Table 2:

Clinical and Preclinical Evidence for a Sex-Specific Role of the MR and EC-MR in Cardiovascular Disease

Model	Sex	Intervention	Results	References
ENDOTHELIAL DYSFUNCTION
MR in humans	Men	Spiro, Epl	MR antagonists improve endothelial function in heart failure, diabetes, hypertension (mostly male cohorts).	Farquharson and Struthers 2000; Macdonald et al. 2004; Fujimura et al. 2012; Garg et al. 2015
	Women	Spiro	MR antagonists improve endothelial function in women with polycystic ovarian syndrome.	Studen et al. 2011
		Spiro	MR antagonists improve endothelial function in women with Rheumatoid Arthritis.	Syngle et al. 2009
	Both	Spiro	MR antagonists improve endothelial function in hypertensive African American men and women (analyzed separately).	Mohandas et al. 2015
MR in animals	Male	Epl, Finerenone	MR antagonists improve endothelial function.	Rajagopalan et al. 2002; Gonzalez-Blazquez et al. 2018
	Female	Spiro	MR antagonism improves endothelial function in leptin-sensitized obese females.	Huby et al. 2016
EC-MR-KO mice	Male	Tie2 Cre	EC-MR-KO improves endothelial function of the aorta in obesity.	Schafer et al. 2013
		VE-Cadherin Cre	EC-MR-KO improves endothelial function of the mesenteric arterioles in hypertension.	Mueller et al. 2015
		VE-Cadherin Cre	EC-MR-KO does not alter endothelial function of the mesenteric arterioles in obesity or hyperlipidemia.	Davel et al. 2018b
	Female	VE-Cadherin Cre	EC-MR-KO corrects the endothelial dysfunction with obesity and hyperlipidemia.	Davel et al. 2018b
HYPERTENSION
MR in humans	Men	Epl	MR antagonism reduces blood pressure (mostly male cohort).	Pitt et al. 2003a
	Women	Salt restriction, angiotensin-II	RAAS stimulation increases blood pressure more in women than in men.	Jurgens and Graudal 2004; Shukri et al. 2018
		Spiro, Epl	Women with Resistant Hypertension experienced greater blood pressure decrease with MR antagonism than men.	Khosla et al. 2009
	Both	Epl	MR antagonism reduces blood pressure (roughly equal male/female cohort).	Williams et al. 2004
MR in animals	Male	Spiro, Epl	MR antagonism reduces blood pressure in gonad-intact and castrated males.	Michaelis et al. 2012; reviewed in DuPont and Jaffe 2017
	Female	Spiro	MR antagonism reduces blood pressure in obese females.	Huby et al. 2016
		Spiro	MR antagonism does not reduce blood pressure in ovariectomized females.	Michaelis et al. 2012
		Epl	MR antagonism prevents endothelial tight junction remodeling in the cerebral arteries of hypertensive females.	Tada et al. 2010
EC-MR-KO mice	Male	VE-Cadherin tetOFF overexpression	EC-MR overexpression increases blood pressure.	Nguyen Dinh Cat et al. 2010
		Tie2 Cre, VE-Cadherin Cre	EC-MR-KO does not affect blood pressure at baseline or in disease models.	Rickard et al. 2014; Mueller et al. 2015; Dinh et al. 2016; Lother et al. 2016; Salvador et al. 2017; Laursen et al. 2018
		Tie2 Cre, VE-Cadherin Cre	EC-MR-KO attenuates the pathologic remodeling that occurs with hypertension.	Rickard et al. 2014; Lother et al. 2016; Diaz-Otero et al. 2017; Diaz-Otero et al. 2018
	Female	VE-Cadherin Cre	EC-MR-KO likely does not affect blood pressure at baseline or in disease models.	Jia et al. 2015b; Davel et al. 2018b
ATHEROSCLEROSIS
MR in humans	Men	Aldo (observational)	Aldo levels correlate with cardiovascular ischemia (mostly male cohorts).	Milliez et al. 2005; Ivanes et al. 2012
	Women	Epl	MR antagonism reduces IMT in primary hyperaldosteronism (mostly female cohort).	Matsuda et al. 2015
	Both	Aldo (observational)	Aldo levels correlate with larger plaques independently of sex.	de Rita et al. 2013
		Spiro	MR antagonism reduces plaque volume in men and women with end-stage renal disease.	Vukusich et al. 2010
		Aldo (observational)	Aldo levels correlate with soluble inflammatory markers independently of sex.	Tomaschitz et al. 2011
MR in animals	Male	Aldo, 11βHSD2-KO	MR activation increases plaque size, inflammation.	Deuchar et al. 2011; McGraw et al. 2013; Marzolla et al. 2017
		Spiro, Epl	MR antagonism reduce plaque size, inflammation.	Rajagopalan et al. 2002; Keidar et al. 2003; Suzuki et al. 2006; Raz-Pasteur et al. 2012; Raz-Pasteur et al. 2014; Kratz et al. 2016; Li et al. 2017; Moss et al. 2019
	Female	Spiro	MR antagonism does not reduce plaque inflammation in female mice	Moss et al. 2019
EC-MR-KO mice	Male	VE-Cadherin Cre	EC-MR-KO attenuates atherosclerotic plaque inflammation and inflammatory cell recruitment without changing plaque size.	Moss et al. 2019
	Female	VE-Cadherin Cre	Females have less plaque inflammation and inflammatory cell recruitment than males, and EC-MR-KO does not confer further protection in females.	Moss et al. 2019
HFrEF
MR in humans	Men	Epl	MR antagonists reduce mortality (mostly male cohorts). Significant effect remains in male sub-group of meta-analysis.	Pitt et al. 1999; Pitt et al. 2003b; Zannad et al. 2011; Rossello et al. 2019
	Women	Epl	MR antagonism may reduce mortality in women (trend but not significant in meta-analysis).	Rossello et al. 2019
		Aldo (observational)	Aldo levels correlate with cardiac remodeling in women but not men.	Vasan et al. 2004
MR in animals	Male	Epl, Aldosterone synthase inhibitor	MR antagonists improve systolic function and reduce mortality.	Fraccarollo et al. 2003; Wang et al. 2004; Munoz-Pacheco et al. 2013; Furuzono et al. 2017
		pH1tet-inducible anti-MR shRNA expression	Inducible genetic MR knockdown improves systolic function and reduces mortality.	Montes-Cobos et al. 2015
	Female	Epl	Female rats had larger improvements in systolic function and cardiac remodeling than males.	Kanashiro-Takeuchi et al. 2009
EC-MR-KO mice	Male	Tie2 Cre, VE-Cadherin Cre	EC-MR-KO improves systolic function and prevents cardiac remodeling.	Rickard et al. 2014; Lother et al. 2016; Salvador et al. 2016; Salvador et al. 2017
	Female	---	Not studied	---
HFpEF
MR in humans	Men	Spiro	MR antagonism does not improve mortality in men (no trend or significant effect in TOPCAT meta-analysis).	Merrill et al. 2019
	Women	Spiro	MR antagonism improves diastolic dysfunction (mostly-female cohorts).	Pandey et al. 2015; Fukuta et al. 2018
		Spiro	MR antagonism may or may not improve exercise capacity (mostly-female cohorts).	Daniel et al. 2009; Upadhya et al. 2017a
		Spiro	MR antagonism improves mortality in women (significant effect in TOPCAT meta-analysis).	Merrill et al. 2019
	Both	Spiro	MR antagonism improves left ventricular function and structure and reduces hospitalization rates, with no overall effect on mortality (roughly equal male/female cohorts).	Edelmann et al. 2013; Pitt et al. 2014
MR in animals	Male	---	Male mice do not develop diastolic dysfunction with Western diet.	Manrique et al. 2013
	Female	Spiro	MR antagonism prevents diastolic dysfunction and cardiac inflammation with Western diet.	Bostick et al. 2015
EC-MR-KO mice	Male	---	Not studied	---
	Female	VE-Cadherin Cre	EC-MR-KO prevents diastolic dysfunction and cardiac inflammation with Western diet.	Jia et al. 2015b

MR=mineralocorticoid receptor; EC-MR=endothelial-specific MR; KO=knockout; Aldo=aldosterone; Spiro=spironolactone; Epl=eplerenone; RAAS=renin-angiotensin-aldosterone system; 11βHSD2=11β-hydroxysteroid dehydrogenase 2; shRNA=short hairpin RNA