help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0393
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
92/7/2552    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joffe, H. V.
Right arrow Articles by Adler, G. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joffe, H. V.
Right arrow Articles by Adler, G. K.
Related Collections
Right arrow Cardiovascular Endocrinology
Right arrow Diabetes and Insulin
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2552-2558
Copyright © 2007 by The Endocrine Society

Beneficial Effects of Eplerenone Versus Hydrochlorothiazide on Coronary Circulatory Function in Patients with Diabetes Mellitus

Hylton V. Joffe, Raymond Y. Kwong, Marie D. Gerhard-Herman, Caitlin Rice, Kathryn Feldman and Gail K. Adler

Division of Endocrinology, Diabetes, and Hypertension (H.V.J., C.R., K.F., G.K.A.) and Cardiovascular Division (R.Y.K., M.D.G.-H.), Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gail K. Adler, M.D., Ph.D., Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: gadler{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Impaired coronary circulatory function predicts cardiovascular events, the leading cause of death in patients with diabetes mellitus. Aldosterone causes cardiovascular injury and is not suppressed by chronic angiotensin converting enzyme (ACE) inhibitor therapy.

Objective: Our objective was to assess whether mineralocorticoid receptor activation contributes to coronary circulatory dysfunction in patients with diabetes who are already receiving ACE inhibitor therapy.

Design and Setting: A randomized, double-blind, crossover study with an intervening washout period of at least 4 wk was conducted with ambulatory patients from the community.

Patients: Patients included 16 subjects (11 men, eight Caucasians; mean age, 53 yr; mean body mass index, 38.0 kg/m2) with diabetes and albuminuria but without clinical cardiovascular disease.

Interventions: ACE inhibitors were switched to enalapril 20 mg daily, and other antihypertensives were discontinued. Amlodipine 5–10 mg daily was added to achieve blood pressures less than 130/80 mm Hg. Subjects then received, in random order, 6 wk of the mineralocorticoid receptor antagonist eplerenone 50 mg (with placebo pill) daily and 6 wk of another diuretic, hydrochlorothiazide 12.5 mg (with potassium 10 mEq) daily.

Main Outcome Measures: Before and after each 6-wk treatment period, we measured coronary circulatory function (adenosine-stimulated myocardial perfusion reserve) and endothelial function (brachial artery reactivity and peripheral arterial tonometry).

Results: The eplerenone and hydrochlorothiazide groups had similar blood pressures, serum potassium, glycemia, and endothelial function. Although pretreatment myocardial perfusion reserve did not differ between groups, myocardial perfusion reserve was significantly higher after eplerenone than after hydrochlorothiazide (median 1.57 vs. 1.30; P = 0.03).

Conclusions: Mineralocorticoid receptor blockade improves coronary circulatory function compared with hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CORONARY CIRCULATORY FUNCTION is impaired in patients with type 1 and type 2 diabetes mellitus (1, 2), precedes clinically overt heart disease (2, 3), and independently predicts acute cardiovascular events (4), the leading cause of death in patients with diabetes (5). The angiotensin converting enzyme (ACE) inhibitor perindoprilat acutely improves myocardial perfusion in patients with diabetes and left ventricular (LV) hypertrophy, suggesting that an activated renin-angiotensin-aldosterone system may have detrimental effects on coronary circulatory function in patients with diabetes (6). In contrast, mineralocorticoid receptor (MR) blockade has been shown to impair endothelial function in individuals with type 2 diabetes (7), raising the question as to whether MR antagonists have beneficial or adverse effects on vascular function in diabetes and whether these effects differ depending on the vascular bed under study.

Furthermore, ACE inhibitors do not chronically suppress aldosterone concentrations (8, 9, 10). In patients with heart failure already receiving ACE inhibitor therapy, the addition of an MR antagonist substantially reduces cardiac morbidity and mortality (11, 12). Similarly, combination therapy with an ACE inhibitor and MR antagonist more effectively reduces LV hypertrophy (13) and diabetic albuminuria (14) than ACE inhibitor monotherapy despite similar reductions in blood pressure between the combination therapy and monotherapy groups.

Based on these observations, we hypothesized that MR activation contributes to coronary circulatory dysfunction in patients with diabetes already receiving ACE inhibitor therapy.

Therefore, we performed a randomized, double-blind, crossover, proof-of-concept study comparing the effects of eplerenone, an MR antagonist, vs. another diuretic, hydrochlorothiazide (HCTZ) on vascular function in subjects with diabetes already receiving ACE inhibitor therapy. We used cardiac magnetic resonance imaging (CMR) to assess changes in adenosine-stimulated myocardial perfusion reserve (coronary circulatory function), proteinuria to assess renovascular function, and brachial artery reactivity and peripheral arterial tonometry (PAT) to assess endothelial function in peripheral blood vessels.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient population

We recruited 21- to 64-yr-old subjects with diabetes. To increase the likelihood that these subjects would have coronary circulatory dysfunction, we required the presence of albuminuria (albumin-to-creatinine ratio ≥ 30 mg/g on two occasions). Exclusion criteria included serum creatinine more than 1.5 mg/dl (>132.6 µmol/liter), clinical evidence of cardiac or cerebrovascular disease, severe peripheral vascular disease, poorly controlled hypertension, contraindications to CMR or adenosine, cigarette smoking, and pregnancy. The Institutional Review Board at Brigham and Women’s Hospital (Boston, MA) approved the study protocol, and all subjects provided written, informed consent. Studies were performed in the General Clinical Research Center.

Study protocol

This randomized, double-blind, crossover study compared the effects of 6 wk of eplerenone 50 mg plus placebo pill daily vs. HCTZ 12.5 mg plus potassium chloride 10 mEq daily on measures of vascular function in subjects with diabetes receiving enalapril 20 mg daily. Subjects not on ACE inhibitor or angiotensin receptor blocker (ARB) therapy at enrollment were started on enalapril 20 mg daily 3 months before the first vascular studies (decreases in aldosterone concentrations after initiation of ACE inhibitor therapy usually reverse within 3 months) (10). All other subjects were switched to enalapril 20 mg daily 4 wk before the first vascular studies. Other antihypertensives were discontinued 2–4 wk before the first vascular studies and amlodipine 5–10 mg daily was initiated for blood pressures higher than 130/80 mm Hg (15). During the run-in period, we adjusted hypoglycemic agents to achieve fasting and preprandial blood glucose to less than 150 mg/dl (<8.3 mmol/liter; approximates hemoglobin A1C of <7%) (16).

We monitored potassium (baseline, d 2, and wk 1, 2, 4, and 6) and blood pressure (baseline and wk 2, 4, and 5.5) during each 6-wk treatment period. Blood pressure was measured using a manual cuff (three readings five min apart) after the subject was seated for 20 min. After the first 6-wk treatment period, subjects entered a washout period of at least 4 wk (median, 34 d; range, 28–95 d due to scheduling conflicts) during which time study medications were discontinued except for enalapril and amlodipine. Subjects then received the alternate treatment for 6 wk.

Vascular studies were performed at the beginning and end of each 6-wk treatment period. For 3 d before vascular testing, subjects consumed an isocaloric diet (50–60% of calories from carbohydrates) containing 200 ± 10 mmol/d sodium, 100 ± 10 mmol/d potassium, 1000 ± 50 mg/d calcium, and 300 ± 50 mg/d magnesium. A 24-h urine sample was collected on each vascular study day for volume, sodium, potassium, protein, and creatinine. Subjects withheld amlodipine for 48 h, avoided caffeine for 24 h, and fasted for at least 8 h before testing. Subjects withheld oral hypoglycemic agents, fast-acting insulin (except for one subject with type 1 diabetes using an insulin pump), long-acting insulin (except for the two other subjects with type 1 diabetes), antioxidants, and multivitamins on the morning of the vascular studies.

On each vascular study day, we obtained two Dynamap blood pressure measurements 10 min apart after subjects were supine for 10 min. An indwelling iv catheter was placed, and subjects lay supine for an additional 45 min before collecting blood for chemistries, hemoglobin A1C, fructosamine, serum aldosterone, and plasma renin activity. Brachial artery reactivity and PAT testing were performed first, followed by CMR. Blood glucose measurements were obtained before ultrasound and CMR testing. No subject required fast-acting insulin for preprocedure hyperglycemia.

Myocardial perfusion reserve

We used CMR to quantify myocardial blood flow (MBF) at rest and during maximal vasodilation with adenosine. We calculated myocardial perfusion reserve by dividing MBF during vasodilation by MBF at rest (17, 18, 19). CMR quantification of MBF correlates well with radioisotope-labeled microspheres in animals (r = 0.99) and intracoronary Doppler measurements in humans (r = 0.84) (17, 18).

We performed CMR examinations with subjects supine in a 1.5-Tesla scanner (General Electric Healthcare, Milwaukee, WI; Signa CV/i) with electrocardiogram gating and an eight-element phase-array surface coil. We used a saturation-prepared fast gradient echo perfusion technique (TR 6.8, TE 2.1, echo-train 4, matrix 128 x 96; FOV = 32 cm) to capture first-pass MBF kinetics. We acquired MBF data during a breath hold of 20–30 sec. During image acquisition, we infused gadolinium-diethylenetriamine pentaacetic acid (DTPA) (Magnevist; Berlex Pharmaceuticals, Wayne, NJ) via a peripheral vein (0.05 mmol/kg at 5 ml/sec followed by a 20-ml saline flush at 5 ml/sec). One image per cardiac cycle was used to maintain adequate temporal resolution of myocardial perfusion imaging at rest and during vasodilation. Myocardial perfusion imaging covering three short-axis locations were acquired after 4 min of adenosine infusion (140 mg/kg·min) and repeated at rest 15 min later in matching locations.

The dose of gadolinium was chosen based on existing literature (20, 21) and from phantom experiments using our current first-pass perfusion sequence demonstrating signal saturation at gadolinium concentrations of at least 4 mmol/liter. In large animal experiments, a peak change of approximately 15 sec–1 in the T1 relaxation rate ({Delta}R1, where {Delta}R1 = 1/{Delta}T1) of the LV cavity occurred during a first-pass bolus of 0.05 mmol/kg gadolinium (21). With a gadolinium-DTPA r1 relaxivity of 4.45 mmol–1 sec–1, we calculated a peak contrast concentration of 3.37 mmol/liter in the LV blood. In human experiments, this concentration is expected to be slightly lower due to a higher volume of first-pass distribution in the LV and contrast extraction from the pulmonary circulation. Therefore, a 0.05 mmol/kg iv gadolinium-DTPA bolus injection is appropriate for blood flow assessment in the LV cavity.

An investigator blinded to treatment assignment used dedicated software (CineTool, GE Healthcare, version 3.9.1) to analyze CMR data according to validated methodology (19, 22). LV endocardial and epicardial borders were manually mapped as circles. Careful positioning of the tracing at the endocardial border excluded high signal from the blood, which would falsely elevate MBF results. LV myocardium confined between endocardial and epicardial circles was divided into three radial segments by the centerline method. These segments represent the region of myocardium supplied by the major coronary arteries (left anterior descending, left circumflex, and right coronary arteries) according to the American College of Cardiology/American Heart Association myocardial segment model (23). These regions of interest were copied and pasted into all images across different time points to capture MBF in each segment during first-pass transit of the contrast bolus. Image motion due to breathing was manually corrected using landmarks such as endocardial borders to ensure proper alignment of the myocardial segments and the regions of interest. We used a validated Fermi-function deconvolution model (19) to quantify regional and global MBF in milliliters per minute per gram of LV mass. For all experimental data (including the arterial input function curve), the mean value of the baseline signal before appearance of the contrast agent in the LV blood pool was subtracted from all signal vs. time curves. We did not correct for surface coil intensity because the myocardial perfusion reserve calculation canceled out the heterogeneous effect from surface coil placement. The slight delay between myocardial and LV arterial input signal-time curves was adjusted by shifting the LV arterial input function to the right.

Brachial artery reactivity and peripheral arterial tonometry

The brachial artery was imaged in the longitudinal plane with high-resolution ultrasonography (Toshiba Power Vision 8000) equipped with a 7.5-MHz linear array probe using well-validated techniques (24). Pulse wave amplitude was measured with a finger plethysmograph (Itamar-Medical Ltd., Caesarea, Israel), which quantifies pulsatile blood volume changes (25).

Studies were performed in a quiet, temperature-controlled room after subjects rested supine for 10 min. Arterial inflow was occluded to induce reactive hyperemia by inflating a blood pressure cuff placed on the upper arm to at least 50 mm Hg above systolic pressure for 5 min. Images obtained 1 min after cuff release corresponded to the period of maximal endothelium-dependent vasodilation. Ten or more minutes later, rest measures were repeated, and subjects with systolic blood pressure higher than 100 mm Hg and heart rate more than 60 beats/min received 0.3 mg sublingual nitroglycerin. The brachial artery was reimaged 3 min later.

Two independent investigators blinded to subject characteristics analyzed the brachial arterial diameter with edge detection software (Medical Imaging Applications, Coralville, IA). Flow-mediated (endothelium-dependent) vasodilation (FMD) is the percent change in arterial diameter from baseline to reactive hyperemia. Nitroglycerin-mediated (endothelium-independent) vasodilation is the percent change in arterial diameter from second baseline to post-nitroglycerin administration. PAT hyperemia ratio is defined as the ratio of pulse wave amplitude during reactive hyperemia to baseline. PAT data from the study arm were normalized to data obtained from the control arm.

Blood and urine assays

Serum aldosterone was measured with the solid-phase RIA Coat-A-Count procedure (Diagnostic Products Corp., Los Angeles, CA). Plasma renin activity was assayed with the GammaCoat 125I RIA kit (DiaSorin, Stillwater, MN) that measures the generation of angiotensin I. Hemoglobin A1C was measured by HPLC using the Tosoh G7 analyzer (Tosoh Medics Inc., San Francisco, CA). The fructosamine assay was performed on a Roche Modular Analytics P (Hitachi, Japan). Urinary sodium levels were determined with flame photometry with lithium as an internal standard (Nova Biomedical, Waltham, MA). Urinary creatinine levels were assayed with the ACE creatinine reagent (Alfa Wasserman, West Caldwell, NJ). Urine creatinine, protein, and microalbumin were assayed on an Olympus analyzer (Olympus America Inc., Melville, NY).

Statistical analyses

The primary endpoint for our study was the posttreatment analysis of total LV myocardial perfusion reserve. During the design of our protocol, we performed CMR power calculations based on data from a report of myocardial perfusion reserve in patients with microvascular dysfunction without significant coronary lesions (17). These patients had a mean myocardial perfusion reserve of 2.14 (SD 0.57). Assuming a conservative improvement of 25% and {alpha} = 0.05, we determined that 11 subjects would be needed for 80% power.

The power analysis calculations for brachial artery reactivity studies have been extensively reviewed (26). For a crossover trial, 10 subjects are required for 80% power at {alpha} = 0.05, assuming a conservative improvement of 2.5%.

We describe the continuous data using means with SD or medians with interquartile ranges. Variables collected during the two treatment periods were compared with the Wilcoxon signed rank test (continuous data) and Fisher’s exact test (proportions). All analyses were performed using Stata 8.0 (StataCorp, College Station, TX), and a two-sided P value of ≤0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Subject characteristics

Sixteen subjects completed the study protocol (Table 1Go). CMR data were incomplete in four subjects due to technical issues (n = 3) or MRI intolerance (n = 1). Nitroglycerin-mediated vasodilation was not performed in one subject because of low-normal blood pressures. PAT was performed in 11 subjects (PAT was introduced several months after study initiation). Five additional subjects withdrew from the study before the second treatment period and are not included in any of the analyses; three withdrew due to other commitments, and two (both received HCTZ) withdrew due to medical issues (recurrent depression and new-onset atrial fibrillation).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Subject characteristics at the time of enrollment

 
Participant characteristics during the treatment periods

Eight subjects received eplerenone as the first treatment. Eleven subjects required amlodipine (10 mg in seven subjects and 5 mg in four subjects) in addition to enalapril for blood pressure control. There were no differences between the eplerenone and HCTZ groups with respect to pretreatment and posttreatment body mass index, serum sodium, serum creatinine, total cholesterol, high-density lipoprotein cholesterol, and urinary sodium, and neither therapy significantly altered any of these characteristics (Table 2Go). Posttreatment serum triglycerides were lower in the eplerenone group than in the HCTZ group (Table 2Go).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Subject characteristics (n = 16) on the initial study day and after 6 wk of treatment with eplerenone vs. HCTZ

 
Blood pressure

Blood pressures trended downwards over both treatment periods [with eplerenone, systolic decreased from 130 ± 16 to 123 ± 11 mm Hg (P = 0.09) and diastolic from 76 ± 9 to 70 ± 8 mm Hg (P = 0.03); with HCTZ, systolic decreased from 132 ± 22 to 125 ± 19 mm Hg (P = 0.23) and diastolic from 76 ± 11 to 73 ± 9 mm Hg (P = 0.27)]. However, blood pressures measured during eplerenone treatment did not differ from those obtained at corresponding time points during HCTZ treatment (Table 2Go).

Serum potassium

Serum potassium concentrations were similar during HCTZ and eplerenone treatment (Table 2Go). Nine serum potassium measurements exceeded 5.0 mmol/liter (five with eplerenone and four with HCTZ). Two values exceeded 5.5 mmol/liter (5.7 and 5.6 mmol/liter with eplerenone and HCTZ, respectively); both were less than 5.5 mmol/liter on repeat. There was no dose reduction, discontinuation, or unblinding because of hyperkalemia.

Glycemic control

On vascular testing days, we measured hemoglobin A1C, fructosamine, and preprocedure blood glucose to assess chronic, subacute, and acute glycemic control, respectively. None of these measures differed between the eplerenone and HCTZ groups (Table 2Go).

Proteinuria

There were no differences between the eplerenone and HCTZ groups with respect to pretreatment and posttreatment 24-h proteinuria, and neither therapy significantly altered proteinuria (Table 2Go).

Vascular function

Adenosine-stimulated myocardial perfusion reserve. None of the patients had CMR perfusion defects suggestive of occlusive coronary artery disease (CAD). Pretreatment myocardial perfusion reserve was similar before initiation of eplerenone and HCTZ (P = 0.96). After treatment, total LV myocardial perfusion reserve was significantly higher with eplerenone than with HCTZ (median 1.57 vs. 1.30; P = 0.03) (Table 3Go and Fig. 1Go). Nine (75%) subjects had higher myocardial perfusion reserve with eplerenone than with HCTZ (Fig. 2Go). These results retain statistical significance even after excluding the one potential outlier with a post-eplerenone myocardial perfusion reserve of 4.31 (P = 0.05). When compared with the first study day values, there was a trend (P = 0.09) toward improvement in total LV myocardial perfusion reserve with eplerenone and no change (P = 0.72) with HCTZ. Similar results were obtained when the three coronary territories were evaluated separately (Table 3Go).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Vascular function on the initial study day and after 6 wk of treatment with eplerenone vs. HCTZ

 

Figure 1
View larger version (14K):
[in this window]
[in a new window]

  		FIG. 1. Effects of eplerenone vs. HCTZ on coronary circulatory function of the left ventricle. Summary data shows myocardial perfusion reserve (ratio of adenosine-stimulated to rest myocardial blood flow through the left ventricle) measured at the beginning and end of each 6-wk treatment period with eplerenone and HCTZ. The box plot represents 25–75th percentiles; line within box represents median; whiskers indicate 10th and 90th percentiles; circles show outliers.

 

Figure 2
View larger version (18K):
[in this window]
[in a new window]

  		FIG. 2. Myocardial perfusion reserve for individual subjects measured at the end of HCTZ and eplerenone treatments. Median value and interquartile ranges for each treatment are displayed to the side of the individual values.

 
Peripheral measures of vascular function. The eplerenone and HCTZ groups had comparable pretreatment FMD (P = 0.35), nitroglycerin-mediated vasodilation of the brachial artery (P = 0.50), and PAT hyperemia ratios (P = 0.14). On the last day of treatment, there were no differences between the eplerenone and HCTZ groups with regard to these peripheral measures of vascular function (Table 3Go). Furthermore, there were no statistically significant correlations between myocardial perfusion reserve and any of the peripheral measures of vascular function on any of the four study days (P = 0.10–0.89).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Patients with diabetes have impaired coronary circulatory function (2, 3). In this proof-of-concept study, short-term treatment with eplerenone resulted in better coronary circulatory function than did HCTZ in subjects with diabetes and albuminuria already receiving ACE inhibitor therapy.

This finding is most likely related to study medication because the two treatments resulted in similar blood pressures, serum potassium concentrations, and glycemic control. We chose HCTZ as the active control because this medication is considered inexpensive, first-line antihypertensive therapy for most patients (27). Furthermore, HCTZ has no known direct effects on the structure of small arteries or forearm vasoreactivity (28, 29).

In a cross-sectional study of adults without clinical CAD, the mean myocardial perfusion reserve assessed by CMR was 3.08 in subjects without diabetes and 2.82 in subjects with diabetes (30). The lower myocardial perfusion reserve in our subjects may be related to more severe microvascular disease (our subjects were required to have albuminuria, a marker of microvascular injury). None of our subjects had evidence of occlusive CAD based on clinical history and absence of perfusion defects during stress CMR. Of note, two subjects achieved myocardial perfusion reserve in the nondiabetic range after treatment with eplerenone.

A few studies have evaluated the effects of medications on coronary vasomotor function in patients with diabetes. Neither pravastatin nor pioglitazone improved coronary circulatory function in this patient population (31, 32). In normotensive subjects with diabetes and LV hypertrophy, iv perindoprilat (ACE inhibitor) acutely improved dipyridamole-stimulated myocardial perfusion reserve (6). Our study extends these results. We demonstrated beneficial effects of MR blockade on coronary circulatory function in subjects with diabetes above and beyond potential effects of ACE inhibitor therapy.

Data from human (11, 12, 13, 33, 34) and animal (35) studies support adverse cardiovascular effects of aldosterone and suggest a beneficial effect of MR blockade. In healthy volunteers, a 4-h aldosterone infusion induces endothelial dysfunction (34). In heart failure, combination MR antagonist and ACE inhibitor therapy improves endothelial function within 4 wk; long-term coadministration improves cardiac morbidity and mortality (11, 12, 33). In essential hypertension, combination MR antagonist and ACE inhibitor therapy more effectively reduces LV hypertrophy than monotherapy with either agent alone, effects not fully explained by changes in blood pressure (13).

In contrast to the beneficial effect of eplerenone on myocardial perfusion reserve, we did not detect changes in endothelial function using brachial artery reactivity or PAT despite more than 80% power for detecting a conservative improvement of 2.5% with the former technique (26). Therefore, in patients with type 2 diabetes and albuminuria, endothelial function in the forearm does not appear to reflect endothelial function in the coronary bed. Similar discrepancies between myocardial perfusion reserve and peripheral endothelial function (using different techniques) have been reported in various patient populations (36, 37, 38). In the current study, these disparate results may reflect a preferential effect of MR blockade on the coronary circulation. Alternatively, these findings may be related to differences in the mechanism of vasodilation between CMR and the peripheral tests (adenosine has direct effects on vascular smooth muscle; FMD involves shear stress-mediated production of endothelium-derived nitric oxide).

Our brachial artery reactivity results are not consistent with a report showing impaired endothelial function with spironolactone in patients with type 2 diabetes (7). However, spironolactone was administered for only 4 wk, and there was worsening glycemic control, which may have confounded the results.

We did not detect an effect of our interventions on proteinuria. In contrast, a few studies (14, 39) have shown that an MR antagonist plus ACE inhibitor more effectively reduces proteinuria than either therapy alone in patients with diabetic nephropathy. However, these studies enrolled patients with greater proteinuria, used higher doses of the MR antagonist, or treated patients longer. Perhaps different vascular beds have different sensitivities or response times to MR blockade. Any of these factors in addition to a potential lack of statistical power may explain our proteinuria results.

Although there is a risk of hyperkalemia with combination ACE inhibitor and MR antagonist therapy (40), none of our patients required dose reduction or study discontinuation because of hyperkalemia. The absence of significant hyperkalemia is likely due to the low dose of eplerenone and the discriminating selection of patients with relatively preserved renal function. Epstein et al. (14) also noted no increase in the risk of hyperkalemia with the addition of eplerenone 50 mg daily to enalapril 20 mg daily in patients with type 2 diabetes and good renal function.

Strengths of our study include the randomized, double-blind design with control of confounders (blood pressure, potassium, and glycemia) and the use of each subject as his/her own control. Potential limitations include the short duration of treatment and carryover of medication across treatment periods, although a formal statistical test for carryover was not significant. Because HCTZ has minimal, if any, direct effects on artery structure and function (28, 29), carryover effects from eplerenone into the HCTZ treatment period would be expected to improve the HCTZ results, which would minimize observed differences between groups, and potentially bias our results toward the null hypothesis. We did not assess vascular effects of eplerenone in the absence of background ACE inhibitor therapy or in individuals with clinical evidence of CAD, and the sample size limits conclusions across specific subpopulations. However, there were improvements in myocardial perfusion reserve with eplerenone in men and women, in patients with type 1 and type 2 diabetes, and in those who did and did not use statins. Our study was not designed to assess whether the vascular findings were driven mostly by improvements in vessel function, structure, or both. Finally, our findings could be due to differences in triglyceride concentrations between the two treatments, although this is unlikely because serum triglycerides did not correlate with myocardial perfusion reserve (data not shown).

In conclusion, we have shown that compared with HCTZ, short-term treatment with eplerenone improves coronary circulatory function in patients with diabetes and albuminuria who are already receiving ACE inhibitor therapy. This pilot, proof-of-concept study suggests that the MR is involved in the pathophysiology of impaired myocardial perfusion reserve in diabetes and that MR blockade is a better choice than HCTZ for improving coronary circulatory function in these patients. Future studies should confirm and extend these preliminary findings.


   Footnotes
 
This work was supported by National Institutes of Health funds from P30DK36836 through the Joslin Diabetes and Endocrinology Research Center Pilot and Feasibility Program, GCRC M01-RR-02635 and T32HL07609.

Disclosure Summary: The authors have nothing to disclose.

First Published Online May 8, 2007

Abbreviations: ACE, Angiotensin converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CMR, cardiac magnetic resonance imaging; DTPA, diethylenetriamine pentaacetic acid; FMD, flow-mediated vasodilation; HCTZ, hydrochlorothiazide; LV, left ventricular; MBF, myocardial blood flow; MR, mineralocorticoid receptor; PAT, peripheral arterial tonometry.

Received February 20, 2007.

Accepted April 27, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Prior JO, Quinones MJ, Hernandez-Pampaloni M, Facta AD, Schindler TH, Sayre JW, Hsueh WA, Schelbert HR 2005 Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation 111:2291–2298[Abstract/Free Full Text]
  2. Pitkanen OP, Nuutila P, Raitakari OT, Ronnemaa T, Koskinen PJ, Iida H, Lehtimaki TJ, Laine HK, Takala T, Viikari JS, Knuuti J 1998 Coronary flow reserve is reduced in young men with IDDM. Diabetes 47:248–254[Abstract]
  3. Yokoyama I, Momomura S, Ohtake T, Yonekura K, Nishikawa J, Sasaki Y, Omata M 1997 Reduced myocardial flow reserve in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 30:1472–1477[Abstract]
  4. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA 2002 Prognostic value of coronary vascular endothelial dysfunction. Circulation 106:653–658[Abstract/Free Full Text]
  5. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M 1998 Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339:229–234[Abstract/Free Full Text]
  6. Hesse B, Meyer C, Nielsen FS, Sato A, Hove JD, Holm S, Bang LE, Kofoed KF, Svendsen TL, Parving HH, Opie LH 2004 Myocardial perfusion in type 2 diabetes with left ventricular hypertrophy: normalisation by acute angiotensin-converting enzyme inhibition. Eur J Nucl Med Mol Imaging 31:362–368[CrossRef][Medline]
  7. Davies JI, Band M, Morris A, Struthers AD 2004 Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia 47:1687–1694[CrossRef][Medline]
  8. Sato A, Saruta T 2001 Aldosterone escape during angiotensin-converting enzyme inhibitor therapy in essential hypertensive patients with left ventricular hypertrophy. J Int Med Res 29:13–21[Medline]
  9. Sato A, Hayashi K, Naruse M, Saruta T 2003 Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension 41:64–68[Abstract/Free Full Text]
  10. Sato A, Saruta T 2003 Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am J Hypertens 16:781–788[CrossRef][Medline]
  11. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J 1999 The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 341:709–717[Abstract/Free Full Text]
  12. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M 2003 Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348:1309–1321[Abstract/Free Full Text]
  13. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns D, Williams GH 2003 Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 108:1831–1838[Abstract/Free Full Text]
  14. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B 2006 Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol 1:940–951[CrossRef][Medline]
  15. 2006 Standards of medical care in diabetes. Diabetes Care 29:S4–S42
  16. Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM, Sacks DB 2004 Tests of glycemia in diabetes. Diabetes Care 27:1761–1773[Free Full Text]
  17. Jerosch-Herold M, Wilke N, Stillman AE 1998 Magnetic resonance quantification of the myocardial perfusion reserve with a Fermi function model for constrained deconvolution. Med Phys 25:73–84[CrossRef][Medline]
  18. Jerosch-Herold M, Swingen C, Seethamraju RT 2002 Myocardial blood flow quantification with MRI by model-independent deconvolution. Med Phys 29:886–897[CrossRef][Medline]
  19. Jerosch-Herold M, Seethamraju RT, Swingen CM, Wilke NM, Stillman AE 2004 Analysis of myocardial perfusion MRI. J Magn Reson Imaging 19:758–770[CrossRef][Medline]
  20. Al-Saadi N, Nagel E, Gross M, Bornstedt A, Schnackenburg B, Klein C, Klimek W, Oswald H, Fleck E 2000 Noninvasive detection of myocardial ischemia from perfusion reserve based on cardiovascular magnetic resonance. Circulation 101:1379–1383[Abstract/Free Full Text]
  21. McKenzie CA, Pereira RS, Prato FS, Chen Z, Drost DJ 1999 Improved contrast agent bolus tracking using T1 FARM. Magn Reson Med 41:429–435[CrossRef][Medline]
  22. Selvanayagam JB, Jerosch-Herold M, Porto I, Sheridan D, Cheng AS, Petersen SE, Searle N, Channon KM, Banning AP, Neubauer S 2005 Resting myocardial blood flow is impaired in hibernating myocardium: a magnetic resonance study of quantitative perfusion assessment. Circulation 112:3289–3296[Abstract/Free Full Text]
  23. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS 2002 Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 105:539–542[Free Full Text]
  24. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R 2002 Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39:257–265[Abstract/Free Full Text]
  25. Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A 2004 Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 44:2137–2141[Abstract/Free Full Text]
  26. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Thomas O, Deanfield JE 1995 Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 74:247–253[Abstract/Free Full Text]
  27. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ 2003 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 289:2560–2572[Abstract/Free Full Text]
  28. Pickkers P, Russel FG, Hughes AD, Thien T, Smits P 1995 Hydrochlorothiazide exerts no direct vasoactivity in the human forearm. J Hypertens 13:1833–1836[Medline]
  29. Sihm I, Schroeder AP, Aalkjaer C, Mulvany MJ, Thygesen K, Lederballe O 1998 Effect of antihypertensive treatment on cardiac and subcutaneous artery structure: a comparison between calcium channel blocker and thiazide-based regimens. Am J Hypertens 11:263–271[CrossRef][Medline]
  30. Wang L, Jerosch-Herold M, Jacobs Jr DR, Shahar E, Folsom AR 2006 Coronary risk factors and myocardial perfusion in asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 47:565–572[Abstract/Free Full Text]
  31. Janatuinen T, Knuuti J, Toikka JO, Ahotupa M, Nuutila P, Ronnemaa T, Raitakari OT 2004 Effect of pravastatin on low-density lipoprotein oxidation and myocardial perfusion in young adults with type 1 diabetes. Arterioscler Thromb Vasc Biol 24:1303–1308[Abstract/Free Full Text]
  32. McMahon GT, Plutzky J, Daher E, Bhattacharyya T, Grunberger G, DiCarli MF 2005 Effect of a peroxisome proliferator-activated receptor-{gamma} agonist on myocardial blood flow in type 2 diabetes. Diabetes Care 28:1145–1150[Abstract/Free Full Text]
  33. Farquharson CA, Struthers AD 2000 Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 101:594–597[Abstract/Free Full Text]
  34. Farquharson CA, Struthers AD 2002 Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond) 103:425–431[Medline]
  35. Joffe HV, Adler GK 2005 Effect of aldosterone and mineralocorticoid receptor blockade on vascular inflammation. Heart Fail Rev 10:31–37[CrossRef][Medline]
  36. Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT, Sorensen K 2001 Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation 103:1109–1114[Abstract/Free Full Text]
  37. Kalliokoski RJ, Kalliokoski KK, Sundell J, Engblom E, Penttinen M, Kantola I, Raitakari OT, Knuuti J, Nuutila P 2005 Impaired myocardial perfusion reserve but preserved peripheral endothelial function in patients with Fabry disease. J Inherit Metab Dis 28:563–573[CrossRef][Medline]
  38. Stolen KQ, Kemppainen J, Kalliokoski KK, Karanko H, Toikka J, Janatuinen T, Raitakari OT, Airaksinen KE, Nuutila P, Knuuti J 2004 Myocardial perfusion reserve and peripheral endothelial function in patients with idiopathic dilated cardiomyopathy. Am J Cardiol 93:64–68[Medline]
  39. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH 2005 Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care 28:2106–2112[Abstract/Free Full Text]
  40. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA 2004 Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 351:543–551[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 CirculationHome page
C. Guo, V. Ricchiuti, B. Q. Lian, T. M. Yao, P. Coutinho, J. R. Romero, J. Li, G. H. Williams, and G. K. Adler
Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, Peroxisome Proliferator-Activated Receptor-{gamma}, and Proinflammatory Adipokines
Circulation, April 29, 2008; 117(17): 2253 - 2261.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
92/7/2552    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Joffe, H. V.
Right arrow Articles by Adler, G. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Joffe, H. V.
Right arrow Articles by Adler, G. K.
Related Collections
Right arrow Cardiovascular Endocrinology
Right arrow Diabetes and Insulin

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals