Among patients with Hx-HTN, the coprimary combined end points of CV hospitalization or CV mortality occurred in 32.8% patients in the placebo group and 28.2% of patients in the eplerenone group (HR: 0.82; 95% CI: 0.72 to 0.94; P=0.003; Figure 2A and Table 2). Among patients without Hx-HTN, the coprimary combined end points of CV hospitalization or CV mortality occurred in 25.3% of patients in the placebo group and 23.6% of patients in the eplerenone group (HR: 0.91; 95% CI: 0.76 to 1.10; P=0.331; Figure 2B and Table 2).


Figure 2
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  		Figure 2. Kaplan–Meier plots for the coprimary combined end point of CV hospitalization or CV mortality in patients (A) with and (B) without Hx-HTN.

Eplerenone, SCD, and Other Secondary Study End Points
SCD occurred in 6.5% of patients with Hx-HTN in the placebo group and 5.0% of patients with Hx-HTN in the eplerenone group (Figure 3A and Table 2). Among patients without Hx-HTN, SCD occurred in 5.2% patients in the placebo group and 4.4% patients in the eplerenone group (Figure 3B and Table 2). Effects of eplerenone on other secondary end points in patients with and without Hx-HTN are displayed in Table 2.


Figure 3
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  		Figure 3. Kaplan–Meier plots for sudden cardiac death in patients (A) with and (B) without Hx-HTN.

Eplerenone and Adverse Events
In patients with Hx-HTN, the incidence of severe hyperkalemia was significantly higher in patients receiving eplerenone (5.9% versus 4.2%; odds ratio for patients receiving eplerenone: 1.43; 95% CI: 1.06 to 1.93; P=0.019; Table 3). The incidence of severe hypokalemia was lower in patients receiving eplerenone (14.7% versus 9.6%; odds ratio for patients receiving eplerenone: 0.62; 95% CI: 0.51 to 0.76; P<0.0001). Other adverse events are displayed in Table 3.


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  		Table 3. Adverse Events in Patients With a Hx-HTN

Eplerenone, History of Hypertension, and Baseline Blood Pressure
Eplerenone had a favorable effect on outcomes in patients with Hx-HTN regardless of their baseline systolic blood pressure (SBP). In the subgroups of patients with Hx-HTN and a baseline SBP of ≤120 mm Hg, all-cause mortality occurred in 191 placebo patients (rate: 1465/10 000 person-years) and 157 eplerenone patients (rate: 1176/10,000 person-years; HR: 0.80; 95% CI: 0.65 to 0.99; P=0.043). Eplerenone also reduced CV hospitalization or CV mortality (HR: 0.86; 95% CI: 0.73 to 0.997; P=0.046) in these patients. In Hx-HTN patients with a baseline SBP of >120 mm Hg, similarly, eplerenone reduced both all-cause mortality (HR: 0.68; 95% CI: 0.52 to 0.87; P=0.002) and the coprimary composite end point (HR: 0.79; 95% CI: 0.66 to 0.94; P=0.010).

Eplerenone and Changes in Baseline Blood Pressure
Increases in SBP from baseline (Table 1) were similar in both groups of patients with or without Hx-HTN and were slightly greater in the placebo group. The SBP increased by 6 and 3 mm Hg in the placebo and eplerenone patients, respectively, in both groups with and without Hx-HTN.

Results of Sensitivity Analyses
Because the group with Hx-HTN (n=3676) was larger than the group without Hx-HTN (n=2352), we assembled a cohort of patients with Hx-HTN that was similar in size to that of those without Hx-HTN (please see the data supplement, available online at http://hyper.ahajournals.org). In this smaller group of patients with Hx-HTN (n=2334), we observed that eplerenone use was associated with reduction in all-cause mortality (HR: 0.76; 95% CI: 0.61 to 0.95; P=0.014).

Within the Hx-HTN–matched cohort, sign-score tests for matched survival data with censoring provide evidence that the use of eplerenone, compared with placebo, was associated with decreased all-cause mortality (z=3.73; 2-tailed, P=0.0002) and decreased rates of CV hospitalization or CV mortality (z=2.92; P=0.0035). Sensitivity analyses suggest that an unmeasured binary covariate would need to increase the odds of eplerenone use by >17.6% to explain the all-cause mortality association and by >6.6% to explain the association with the coprimary end points.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The results of this analysis demonstrate that the use of eplerenone in patients with Hx-HTN within 3 to 14 days of an AMI, complicated by reduced LVEF and symptomatic HF, was associated with significant reductions in all-cause mortality and the coprimary end points of CV hospitalization or CV mortality. In addition, the use of eplerenone was associated with a significant reduction in SCD in these patients. Although the direction of change with eplerenone in the subgroup of patients without Hx-HTN was similar, significant reductions in these end points were not observed in this subgroup; however, in patients without Hx-HTN, eplerenone significantly reduced hospitalization for HF, suggesting a long-term effect on ventricular remodeling. Although approximately two thirds of patients in EPHESUS had Hx-HTN, their mean blood pressure at the time of random assignment post-AMI was within normal limits.

There are several plausible explanations for the differential benefit of eplerenone in patients with Hx-HTN. Effects of a treatment on outcomes are known to vary between groups of patients based on differences in pathophysiology, natural history, severity of disease, comorbidity, and absolute risks between groups.10 EPHESUS patients with Hx-HTN were older and had more severe disease and comorbidity burden than those without Hx-HTN. They had 14% greater risk for all-cause mortality and 28% increased risk for CV mortality or CV hospitalizations than those without Hx-HTN. Pathophysiologically, compared with patients without Hx-HTN, those with Hx-HTN are at an increased risk of incident AMI, subsequent ventricular remodeling, and CV mortality.11–14 Hypertension predisposes patients to an increase in reactive oxygen species, vascular remodeling, and myocardial collagen formation.15–18 After AMI, patients with Hx-HTN have been found to have a greater degree of ventricular remodeling than those without Hx-HTN.13,19,20 Ventricular remodeling results in myocardial stretch, which is an important stimulus for activation of various neurohormones, including angiotensin II and aldosterone.21,22 HF is associated with an upregulation of mineralocorticoid receptors and aldosterone with an increase in myocardial calcium channel expression.23–26 Recently, AMI has been shown to cause electric remodeling before mechanical remodeling and LV hypertrophy.27 The increase in intracellular calcium associated with electric remodeling has been suggested to increase the risk of ventricular arrhythmias and SCD.28,29 Alterations in intracellular calcium and potassium may be greater in patients with AMI and Hx-HTN, many of whom have LV hypertrophy, and an increase in mineralocorticoid receptors and calcium channel expression.25,26 Therefore, the effectiveness of eplerenone in patients with Hx-HTN, most of whom were treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a β-adrenergic receptor blocker, in reducing total mortality and SCD along with a trend toward a reduction in death because of progressive HF can be explained by the effects of aldosterone blockade in preventing electric remodeling, as well as by improving sympathetic/parasympathetic balance related to a decrease in reactive oxygen species production and an improvement in NO availability.30–33 These effects are in addition to the effects of eplerenone on ventricular mechanical remodeling, LV hypertrophy, and collagen formation, all of which are likely of greater magnitude in those with Hx-HTN.34–38

Results of our subgroup analysis suggest that the effects of eplerenone were observed regardless of baseline SBP, suggesting a long-term effect of HTN on target organs rather than baseline blood pressure levels as the underlying mechanistic explanation for the differential effect of eplerenone in the group with Hx-HTN. Another plausible explanation of a differential benefit of eplerenone in patients with Hx-HTN is the larger sample of these patients; however, sensitivity analysis suggests that eplerenone was beneficial in a smaller subset of patients with Hx-HTN. In addition, statistical analysis showed no significant difference in the treatment effect of eplerenone on SBP between patients with and without Hx-HTN, suggesting that our findings were not driven by higher absolute reductions in SBP among patients with Hx-HTN.

This analysis suggests that patients with AMI complicated by a low LVEF and symptomatic HF should be risk-stratified based on Hx-HTN. Those with Hx-HTN should be prescribed eplerenone to improve outcomes. Although we did not observe a significant effect of eplerenone on mortality in patients without Hx-HTN, we did observe a significant reduction in HF hospitalization, likely mediated by a reduction in ventricular remodeling. There was a trend toward a reduction in mortality, but analysis of this subgroup may have been underpowered to detect a significant difference in mortality and other outcomes, which is not surprising given the low baseline risk in these patients.11 Reduction in HF hospitalization would suggest a long-term effect of eplerenone on mortality in these patients.

Eplerenone was well tolerated in patients with and without Hx-HTN. Although more patients receiving eplerenone experienced hyperkalemia (>6 mEq/L), overall absolute rates were low, and no deaths were attributed to hyperkalemia in patients receiving eplerenone. Patients receiving eplerenone had a lower risk of developing hypokalemia (<3.5 mEq/L). This is important, because the overall absolute rate of hypokalemia was higher than that of hyperkalemia, which has been associated with increased mortality.39–42

Perspectives
This analysis suggests that patients with AMI, reduced LVEF, and symptomatic HF should be risk stratified based on their Hx-HTN; and those with Hx-HTN should be treated early post-AMI with eplerenone to prevent death, especially SCD. Because HF hospitalization is an important predictor of CV death and eplerenone reduced HF hospitalization in patients without Hx-HTN, eplerenone should also be initiated in these patients.


*    Acknowledgments
 
We thank Sijian Zhang, University of Alabama at Birmingham, and Gabriel Saltan, COMSYS (Chicago, Ill), for their assistance in data preparation and cleanup. B.P. conceived the study hypothesis for this subanalysis of EPHESUS.

Sources of Funding

This study was funded by Pfizer Inc. Editorial support was provided by PAREXEL and was funded by Pfizer Inc. A.A. is supported by the National Institutes of Health through grants from the National Heart, Lung, and Blood Institute (5-R01-HL085561-02 and P50-HL077100) and a generous gift from Jean B. Morris of Birmingham, Alabama.

Disclosures

J.S.C. has served on an advisory board for Pfizer Inc; H. Solomon is an employee of Pfizer Inc; H. Shi is an employee of Pfizer Inc; and B.P. and F.Z. have received honoraria from and served on advisory boards for Pfizer Inc. The remaining authors report no conflicts.


*    Footnotes
 
A.A. developed the subanalysis design and wrote the first draft of the article. A.A. conducted statistical analyses in consultation with T.E.L. All of the authors interpreted the data, participated in critical revision of the article for important intellectual content, and approved the final version of the article. A.A. had full access to the data.

Received January 6, 2008; first decision January 17, 2008; accepted May 19, 2008.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
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 up arrowResults
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 *References
 

  1. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.[Abstract/Free Full Text]
  2. Rosenbaum PR, Rubin DB. The central role of propensity score in observational studies for causal effects. Biometrika. 1983; 70: 41–55.[Abstract/Free Full Text]
  3. Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc. 1984; 79: 516–524.[CrossRef]
  4. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997; 127: 757–763.[Abstract/Free Full Text]
  5. Rubin DB. Using propensity score to help design observational studies: application to the tobacco litigation. Health Services Outcomes Res Methodol. 2001; 2: 169–188.[CrossRef]
  6. Ahmed A, Husain A, Love TE, Gambassi G, Dell'Italia LJ, Francis GS, Gheorghiade M, Allman RM, Meleth S, Bourge RC. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: an observational study using propensity score methods. Eur Heart J. 2006; 27: 1431–1439.[Abstract/Free Full Text]
  7. D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998; 17: 2265–2281.[CrossRef][Medline] [Order article via Infotrieve]
  8. Rosenbaum PR. Sensitivity to hidden bias. In: Rosenbaum PR, ed. Observational Studies. 2nd Ed. New York, NY: Springer-Verlag; 2002: 110–124.
  9. Rosenbaum PR. Sensitivity analysis for matching with multiple controls. Biometrika. 1988; 75: 577–581.[Abstract/Free Full Text]
  10. Rothwell PM. Treating individuals. 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005; 365: 176–186.[CrossRef][Medline] [Order article via Infotrieve]
  11. Tuomilehto J, Salonen JT, Nissinen A. Isolated systolic hypertension and its relationship to the risk of myocardial infarction, cerebrovascular disease and death in a middle-aged population. Eur Heart J. 1984; 5: 739–744.[Abstract/Free Full Text]
  12. Haider AW, Chen L, Larson MG, Evans JC, Chen MH, Levy D. Antecedent hypertension confers increased risk for adverse outcomes after initial myocardial infarction. Hypertension. 1997; 30: 1020–1024.[Abstract/Free Full Text]
  13. Richards AM, Nicholls MG, Troughton RW, Lainchbury JG, Elliott J, Frampton C, Espiner EA, Crozier IG, Yandle TG, Turner J. Antecedent hypertension and heart failure after myocardial infarction. J Am Coll Cardiol. 2002; 39: 1182–1188.[Abstract/Free Full Text]
  14. Kenchaiah S, Davis BR, Braunwald E, Rouleau JL, Dagenais GR, Sussex B, Steingart RM, Brown EJ Jr, Lamas GA, Gordon D, Bernstein V, Pfeffer MA. Antecedent hypertension and the effect of captopril on the risk of adverse cardiovascular outcomes after acute myocardial infarction with left ventricular systolic dysfunction: insights from the Survival and Ventricular Enlargement Trial. Am Heart J. 2004; 148: 356–364.[CrossRef][Medline] [Order article via Infotrieve]
  15. Peterson JR, Sharma RV, Davisson RL. Reactive oxygen species in the neuropathogenesis of hypertension. Curr Hypertens Rep. 2006; 8: 232–241.[CrossRef][Medline] [Order article via Infotrieve]
  16. Zhou MS, Jaimes EA, Raij L. Vascular but not cardiac remodeling is associated with superoxide production in angiotensin II hypertension. J Hypertens. 2005; 23: 1737–1743.[Medline] [Order article via Infotrieve]
  17. Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001; 38: 581–587.[Abstract/Free Full Text]
  18. Davies MJ. Hypertension and atherosclerotic (ischaemic) heart disease. J Hum Hypertens. 1991; 5 (suppl 1): 23–29.
  19. Parodi G, Carrabba N, Santoro GM, Memisha G, Valenti R, Buonamici P, Dovellini EV, Antoniucci D. Heart failure and left ventricular remodeling after reperfused acute myocardial infarction in patients with hypertension. Hypertension. 2006; 47: 706–710.[Abstract/Free Full Text]
  20. Kenchaiah S, Pfeffer MA, St John Sutton M, Plappert T, Rouleau JL, Lamas GA, Sasson Z, Parker JO, Geltman EM, Solomon SD. Effect of antecedent systemic hypertension on subsequent left ventricular dilation after acute myocardial infarction (from the Survival and Ventricular Enlargement Trial). Am J Cardiol. 2004; 94: 1–8.[Medline] [Order article via Infotrieve]
  21. Pitt B. Aldosterone blockade in patients with acute myocardial infarction. Circulation. 2003; 107: 2525–2527.[Free Full Text]
  22. Yamazaki T, Komuro I, Kudoh S, Zou Y, Shiojima I, Mizuno T, Takano H, Hiroi Y, Ueki K, Tobe K, Kadowaki T, Nagai R, Yazaki Y. Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res. 1995; 77: 258–265.[Abstract/Free Full Text]
  23. Ohtani T, Ohta M, Yamamoto K, Mano T, Sakata Y, Nishio M, Takeda Y, Yoshida J, Miwa T, Okamoto M, Masuyama T, Nonaka Y, Hori M. Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: beneficial effects of mineralocorticoid receptor blocker. Am J Physiol Regul Integr Comp Physiol. 2007; 292: R946–R954.[Abstract/Free Full Text]
  24. Yoshida M, Ma J, Tomita T, Morikawa N, Tanaka N, Masamura K, Kawai Y, Miyamori I. Mineralocorticoid receptor is overexpressed in cardiomyocytes of patients with congestive heart failure. Congest Heart Fail. 2005; 11: 12–16.[CrossRef][Medline] [Order article via Infotrieve]
  25. Hersel J, Jung S, Mohacsi P, Hullin R. Expression of the L-type calcium channel in human heart failure. Basic Res Cardiol. 2002; 97 (suppl 1): I4–I10.[Medline] [Order article via Infotrieve]
  26. Lalevee N, Rebsamen MC, Barrere-Lemaire S, Perrier E, Nargeot J, Bénitah JP, Rossier MF. Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc Res. 2005; 67: 216–224.[Abstract/Free Full Text]
  27. Perrier E, Kerfant BG, Lalevee N, Bideaux P, Rossier MF, Richard S, Gómez AM, Benitah JP. Mineralocorticoid receptor antagonism prevents the electrical remodeling that precedes cellular hypertrophy after myocardial infarction. Circulation. 2004; 110: 776–783.[Abstract/Free Full Text]
  28. Zhou S, Cao JM, Ohara T, KenKnight BH, Chen LS, Karagueuzian HS, Chen PS. Torsade de pointes and sudden death induced by thiopental and isoflurane anesthesia in dogs with cardiac electrical remodeling. J Cardiovasc Pharmacol Ther. 2002; 7: 39–43.[Abstract/Free Full Text]
  29. Chen PS, Chen LS, Cao JM, Sharifi B, Karagueuzian HS, Fishbein MC. Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death. Cardiovasc Res. 2001; 50: 409–416.[Abstract/Free Full Text]
  30. Shroff SC, Ryu K, Martovitz NL, Hoit BD, Stambler BS. Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure. J Cardiovasc Electrophysiol. 2006; 17: 534–541.[CrossRef][Medline] [Order article via Infotrieve]
  31. Boixel C, Gavillet B, Rougier JS, Abriel H. Aldosterone increases voltage-gated sodium current in ventricular myocytes. Am J Physiol Heart Circ Physiol. 2006; 290: H2257–H2266.[Abstract/Free Full Text]
  32. Healey JS, Morillo CA, Connolly SJ. Role of the renin-angiotensin-aldosterone system in atrial fibrillation and cardiac remodeling. Curr Opin Cardiol. 2005; 20: 31–37.[Medline] [Order article via Infotrieve]
  33. Benitah JP, Vassort G. Aldosterone upregulates Ca(2+) current in adult rat cardiomyocytes. Circ Res. 1999; 85: 1139–1145.[Abstract/Free Full Text]
  34. Nishiyama A, Yao L, Nagai Y, Miyata K, Yoshizumi M, Kagami S, Kondo S, Kiyomoto H, Shokoji T, Kimura S, Kohno M, Abe Y. Possible contributions of reactive oxygen species and mitogen-activated protein kinase to renal injury in aldosterone/salt-induced hypertensive rats. Hypertension. 2004; 43: 841–848.[Abstract/Free Full Text]
  35. Rude MK, Duhaney TA, Kuster GM, Judge S, Heo J, Colucci WS, Siwik DA, Sam F. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension. 2005; 46: 555–561.[Abstract/Free Full Text]
  36. Liu SL, Schmuck S, Chorazcyzewski JZ, Gros R, Feldman RD. Aldosterone regulates vascular reactivity: short-term effects mediated by phosphatidylinositol 3-kinase-dependent nitric oxide synthase activation. Circulation. 2003; 108: 2400–2406.[Abstract/Free Full Text]
  37. Thai HM, Do BQ, Tran TD, Gaballa MA, Goldman S. Aldosterone antagonism improves endothelial-dependent vasorelaxation in heart failure via upregulation of endothelial nitric oxide synthase production. J Card Fail. 2006; 12: 240–245.[CrossRef][Medline] [Order article via Infotrieve]
  38. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003; 108: 1831–1838.[Abstract/Free Full Text]
  39. Packer M. Potential role of potassium as a determinant of morbidity and mortality in patients with systemic hypertension and congestive heart failure. Am J Cardiol. 1990; 65: 45E–51E; discussion 52E.[CrossRef][Medline] [Order article via Infotrieve]
  40. Macdonald JE, Struthers AD. What is the optimal serum potassium level in cardiovascular patients? J Am Coll Cardiol. 2004; 43: 155–161.[Abstract/Free Full Text]
  41. Srivastava TN, Young DB. Impairment of cardiac function by moderate potassium depletion. J Card Fail. 1995; 1: 195–200.[CrossRef][Medline] [Order article via Infotrieve]
  42. Ahmed A, Zannad F, Love TE, Tallaj J, Gheorghiade M, Ekundayo OJ, Pitt B. A propensity matched study of the association of low serum potassium levels and mortality in chronic heart failure. Eur Heart J. 2007; 28: 1334–1143.[Abstract/Free Full Text]

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