Mineralocorticoid Accelerates Transition to Heart Failure With Preserved Ejection Fraction Via “Nongenomic Effects”
Background— Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-β hydroxysteroid dehydrogenase, salt-mineralocorticoid–induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction.
Methods and Results— Cardiac structure and function, oxidative stress, and mineralocorticoid receptor–dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor–dependent gene transcription.
Conclusions— Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor–dependent gene transcription.
- deoxycorticosterone acetate
- ventricular ejection fraction
- heart failure
Received October 13, 2009; accepted May 19, 2010.
Heart failure (HF) with preserved ejection fraction (HFpEF) makes up nearly 50% of HF, and so far, no effective therapy exists.1 Hypertensive heart disease is a prominent risk factor for HFpEF, but the mechanisms that contribute to the transition from compensated hypertensive heart disease to HFpEF are poorly understood.2
Clinical Perspective on p 378
Aldosterone levels are associated with increased mortality in HFpEF3 and with incident hypertension in the population.4 Mineralocorticoid receptor (MR) antagonists regressed hypertrophy, fibrosis, and diastolic dysfunction in human and experimental hypertensive heart disease.5–7 However, whether aldosterone itself causes adverse cardiac remodeling, which could promote the transition from compensated hypertensive heart disease to HFpEF, has been questioned.8,9
The heart contains abundant MRs but is not considered a mineralocorticoid target because it lacks significant amounts of 11-β hydroxysteroid dehydrogenase type II (11β-HSD2), an enzyme that confers aldosterone specificity in renal epithelial cells, vascular smooth muscle, endothelial cells, and circulating inflammatory cells.10–13 Indeed, marked transient endogenous activation of aldosterone associated with volume depletion or chronic exogenous mineralocorticoid excess with salt deprivation to mimic volume depletion does not produce adverse cardiac remodeling.14,15 However, exogenous excess mineralocorticoid (deoxycorticosterone acetate [DOCA] or aldosterone) does induce cardiac hypertrophy, fibrosis, and diastolic dysfunction when inappropriate for salt intake, ie, in the absence of salt deprivation. Above-normal salt intake and unilateral nephrectomy (DOCA-salt model) accelerate DOCA-induced cardiac effects.14,15 From these observations, some have concluded that mineralocorticoid occupancy and activation of cardiac MR occur in the DOCA-salt model and human HF despite the lack of 11β-HSD2.13,16,17 Alternatively, it has been proposed that adverse cardiac remodeling in mineralocorticoid excess (inappropriate for salt status) is mediated not by mineralocorticoid binding to cardiac MR but by synergistic effects of sodium and mineralocorticoid on noncardiomyocyte mineralocorticoid target (11β-HSD2 containing) tissues and that these noncardiomyocyte effects ultimately increase myocardial oxidative stress.9,10,18,19 Oxidative stress is known to initiate multiple adverse signaling pathways, may lead directly to myocyte necrosis and fibrosis,19 and/or may activate glucocorticoid-bound cardiac MR via redox sensitive corepressors.18,20,21
Although previous studies have focused on a pivotal role for increased salt/nephrectomy in accelerating mineralocorticoid induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and thus sensitizes the heart to mineralocorticoid, accelerating the development of hypertrophy, fibrosis, and diastolic dysfunction. Furthermore, we sought to determine whether oxidative stress and/or mineralocorticoid excess in hypertensive heart disease are associated with classic genomic MR actions signified by serum- and glucocorticoid-inducible kinase-1 (SGK1) and sodium-hydrogen exchanger (NHE-1) gene transcription in cardiac tissue. Accordingly, cardiac structure and function, markers of myocardial oxidative stress and MR-dependent gene transcription in the heart, were measured in normal mice without or with exogenous mineralocorticoid (DOCA), in mice with hypertensive heart disease associated with endogenous aldosterone activation (transverse aortic constriction [TAC]), and in TAC mice with exogenous mineralocorticoid (DOCA) administration, all in the setting of normal-salt diet.
All experimental procedures were designed in accordance with the National Institutes of Health guidelines and approved by the Mayo Foundation Institutional Animal Care and Use Committee.
Minimally Invasive TAC
Eight-week-old male FVB/NJ mice (Jackson Laboratory, Bar Harbor, Me) were subjected to minimally invasive TAC wherein a ligature was placed in the arch of the aorta between the brachiocephalic trunk and left common carotid artery as previously described by Hu et al.22 Control mice underwent an identical procedure without placement of a suture (sham).
Sham (n=10) or TAC (n=25) mice assigned to DOCA underwent subcutaneous implantation of extended-release DOCA pellets (2.4 mg/d; Innovative Research of America, Sarasota, Fla) immediately after the TAC/sham procedure. Sham (n=24) or TAC (n=27) mice not assigned to DOCA had no pellet placed. All mice were fed a normal-salt diet (rodent chow containing 0.3% sodium). Mice were studied 2 weeks after surgery.
A separate group (n=21) of normal mice underwent sham (n=9) or DOCA pellet (n=12) implantation (normal-salt diet) with blood pressure (BP) measured daily by tail cuff method and averaged over the third week after surgery. These 21 mice were used solely for BP measurement and were not included in any other analyses.
Mice (n=82, 95% of the first group of 86 mice) underwent 2-dimensional guided M-mode echocardiography (GE Healthcare, Milwaukee, Wis) with a 13-MHz probe under light isoflurane anesthesia (0.5% to 1.0%) administered via nose cone. Digital images were analyzed offline by EchoPAC software allowing anatomic M-mode measurements. Proximal descending aortic flow velocity (distal to constriction in TAC mice) was measured by pulsed-wave Doppler. Endocardial fractional shortening and left ventricular (LV) mass were measured by standard formulas, and midwall fractional shortening was calculated by the ellipsoidal 2-shell method by Shimizu et al.23,24 Echocardiographic images on 4 mice were suboptimal for quantitative measurement and thus were not included in the analysis.
Immediately after echocardiography, isoflurane-anesthetized mice were intubated and mechanically ventilated (Hugo Sachs Elektronik, Hugstetten, Germany). A conductance catheter (Millar Instruments, Houston, Tex) was inserted into the LV via the right carotid artery.
Data were acquired at steady states and during acute inferior vena caval occlusions (variable loading conditions). Data analysis was performed by PVAN software (ADInstruments, Inc, Colorado Springs, Colo). The end-systolic and end-diastolic pressure-volume relationships during inferior vena caval occlusions were used to calculate end-systolic and end-diastolic stiffness (slope of linear fit of end-diastolic pressure-volume relationship). The LV pressure and echocardiography measurements were used to calculate end-systolic wall stress as previously described.25 Catheterization was attempted in all mice (n=86) and was successful in 58 (67%).
Tissue and Blood Harvest
After catheterization, blood was collected, and organs were weighed and then flash-frozen in liquid nitrogen with 1 LV section preserved in 10% formalin, embedded in paraffin, and cross-sectioned into 5-μm sections. Plasma aldosterone level was measured by radioimmunoassay as previously described.26
Gene Expression (Quantitative Real-Time Reverse-Transcription Polymerase Chain Reaction)
Total RNA was extracted from snap-frozen LV tissue. RNA was reverse transcribed to complementary DNA by an iScript complementary DNA synthesis kit (Bio-Rad Laboratories, Hercules, Calif). Complementary DNA was amplified and levels of gene expression were quantified by real-time quantitative polymerase chain reaction (TaqMan Gene Expression Assays and Universal Probelibrary Gene Assays). Primers for the following messenger RNAs were used: atrial natriuretic peptide, collagen I, collagen III (Roche Applied Science, Indianapolis, Ind), osteopontin, NADPH oxidase subunit 2 (NOX2, gp91phox), NADPH oxidase subunit 4 (NOX4), p22phox, SGK1, NHE-1, and elongation factor RNA polymerase II (Applied Biosystems, Foster City, Calif).
Histology and Histomorphometry
LV sections were stained with picrosirius red. Perivascular fibrosis and interstitial fibrosis were assessed independently by 2 blinded experienced observers by a semiquantitative visual analog fibrosis with 4 grades: 1 to 3 (1=no fibrosis, 2=mild fibrosis, 3=moderate fibrosis, and 4=severe fibrosis). Representative examples from previous studies showing each grade of fibrosis were used to enhance consistency of scoring between observers. Fibrosis analysis was performed in 77 (90%) of studied mice. Tissue slides for 9 mice were missing or uninterpretable and thus were not included in the analysis.
LV sections were stained with biotinylated isolectin subunit 4 (1:100 dilution) and detected by peroxidase (Vector Laboratories, Burlingame, Calif). Capillary density was evaluated by a computer-assisted histomorphometry (Zeiss Vision, Hallbergmoos, Germany) and expressed as a percent of LV area in 32 (37%) of the studied mice.
Data are presented as mean±SD. Although most parameters appeared to be normally distributed, a few were not. Therefore, comparison between TAC and sham groups was by the Wilcoxon (rank-sums) test with a 2-tailed α of 0.05. Comparison across all groups was performed by Kruskal-Wallis test, followed by Wilcoxon (rank-sums) test comparing sham with sham+DOCA and TAC with TAC+DOCA or test for linear trend between physiological parameters and group (treated as an ordinal variable in the following order: sham, sham+DOCA, TAC, TAC+DOCA as physiologically appropriate, consistent with the magnitude and interaction of mineralocorticoid activation and pressure overload). The P value for the linear trend was calculated on the basis of the Spearman rank correlation.
The figures are displayed as Tukey (outlier) box plots in which the whiskers extend to a length equal to 1.5 times the interquartile range or to the most extreme value if it falls within this boundary. Values above or below the whiskers are drawn as individual points.
Transverse Aortic Constriction
Compared with sham-operated mice, TAC mice displayed expected findings of chronic pressure overload with higher maximum LV pressure and increased postconstriction flow velocity (the Table). TAC mice displayed concentric hypertrophy (assessed by echocardiography, autopsy heart and LV weights, and LV atrial natriuretic peptide gene expression), which normalized wall stress. Cardiac fibrosis was increased (significant increases in picrosirius staining and increases in collagen I gene expression). The increase in collagen III gene expression was marginally significant (P=0.055).
However, this degree of TAC was well compensated for by maintenance of endocardial and midwall fractional shortening, diastolic pressure and stiffness, and lung weights. TAC was associated with evidence of increased oxidative stress with increased osteopontin and NOX4 gene expression. TAC was also associated with endogenous mineralocorticoid activation with increased serum aldosterone levels, likely secondary to renal hypoperfusion.27 However, classic MR-dependent gene transcription, as assessed by LV SGK1 and NHE-1 gene expression, was not increased.
Effect of DOCA on LV Load
After 2 weeks, systolic BP was similar in mice without (136±3 mm Hg) and with (142±3 mm Hg) DOCA pellet implantation (P=0.17). However, maximum LV pressure measured at terminal hemodynamic study was slightly but significantly higher in sham+DOCA versus sham mice (Figure 1). Both the postconstriction flow velocity and maximum LV pressure were similar in TAC and TAC+DOCA mice. In contrast to TAC versus sham mice (the Table) in which wall stress was normalized by compensatory hypertrophy, end-systolic wall stress was lower in sham+DOCA versus sham and in TAC+DOCA versus TAC owing to altered LV geometry, suggesting that hypertrophy was out of proportion to load.
Effect of DOCA on LV Structure
In sham mice, DOCA resulted in concentric remodeling with smaller LV dimension and increased relative wall thickness on echocardiographic study (Figure 2). Heart, LV, and atria plus right ventricular weights indexed to body weight were significantly increased compared with sham with increased LV atrial natriuretic peptide gene expression. Similarly, in TAC mice, DOCA enhanced concentric remodeling with smaller LV dimension. DOCA also increased relative wall thickness and heart and LV weights. LV atrial natriuretic peptide gene expression was increased, but the difference was not statistically significant.
In agreement with previous studies, in sham mice, DOCA did not result in LV fibrosis as assessed by picrosirius staining (Figure 3) or LV collagen I or III gene expression. In contrast, in TAC mice, DOCA resulted in increased interstitial fibrosis. Perivascular fibrosis and LV collagen I and III gene expression increased, but the difference was not statistically significant.
Effect of DOCA on Systolic Function
Compared with sham, sham+DOCA mice had higher endocardial and midwall fractional shortening, as would be expected with lower wall stress, but the load-independent measure of contractility (end-systolic elastance) was not increased (Figure 4). Compared with TAC mice, TAC+DOCA mice had increased endocardial fractional shortening in association with lower wall stress, but midwall fractional shortening and end-systolic elastance were similar to those in TAC mice. Thus, with DOCA, there was no evidence of adverse or favorable effects on systolic function independently of the effects of altered geometry on wall stress.
Effect of DOCA on Diastolic Function
Compared with sham, sham+DOCA mice had similar LV end-diastolic pressure and end-diastolic pressure-volume relationship slope (LV stiffness) (Figures 1D, 1E, and 4⇑). In contrast, compared with TAC mice, each of these parameters was higher in TAC+DOCA mice (Figures 1F, 1G, and 4⇑). Lung weights were higher in TAC+DOCA compared to TAC, but the difference did not reach statistical significance (P=0.07).
Vascular Inflammation and Oxidative Stress
Osteopontin, a matricellular protein activated in the heart in the presence of mechanical, inflammatory, or oxidative stress, showed a significant progressive increase across sham+DOCA, TAC, and TAC+DOCA mice (Figure 5). Likewise, markers of oxidative stress, specifically the membrane-bound NADH oxidase subunit (p22phox) and the 2 NADH oxidase catalytic subunit isoforms (NOX2 and NOX4), showed similar progressive increases.
We examined capillary density to determine whether DOCA altered angiogenesis or caused vascular rarefaction. Although TAC mice tended to have decreased capillary density, it was not altered in TAC+DOCA mice, and DOCA had no effect on capillary density in sham mice (Figure 6).
Classic MR-Dependent Gene Expression
Aldosterone levels were lower in both DOCA-treated groups compared with their respective controls, indicating expected negative feedback suppression of endogenous aldosterone production. However, neither SGK1 nor NHE-1 gene expression was increased in TAC mice (the Table) compared with sham mice or in DOCA-treated sham or TAC mice compared with their respective controls (Figure 7). Furthermore, there was no enhanced expression of a coactivator (elongation factor RNA polymerase II) thought to enhance MR responsiveness to mineralocorticoid.17
In this study, we demonstrate that exogenous mineralocorticoid, inappropriate for salt status, accelerated LV hypertrophy, fibrosis, and diastolic dysfunction in response to chronic pressure overload induced by TAC. Indeed, DOCA-treated TAC mice had elevated filling pressures and lung weights with normal systolic indexes consistent with HFpEF. In contrast, in the absence of TAC, exogenous mineralocorticoid alone caused mild cardiac hypertrophy without fibrosis or diastolic dysfunction. Exogenous mineralocorticoid, TAC, and their combination were associated with progressive activation of markers of inflammation and oxidative stress in cardiac tissue. However, neither endogenous mineralocorticoid activation and oxidative stress evident in TAC nor exogenous mineralocorticoid and TAC were associated with enhanced classic MR-dependent gene transcription in the heart. These data indicate that in the presence of pressure-overload hypertrophy and cardiac oxidative stress, aldosterone may accelerate adverse cardiac remodeling independently of classic genomic MR signaling in the heart. We speculate that pathophysiologically relevant levels of aldosterone may have similar effects over the long term in patients with hypertensive heart disease and may accelerate adverse remodeling and progression to HFpEF.
Mineralocorticoid and Cardiac Remodeling
Despite the proven benefit of MR antagonists in HF and human and experimental hypertension (including TAC7), it remains unclear whether aldosterone itself has direct cardiac effects that are independent of BP. Purported mechanisms underlying the benefit of MR antagonism in cardiac disease include blockade of glucocorticoid-bound but redox-sensitive cardiac MR activated by the oxidative stress/altered redox status associated with hypertensive heart disease or HF (independent of aldosterone)9,21 and/or blockade of mineralocorticoid-activated MR in noncardiomyocyte, mineralocorticoid target (11β-HSD2–containing) tissues that produce secondary cardiac effects (dependent on aldosterone).19,28These alternate hypotheses, although not mutually exclusive, underscore the controversy around the role of aldosterone itself in mediating cardiac remodeling in cardiovascular disease.
In the sham-operated mice, mineralocorticoid excess inappropriate for the normal-salt diet produced mild LV hypertrophy and hypertrophy of the atria plus right ventricle, effects that occurred in the absence of vascular inflammation or classic MR-dependent gene transcription, suggesting either a direct, nongenomic effect on cardiomyocytes or secondary effects from noncardiac MR stimulation as outlined above. Indeed, the degree of hypertrophy was inappropriate for BP, resulting in lower wall stress and increased endocardial and midwall fractional shortening. Although previous studies of exogenous mineralocorticoid plus salt deprivation did not demonstrate hypertrophy, animals subjected to salt deprivation had markedly decreased body weight and reduced cardiac load.15 Previous studies have shown rapid but sustained nongenomic mineralocorticoid effects mediated by protein kinase Cε or ERK1/2 activation, both known to be involved in hypertrophic pathways.29–33 Thus, the current data provide additional in vivo evidence that chronic inappropriate (for salt status) mineralocorticoid excess results in myocardial effects but in the absence of classic MR-dependent gene transcription in the heart as discussed further below.
Intrinsic Myocardial Disease Sensitizes the Heart to Mineralocorticoid Excess
We previously demonstrated cardiac fibrosis with exogenous mineralocorticoid excess alone in experimental systolic dysfunction34 and increased fibrosis and diastolic dysfunction in renal wrapping–induced hypertension,35 although DOCA also increased BP in the renal hypertension model. Here, we confirm and extend these findings in pressure overload induced by TAC independently of further BP elevation or increased salt intake/nephrectomy and provide insight into the mechanism whereby pressure-overload hypertrophy sensitizes the heart to mineralocorticoids.
Cardiac Inflammation and Oxidative Stress With TAC and Mineralocorticoid Excess
In the present study, we saw evidence of progressive activation of genomic markers of inflammation and oxidative stress across the groups, suggesting that both chronic inappropriate (for salt status) mineralocorticoid excess and TAC contribute to cardiac inflammation and increased oxidative stress. Aldosterone has been shown to increase osteopontin and/or other inflammatory cytokine production by vascular endothelial cells, smooth muscle cells, and peripheral blood mononuclear cells.36–38 However, osteopontin is a ubiquitous, proinflammatory cytokine that is also activated in response to hemodynamic, inflammatory, or oxidative stress; thus, one need not implicate the cardiomyocyte MR in elevating cardiac osteopontin gene expression.37
Vascular tissues contain 11β-HSD2, and some studies have shown a predominance of perivascular inflammation in the DOCA-salt model, suggesting that mineralocorticoid inappropriate for salt causes vascular inflammation, which could contribute to oxidative stress and adverse cardiac remodeling.39 Because vascular tissues are susceptible to mineralocorticoid, it has been difficult to reconcile a lack of vascular inflammation or profibrotic effects of appropriate (to salt status) mineralocorticoid excess. Indeed, it may be that aldosterone accelerates the inflammatory response to vascular injury rather than initiating inflammation.40 We observed marked perivascular fibrosis in TAC and a further trend toward increased perivascular fibrosis in TAC mice treated with DOCA. These data suggest that initial vascular injury initiates an inflammatory response, which is then accelerated by mineralocorticoid excess. Interestingly, we also saw evidence of vascular rarefaction along with interstitial fibrosis, suggesting diffuse vascular injury with TAC. Although vascular rarefaction was not significantly enhanced with DOCA, the sensitivity of lectin staining and histomorphometric quantification of vascular density may be inadequate to detect increased vascular rarefaction with DOCA.
Alternatively or additionally, mineralocorticoid stimulation of epithelial MR causes divalent cation excretion and secondary hyperparathyroidism, which ultimately promotes calcium overload in cardiomyocytes and peripheral blood mononuclear cells, contributing to oxidative stress, cardiomyocyte injury, and reparative fibrosis independently of nongenomic or genomic cardiac MR signaling.41–44
Adverse Cardiac Remodeling With Mineralocorticoid Excess is Not Associated With MR-Dependent Gene Transcription in the Heart
The importance of rapid and thus nongenomic mineralocorticoid signaling in a variety of tissues is increasingly apparent.18,31,45 In vitro data suggest that these rapid mineralocorticoid effects may be mediated by classic MR in association with activation of protein kinase Cε or ERK1/2 or independently of classic MR in a manner associated with enhanced calcium ingress. In the present study, we found no evidence of enhanced transcription of 2 fairly well-established MR-activated genes, SGK1 and NHE-1, with DOCA, TAC, or TAC+DOCA.8,46 These data suggest that inappropriate mineralocorticoid excess, TAC, or their combination did not result in classic MR-dependent gene transcription in the LV.
Our findings are consistent with elegant in vitro studies by Grossmann et al29 in which rapid, nongenomic effects of MR activation on collagen synthesis were observed in cultured cells transfected with full-length or truncated MR. Cells transfected with truncated MR constructs were incapable of genomic signaling but displayed intact nongenomic signaling. The truncated MR-transfected cells displayed no increased collagen synthesis in the presence of aldosterone alone but increased collagen synthesis with oxidative stress, an effect that was augmented by adding aldosterone to oxidative stress. These in vitro findings are analogous to the fibrosis and collagen gene expression observed with TAC-induced oxidative stress, increased with TAC+DOCA but absent in DOCA+ sham groups here, and provide in vivo evidence that nongenomic MR signaling enhances cardiac fibrosis associated with pressure overload–induced cardiac injury and oxidative stress.
We depend on SGK1 and NHE-1 as indicators of cardiac MR genomic signaling. Whether the rather striking diastolic dysfunction observed in the TAC+DOCA mice was mediated by increased hypertrophy and fibrosis, altered calcium handling, or other effects is not addressed in the present study. We acknowledge that effects seen with exogenous administration do not necessarily replicate endogenous actions of aldosterone. The tail-cuff method may not accurately characterize BP changes. Furthermore, we cannot exclude long-term changes in LV pressure in the DOCA+TAC group, although none were apparent at LV catheterization under anesthesia. Anesthesia may also have influenced echocardiographic measurements.
We provide in vivo evidence that pressure-overload hypertrophy induces oxidative stress and sensitizes the heart to inappropriate mineralocorticoid excess, which promotes hypertrophy, fibrosis, and diastolic dysfunction without activation of classic MR-mediated gene transcription. These data suggest that aldosterone may promote the transition from compensated hypertensive heart disease to HFpEF.
We are greatly indebted to Jimmy Storlie, Elise Oehler, Sharon M. Sandberg, Denise M. Heublein, and Jilian L. Foxen for their technical expertise.
Sources of Funding
This study was supported by the National Heart, Lung, and Blood Institute (HL-76611-1, HL-07111, and HL-63281). This project was also supported by grant 1 UL1 RR024150 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH); the NIH Roadmap for Medical Research; and the Japan Research Foundation for Clinical Pharmacology. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
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A wealth of data from human systolic heart failure and experimental models of hypertension and heart failure suggests that mineralocorticoid receptor antagonists reduce mortality and attenuate hypertrophy, fibrosis, and diastolic dysfunction. These data have led to the ongoing multicenter randomized Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT). Although aldosterone levels are elevated in heart failure with preserved ejection fraction, whether aldosterone itself causes adverse cardiac remodeling, which could promote the transition from hypertensive heart disease to overt heart failure with preserved ejection fraction, is controversial. In this study, we show that oxidative stress is induced in the hypertensive heart and sensitizes the heart to exogenous mineralocorticoids. In normal mice, exogenous mineralocorticoid had little effect on cardiac structure or function. Mice with pressure-overload hypertrophy had increased myocardial oxidative stress, and in these mice, exogenous mineralocorticoid accentuated hypertrophy, fibrosis, and diastolic dysfunction, suggesting an interaction between excess mineralocorticoid (inappropriate for salt status) and oxidative stress. Interestingly, this effect was observed without evidence of classic mineralocorticoid receptor–mediated gene transcription in the heart (“nongenomic” effects) and independently of changes in the magnitude of pressure overload. These results suggest that aldosterone excess may promote the transition from compensated hypertensive heart disease to heart failure with preserved ejection fraction via nongenomic effects or alternatively through effects on noncardiac cells. Because the nongenomic effects of aldosterone are exerted both via the mineralocorticoid receptor and independent from the mineralocorticoid receptor, development of novel antagonists that target both genomic and nongenomic effects may have benefit beyond mineralocorticoid receptor antagonists.
↵*The first 2 authors contributed equally to this work.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.915215/DC1.
Guest Editor for this article was Mark A. Sussman, PhD.