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. Author manuscript; available in PMC: 2016 May 1.
Published in final edited form as: Hypertension. 2015 Feb 23;65(5):1082–1088. doi: 10.1161/HYPERTENSIONAHA.114.04912

Mineralocorticoid Receptor Antagonism Treats Obesity-associated Cardiac Diastolic Dysfunction

Shawn B Bender 1,2,3,*, Vincent G DeMarco 1,5,7, Jaume Padilla 3,4,8, Nathan T Jenkins 9, Javad Habibi 1,5, Mona Garro 1,5, Lakshmi Pulakat 1,6,7, Annayya R Aroor 1,5, Iris Z Jaffe 10, James R Sowers 1,3,5,7
PMCID: PMC4393340  NIHMSID: NIHMS661105  PMID: 25712719

Abstract

Patients with obesity and diabetes exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure-independent low dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide-independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. Additionally, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure-independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.

Keywords: echocardiography, metabolic syndrome, coronary microcirculation, immune, aldosterone, insulin signaling

Introduction

Results of the recent Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial examining the clinical benefit of mineralocorticoid receptor (MR) antagonism in patients with heart failure with preserved ejection fraction (HFpEF; i.e., diastolic heart failure) were negative1. However, interpretation of these results is hampered by broad inclusion criteria resulting in a heterogeneous patient population that could mask specific patient subgroups that may preferentially benefit from MR antagonism1,2. One of these potential populations are patients with diabetes, obesity and the metabolic syndrome (MetS) that exhibit >30% prevalence of cardiac diastolic dysfunction (DD), the major cardiac functional defect in HFpEF3. Indeed, smaller studies demonstrate improved diastolic function following MR antagonism in these patients4,5. Thus, in conjunction with the renin-angiotensin-aldosterone system activation in obesity and MetS, MR antagonism holds promise for the treatment of obesity-associated DD but this and potential underlying mechanisms have not been studied and remain unclear.

DD contributes to the increase of cardiovascular risk in patients with obesity and diabetes; however, no clear evidence-based therapies for DD have been identified3. DD is often accompanied by left ventricular (LV) hypertrophy, fibrosis, and impaired coronary flow reserve (CFR; i.e., coronary microvascular dysfunction)3,6. It has recently been proposed that DD onset and progression occurs via systemic inflammation contributing to cardiac/vascular oxidative stress and coronary microvascular endothelial dysfunction, ultimately leading to cardiac hypertrophy, fibrosis, and DD7. Such a paradigm may explain recent epidemiological data demonstrating an association between coronary microvascular dysfunction and cardiac mortality in patients with diabetes8. Importantly, the MR has been implicated in many components of this cascade9,10. Specifically, MR activation promotes cardiovascular inflammation, oxidative stress, endothelial dysfunction, impaired CFR, and cardiac fibrosis11–16. In addition, recent reports reveal a role for the MR in enhancing pro-inflammatory immune cell phenotypes, including classically activated M1 macrophages and T-helper 17 (Th17) lymphocytes17,18. Based on these results we hypothesized that MR signaling contributes significantly to obesity-associated DD and that MR blockade will interrupt disease progression providing the first viable therapeutic avenue for DD in this specific patient population.

To test this hypothesis we treated Zucker obese (ZO) rats with a blood pressure-independent low dose of the MR antagonist spironolactone (LSp)19. Previous work from our group and others demonstrates that ZO rats develop pronounced DD with coronary microvascular dysfunction20–22. In addition to examining the effect of MR blockade in ZO rats, a role for the MR in the onset of and mechanisms underlying DD was examined in Sprague-Dawley (SD) rats treated with a subpressor dose of the MR agonist aldosterone.

Methods

For detailed description see Methods in the online-only Data Supplement.

Results

Insulin resistance and kidney injury were not altered by LSp treatment in ZO rats

Compared to ZL, ZO rats exhibited MetS components including increased body weight, epididymal fat pad mass, insulin resistance (HOMA-IR), fasting plasma leptin, glucose, insulin, cholesterol, and triglyceride, but not corticosterone (Table S2). LSp treatment (sc, 1 mg·kg−1·day−1) beginning at 29 weeks of age for 3 weeks had no effect on these parameters or serum potassium in ZO-LSp rats. Plasma aldosterone was reduced in ZO, but not ZO-LSp, rats versus ZL (Table S2) involving reduced plasma AngII despite increased PRA (Figure S1A, S1B). ZO rats exhibited proteinuria that was unchanged by LSp and urinary sodium excretion was similar across all groups (Table S2).

MR inhibition normalized obesity-related cardiac DD independent of blood pressure

Systolic blood pressure was similar between all groups (Table S2). Compared to ZL, cardiac MR mRNA expression was unchanged in ZO but reduced in ZO-LSp while mRNA expression of the MR target gene lipocalin-2 was increased on ZO rats regardless of treatment (Figure S1C). Consistent with our previous report22, ZO rats exhibited abnormal diastolic function versus ZL (Figure 1A–C, Table S3) and increased myocardial performance index (MPI), a heart rate-independent measure of diastolic and systolic function (Figure 1D). MPI is increased due to abnormal diastolic function indicated by abnormal diastolic septal wall motion (decreased E′/A′; Figure 1A), decreased propagation velocity of mitral inflow (Vp; Figure 1B), increased isovolumic relaxation time (IVRT; Figure 1C) and increased LV filling pressure (increased E/E′; Table S3). Fractional shortening and ejection fraction were unchanged indicating normal systolic function in ZO rats (Table S3). The abnormal diastolic parameters were largely ameliorated in ZO-LSp rats indicating that MR antagonism treated established obesity-associated cardiac DD via blood pressure-independent mechanisms.

Figure 1. MR antagonism treats obesity-associated cardiac diastolic dysfunction.

Figure 1

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Indices of cardiac diastolic function in Zucker rats, specifically E′/A′ (A), Vp (B), IVRT (C), and MPI (D). ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, ZO treated with spironolactone; E′/A′, early-to-late diastolic septal annulus motion ratio; IVRT, isovolumic relaxation time; MPI, myocardial performance index; Vp, propagation velocity of mitral inflow. Values are mean±SE; n=8–10; **p<0.05 versus all other groups, §p=0.06 versus ZL.

MR inhibition with LSp reduces cardiac fibrosis, but not hypertrophy, in ZO rats

Given the well described pro-fibrotic action of MR signaling, we examined cardiac hypertrophy and fibrosis after MR inhibition. Compared to ZL, ZO rats exhibited LV hypertrophy, by LV-to-tibia length ratio (Figure 2A) and septal/posterior wall thicknesses (Table S3) that was unchanged by LSp treatment. Cardiomyocyte area tended to be increased in ZO (p=0.07) and was increased in ZO-LSp versus ZL (Figure 2A). However, elevated cardiac interstitial and periarterial fibrosis in ZO rats was reduced by LSp (Figure 2B). Conversely, cardiac mRNA expression of collagen I, collagen III, and TGF-β1 tended to be or was reduced in ZO rats regardless of treatment (Figure S1D). Thus, the normalization of diastolic function in obesity by MR inhibition involves reduced cardiac fibrosis without reduced hypertrophy.

Figure 2. Increased cardiac fibrosis, not hypertrophy, in ZO rats is resolved by MR antagonism.

Figure 2

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Cardiac weights, assessed by left ventricle-to-tibia length (LV:TL) ratio, cardiomyocyte area (A), and cardiac interstitial/periarterial fibrosis (B) in Zucker rats. Interstitial collagen and periarterial fibrosis assessed by picrosirius red (PR) and Verhoeff-Van Gieson (VVG) staining, respectively. Representative images in lower panel, arrows indicate coronary arteries. GSI, gray scale intensity; ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, ZO treated with spironolactone. Values are mean±SE; n=5–10; *p<0.05 versus ZL, **p<0.05 versus all other groups, †p<0.05 versus ZO, §p=0.07 versus ZL.

LSp restores coronary arteriolar endothelial function in ZO rats

We examined coronary microvascular function, an important regulator of cardiac perfusion, as this could underlie the normalization of diastolic function in ZO-LSp rats. Coronary dysfunction prior to LSp treatment was confirmed in a subset of rats at 14–16 weeks of age in that ZO rats had impaired coronary dilation to insulin but not ACh (Figure S2). Similar to previous studies20,21, ZO coronaries exhibited reduced ACh- and insulin-induced vasodilation at 32 wk of age (Figure 3A). Constriction to the thromboxane analog U46619 was similar in all Zucker groups (Figure S3A). LSp treatment restored dilation to ACh (Figure 3A) but did not increase the abolished NOS-dependent component of ACh-induced dilation in ZO rats (Figure S3B). Insulin vasodilation (Figure 3A) and insulin-stimulated aortic endothelial Akt(Thr308) phosphorylation (Figure 3B) were improved by LSp. Lastly, arterioles from Zucker rats were not remodeled (similar wall:lumen ratios), LSp treatment did not reduce the obesity-associated increase in arteriolar elastic modulus (stiffness; Figure S3C), and dilation to SNP (NO donor) was unchanged confirming normal smooth muscle NO sensitivity (Figure S3D) and indicating endothelial cell dysfunction. Together, these data indicate that MR inhibition in ZO rats improves coronary microvascular function in concert with reduced cardiac fibrosis and improved diastolic function.

Figure 3. Impaired coronary arteriolar endothelial function in ZO rats is restored by MR antagonism.

Figure 3

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(A) Vasodilator responses of coronary arterioles from Zucker rats to endothelium-dependent dilators acetylcholine and insulin and (B) insulin-stimulated Akt (Thr308) phosphorylation in endothelial lysates from Zucker aortas. ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, ZO treated with spironolactone. Values are mean±SE; n=5–8; *p<0.05 versus ZL or unstimulated, **p<0.05 versus all other groups, ‡p<0.05 versus ZL.

MR antagonism abrogates obesity-associated elevations in cardiac oxidative stress

To further explore potential mechanism(s) underlying reduced cardiac fibrosis and improved diastolic function in ZO-LSp rats, we examined cardiac oxidative stress. Cardiac oxidative stress was elevated in ZO versus ZL rats (Figure 4A, 4B). Specifically, cardiac ROS production and cardiac 3-NT were increased in ZO rats (Figure 4A, 4B) while NADPH oxidase activity tended to be elevated (p=0.07; Figure 4A) versus ZL. Each of these, particularly NADPH oxidase activity, was reduced in ZO-LSp rats (Figure 4A, 4B). Thus, MR antagonism abrogates obesity-associated cardiac oxidative stress in conjunction with improved diastolic function and reduced fibrosis.

Figure 4. Elevated cardiac oxidative stress in ZO rats is ameliorated by MR antagonism.

Figure 4

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(A) Cardiac reactive oxygen species (ROS) production and NADPH oxidase activity in Zucker rats. (B) Cardiac 3-nitrotryrosine (3-NT) staining in Zucker rats. Representative 3-NT images in lower panel. GSI, gray scale intensity; ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, ZO treated with spironolactone. Values are mean±SE; n=3–10; **p<0.05 versus all other groups, §p=0.07 versus ZL.

LSp treatment attenuates obesity-related visceral adipose inflammation

Due to the role of adipose inflammation and adipose-derived cytokines in obesity-related disease processes, we considered whether the modulation of cardiac oxidative stress was associated with systemic alterations in adipose inflammation/cytokines. Circulating levels of the pro-inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and the oxidative stress marker thiobarbituric acid reactive substances (TBARS) were increased in ZO rats and treatment with LSp reduced circulating MCP-1 (Figure 5A). Similarly, pro-inflammatory gene expression was increased in epididymal fat from ZO rats (Figure 5B). Specifically, expression of MCP-1, TNF-α, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and NADPH oxidase subunits (p22phox/p47phox) were increased in ZO versus ZL rats. LSp treatment normalized some, but not all, adipose inflammatory genes (Figure 5B). Along with increased inflammatory gene expression, ZO rats exhibit marked adipose immune cell infiltration indicated by increased immune marker mRNAs for M1 macrophages, assessed by the generalized macrophage marker F4/80 and M1 marker CD11c, as well as T cells, assessed by CD4 and the regulatory T (Treg) cell marker FoxP3 (Figure 5C). The presence of macrophage mRNAs was reduced in ZO-LSp rats (Figure 5C). Together, these data demonstrate that the MR plays a role in obesity-related adipose inflammation and immune cell recruitment.

Figure 5. Systemic and adipose inflammatory markers are elevated in ZO rats and attenuated by MR antagonism.

Figure 5

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(A) Plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and thiobarbituric acid reactive substances (TBARS) in Zucker rats. (B) Gene expression of inflammatory (MCP-1, TNF-α, VCAM-1, ICAM-1) and oxidative stress (NADPH oxidase subunits p22phox/p47phox) genes in epididymal adipose from Zucker rats. (C) Expression of macrophage (F4/80, CD11c) and T cell (CD4, FoxP3) mRNAs in epididymal adipose of Zucker rats. ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, Zucker obese treated with spironolactone; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intracellular adhesion molecule-1. Values are mean±SE; n=4–6; *p<0.05 versus ZL, †p<0.05 versus ZO, §p=0.07 versus ZL, ¥p=0.08 versus ZL.

MR antagonism induces an anti-inflammatory shift of cardiac immune cell markers in ZO rats

We next examined whether reduced cardiac fibrosis and oxidative stress in ZO-LSp rats was associated with an anti-inflammatory shift in the cardiac immune cell phenotype by examining cardiac immune cell mRNAs. Compared to ZL rats, ZO rats exhibited unchanged cardiac mRNAs for MCP-1 (gene and protein; Figure S4A), and VCAM-1 while TNF-α was reduced and ICAM-1 was elevated indicating cardiac inflammation (Figure S4B). Immune marker mRNAs for total macrophages (F4/80), pro-inflammatory M1 macrophages (CD11c), anti-inflammatory M2 macrophages (CD163), T cells (CD4), or Treg cells (FoxP3) were unchanged in ZO versus ZL (Figure 6). Following LSp treatment, however, ZO-LSp rats exhibited increased mRNA expression for anti-inflammatory M2 macrophages (CD163) and Treg cells (FoxP3) (Figure 6). These data suggest that the improvement in obesity-related cardiac DD, fibrosis, vascular function, and oxidative stress following MR antagonism is associated with an anti-inflammatory shift of cardiac immune cell marker genes.

Figure 6. MR antagonism increases markers of anti-inflammatory immune cells in the heart of ZO rats.

Figure 6

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Gene expression of markers for total macrophages (F4/80), M1 macrophages (CD11c), M2 macrophages (CD163), T cells (CD4), and regulatory T cells (FoxP3) in cardiac tissue from Zucker rats. ZL, Zucker lean; ZO, Zucker obese; ZO-LSp, Zucker obese treated with spironolactone. Values are mean±SE; n=5–6; **p<0.05 versus all groups.

Aldosterone infusion recapitulates some, but not all, consequences of obesity

Infusion of aldosterone (sc, 50 μg·kg−1·day−1) in SD rats for 3 weeks beginning at 8 weeks of age raised plasma aldosterone but not blood pressure (Table S4). SD rats infused with aldosterone (SD-Aldo) exhibited cardiac diastolic, but not systolic, dysfunction (Table S5, Figure S5A) without cardiac/cardiomyocyte hypertrophy (Figure S5B) but elevated cardiac collagen accumulation/fibrosis (Figure S5C). SD-Aldo rats also exhibited impaired coronary arteriolar endothelium-dependent vasodilation to acetylcholine and insulin (Figure S5D) in conjunction with increased cardiac oxidative stress markers TBARS and 3-NT (Figure S5E). Similarly, SD-Aldo rats exhibited increased systemic inflammation (plasma MCP-1 and TNF-α; Figure S6A) and oxidative stress (plasma TBARS; Figure S6B); however, SD-Aldo rats did not exhibit elevated epididymal adipose inflammatory gene expression (Figure S6C). Thus, subpressor MR agonism by aldosterone recapitulated many of the cardiovascular, but not adipose, consequences of obesity suggesting differential MR signaling in the presence of comorbidities.

Discussion

In summary, we have demonstrated that MR antagonism with a blood pressure-independent dose of spironolactone is able to reverse established obesity-related DD. Treatment with LSp largely normalized obesity-associated increases in cardiac fibrosis, oxidative stress, coronary endothelial dysfunction, and systemic and adipose inflammation/immune cell recruitment in ZO rats in vivo. In addition, LSp treatment promoted an anti-inflammatory shift in cardiac immune cell mRNAs involving increased Treg and M2 macrophage markers in the absence of changes in systemic metabolic parameters, serum potassium, or kidney injury. Importantly, the benefit of LSp occurred with reduced circulating aldosterone in this model of normotensive obesity indicating a limitation of plasma aldosterone as a marker of MR activation. Similar improvement in cardiac phenotype with MR blockade was previously reported in a model of low-aldosterone salt-sensitive hypertension23. Reduced circulating aldosterone in the ZO rat can be accounted for by a significant reduction in plasma AngII despite increased PRA indicating reduced hepatic angiotensinogen production and/or reduced angiotensin converting enzyme activity in this model. It is likely that cardiac MR activation occurs mainly via corticosterone (unchanged in ZO rats) due to its equivalent affinity for the MR and the possibility of local cardiac and adipose aldosterone production cannot be ruled out. To our knowledge, this is the first study to demonstrate that MR antagonism effectively treats DD in a model of obesity and insulin resistance and these results reveal novel deleterious roles for MR in the development of obesity-associated cardiovascular dysfunction.

It is established that the benefit of MR antagonists in the treatment of systolic heart failure24,25 involves suppression of cardiac collagen accumulation26,27. Our data support a similar cardiac anti-fibrotic role of MR antagonism in the context of obesity-related DD in agreement with small human studies demonstrating reduced circulating markers of fibrosis with MR blockade in obese patients4,5 In the ZO rat, this likely involves increased collagen degradation and/or decreased production following LSp since collagen gene expression was reduced in these rats. An important departure between this study and those in obese patients, however, relates to the lack of effect of LSp to reduce cardiac hypertrophy in ZO rats whereas LV mass index/cardiac dimensions were reduced by spironolactone in obese patients4,5. The lack of reduction in hypertrophy in ZO-LSp rats involves increased cardiomyocyte area suggesting that reduced hypertrophy is not necessary for improved cardiac diastolic function in obesity and insulin resistance further supporting the importance of reduced fibrosis underlying the clinical benefit of MR antagonists in DD.

The link between coronary perfusion (i.e., coronary arteriolar function) and cardiac diastolic function is well established. For instance, in healthy dogs, reduced coronary perfusion increases cardiac isovolumic relaxation time (i.e., impaired cardiac relaxation)28. In agreement with previous work20,21, ZO rats demonstrated impaired coronary arteriolar vasodilation at 14–16 weeks of age that was normalized by LSp beginning at 29 wk of age and this may explain the improvement in CFR in type 2 diabetic patients following MR blockade13. Our data suggest that improved endothelium-dependent vasodilation following LSp involves non-NO pathways (i.e., prostacyclin/EDHF) and direct improvement of endothelial insulin signaling without improved arteriolar stiffness. To our knowledge, this is the first report of MR-dependent modulation of endothelial insulin signaling. Our data are consistent with a recent study demonstrating that knockout of the leukocyte/endothelial MR prevented aortic endothelial dysfunction in diet-induced obesity involving modulation of cyclooxygenase-1-dependent pathways29. Future studies are necessary to fully delineate MR-dependent modulation of endothelium-dependent vasodilator pathways in obesity. Regardless, the improvement in coronary endothelium-dependent vasodilation by LSp is clinically relevant since coronary endothelial dysfunction and impaired CFR are independently predictive of acute/long-term cardiovascular events8,30.

MR-dependent modulation of inflammatory pathways may be a central component of obesity-related cardiac dysfunction underlying the therapeutic effect of MR antagonists. Our data demonstrate that MR antagonism attenuated systemic and adipose inflammation and immune cell recruitment, particularly involving M1 macrophages, similar to previous mouse studies29,31,32. In addition, we demonstrate that in the presence of cardiac inflammation (i.e., increased ICAM-1 mRNA) but no obesity-related alteration of cardiac immune cell marker mRNAs LSp treatment increased cardiac mRNAs for anti-inflammatory M2 macrophages and Treg cells. Recent evidence demonstrates a direct role of MR signaling as a direct, physiologically relevant modulator of macrophage polarization and of the T helper 17/Treg axis17,18,33. Together with our data demonstrating abrogated cardiac, but not systemic, oxidative stress following LSp treatment these data suggest an important pathogenic role of local MR signaling in obesity-related cardiovascular dysfunction. Thus, we speculate that the anti-inflammatory influence of these cell types may underlie the improved cardiac phenotype following LSp treatment in ZO rats; however, future mechanistic studies addressing this issue are necessary.

Interrogation of the systemic effects of MR activation in this study revealed several additional surprising findings that warrant further examination. First, LSp treatment did not improve kidney injury/proteinuria or increase serum potassium in the ZO rat suggesting that MR activation either does not contribute to kidney injury in this model or that our dose of spironolactone is too low to sufficiently block renal MR. Indeed, the dose utilized in this study inhibits ~35% of radiolabeled aldosterone binding in vivo in the rat34. In addition, our results suggest that MR signaling in various tissues is context-dependent since aldosterone infusion in healthy SD rats recapitulated some (cardiac/coronary dysfunction, cardiac/systemic inflammation/oxidative stress), but not all (adipose inflammation), consequences of pathologic MR signaling revealed by LSp treatment of ZO rats.

Perspectives

We have demonstrated that LSp, too low to cause significant changes in serum potassium or blood pressure, treats established obesity-associated DD. This benefit of MR blockade involves reduced cardiac fibrosis, improved coronary microvascular function, and attenuated cardiac oxidative stress and systemic inflammation. Further, our data suggest a novel anti-inflammatory shift of cardiac immune cell markers following LSp in obesity that warrants further study. In DD caused by etiologies in which the inciting factors are different, MR antagonists may not be beneficial. This context-dependent role of MR signaling in DD may have contributed to the recent negative results of the TOPCAT trial1. Since MR signaling plays an integral role in the development of DD in obesity, further study of MR antagonists to treat DD specifically in patients with insulin resistance and obesity is warranted.

Supplementary Material

1

Novelty and Significance.

What is new?

  • Treatment with the mineralocorticoid receptor (MR) antagonist spironolactone reverses established cardiac diastolic dysfunction in obese, insulin resistant rats and is associated with reduced cardiac oxidative stress and fibrosis, attenuated systemic and adipose inflammation, and improved cardiac immune cell markers.

  • MR blockade improved coronary microvascular endothelial function in obesity via improved nitric oxide-independent vasodilation and restored insulin-dependent signaling to Akt with no change in arteriolar structure/stiffness.

  • The benefit of MR antagonism occurred despite reduced circulating aldosterone highlighting a limitation of using aldosterone as a surrogate for MR signaling.

What is Relevant?

  • Cardiac diastolic dysfunction, the major cardiac defect in diastolic heart failure, is common in patients with obesity and insulin resistance although no clear evidence-based therapies exist.

  • Low dose MR blockade with spironolactone normalized cardiac and coronary vascular function independent of changes in blood pressure, systemic insulin resistance, kidney injury, and serum potassium in a rat model.

Summary.

  • Low dose MR blockade is an effective treatment for cardiac diastolic and coronary microvascular dysfunction associated with obesity and insulin resistance. These results have implications for the use of MR antagonism in the treatment of obesity-related cardiovascular dysfunction.

Acknowledgments

We gratefully acknowledge the assistance of Nathan Rehmer, Alex Meuth, Dr. R. Scott Rector, Kayla Kanosky, Nicholas Fleming, and Yusuf Raja.

Funding

Supported by Department of Veterans Affairs Biomedical Laboratory Research & Development (CDA-2 IK2 BX002030 to SBB, 0018 to JRS), Missouri Foundation for Medical Research (to SBB), NIH (HL073101, HL107910 to JRS; K01HL125503 to JP), and University of Missouri Life Science Mission Enhancement Fund (LP). This work was supported with resources and the use of facilities at the Harry S. Truman Memorial Veterans Hospital in Columbia, MO.

Footnotes

Disclosures

None.

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