A Retrospective Comparative Study of Sex-Based Risk Variations in Heart Failure With Preserved Ejection Fraction (HFpEF) Versus Heart Failure With Reduced Ejection Fraction (HFrEF)

Abstract

Introduction/Objectives:

The prevalence of heart failure (HF) in the United States is currently at an all-time high and is predicted to rise to 8.5 million by 2030. Development of HF differs between men and women. We examined the risk factors associated with HF in women compared to men.

Methods:

A retrospective medical record review of adult men and women with HF. Variables were compared between women and men with Heart failure with Preserved Ejection Fraction (HFpEF) or Heart Failure with Reduced Ejection Fraction (HFrEF).

Results:

There were 460 women with HFpEF (WHFpEF) and 258 men with HFpEF (MHFpEF). Higher prevalences were observed in WHFpEF group compared to the MHFpEF group for older age (82.2 ± 9.5 vs 80.6 ± 9.6 years; P = .029), asthma (34.3 vs 20.2%; P < .001), osteoarthritis (66.5 vs 50.0%; P < .001), depression (39.6 vs 23.6%; P < .001), hypothyroidism (38.0 vs 17.1%; P < .001), and anxiety (43.0 vs 20.9%; P < .001). Greater odds of HFpEF in women was observed with increasing age per year (OR = 1.043, 95% CI = 1.027-1.059; P < .001), increasing BMI (OR = 1.037, 95% CI = 1.018-1.056; P < .001), rheumatological disorder (OR = 1.920, 95% CI = 1.457-2.530; P < .001), mental health disorder, such as depression or anxiety (OR = 1.898, 95% CI = 1.459-2.470; P < .001), asthma (OR = 1.807, 95% CI = 1.350-2.420; P < .001), and hypothyroidism (OR = 1.973, 95% CI = 1.486-2.618; P < .001). Among HFrEF patients, 225 patients were in WHFrEF group and 250 patients were in MHFrEF group. Higher prevalences were observed in WHFrEF group compared to the MHFrEF group for asthma (26.7 vs 16.8%; P = .009), depression (40.0 vs 22.0%; P < .001), hypothyroidism (32.0 vs 20.0%; P = .003), and anxiety (32.9 vs 21.6%; P = .006). Greater odds of HFrEF in women was noted for Black race (OR = 1.455, 95% CI = 1.018-2.080; P = .039).

Conclusion:

In women with HF, old age, elevated BMI and osteoarthritis are associated with HFpEF; Black race is associated with HFrEF; while asthma, depression, anxiety, and hypothyroidism are associated with both HFpEF and HFrEF.

Keywords

women heart failure heart failure risk factors HFpEF HFrEF heart failure sex difference

Introduction

As per the Heart Failure Epidemiology and Outcomes Statistics published in 2023, the prevalence of heart failure (HF) in the United States is at an all-time high and is predicted to rise to 8.5 million by 2030.¹ It is a well-known fact that women are under-represented in studies on cardiovascular disease, especially HF.^2-5 The American College of Cardiology, American Heart Association, and Heart Failure Society of America also explicitly acknowledge this disparity in their HF management guideline, noting that most evidence for guideline-directed medical therapy is derived from predominantly male cohorts.⁶

Studies suggest that the development of HF differs between women and men. Women have a higher lifetime risk of acquiring Heart failure with Preserved Ejection Fraction (HFpEF) than Heart Failure with Reduced Ejection Fraction (HFrEF). On the other hand, HFrEF tends to be more common in men. Studies conclude that women with HF have different anatomical and physiologic features compared to men, such as lower blood pressure, less left ventricular mass, greater contractility, and less cell turnover.⁷ It has also been reported that women with HF have worse quality of life compared to men with HF.⁷

There is a difference in the pathophysiology of HFpEF and HFrEF. HFpEF is preceded by chronic metabolic comorbidities, whereas HFrEF is usually preceded by cardiomyocyte damage due to ischemia, genetic mutation, myocarditis, or valvular disease.⁸ It is believed that compared to women, men are predisposed to macrovascular coronary artery disease and myocardial fibrosis which leads to a higher risk of HFrEF, whereas HFpEF is related to coronary microvascular dysfunction and endothelial inflammation.^7,9 The current literature suggests that HFrEF is associated with male sex, history of cardiomyopathy, and myocardial infarction; whereas HFpEF is associated with atrial fibrillation, pulmonary hypertension, obesity, and valvular heart disease.¹⁰

In addition to traditional risk factors, women have unique or disproportionately potent risk factors, including pregnancy-related complications (eg, preeclampsia and gestational diabetes), premature menopause, and exposure to certain cancer therapies (eg, breast cancer treatment-induced cardiomyopathy).⁷ Nontraditional factors, such as depression, anxiety, caregiver stress, and low socioeconomic status might also contribute more to HF risk in women than in men.⁶ Despite this knowledge, the medical literature highlights persistent gaps, such as sex-specific mechanisms, optimal drug dosing, and tailored risk prediction models are not fully established.^7,11,12 To address these and additional gaps, it is imperative to identify and build a comprehensive list of the variables that are associated with HF in women. Additionally, considering an increasing trend of HF in both sexes, greater emphasis must be given to preventative care, which is only possible through identification of multiple risk factors to provide opportunity to modify or optimally control them. In this study, we aimed to examine multiple risk factors and comorbid medical conditions associated with HF in women compared to men.

Materials and Methods

Study Design and Setting

This study was a retrospective, non-matched, cohort analytic study that utilized convenience sampling of the existing electronic medical records of an entire cohort of adult patients with HF who received care in the outpatient clinics of an urban non-profit tertiary healthcare system between January 1, 2023, and December 31, 2023.

Participants

The inclusion criteria for our study were adult patients who were 18 years of age or older with a documented diagnosis of HFpEF or HFrEF. HFpEF was defined as HF with a left ventricular ejection fraction (LVEF) ≥50% and objective evidence of increased left ventricular (LV) filling pressures, such as documentation of elevated natriuretic peptide levels or abnormal noninvasive/invasive hemodynamic measurements; and HFrEF was defined as HF with a LVEF ≤40%.⁶ Our exclusion criteria were patients who were younger than 18 years of age, or who did not have a diagnosis of HFpEF or HFrEF, or who had a diagnosis of HF with mildly reduced EF, or patients who had documentation of both HFpEF and HFrEF in their medical records, or patients who were asymptomatic without an echocardiogram to support the diagnosis of HF.

Variables

We collected the data on demographics, social factors and family history; biometric values, such as body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP); certain comorbid medical conditions, defined as additional diseases or disorders that coexisted with a primary or index disease in the same individual, but were not direct complications or sequelae of the index disease itself. These included hypertension, dyslipidemia, diabetes mellitus (DM), chronic kidney disease (CKD), coronary artery disease (CAD), peripheral artery disease (PAD), carotid artery disease, chronic obstructive pulmonary disease (COPD), asthma, obstructive sleep apnea (OSA), osteoarthritis (OA), rheumatological disorders, chronic liver disease, mental health disorders, hypothyroidism, hyperthyroidism, anemia, cancer, atrial fibrillation, other cardiac dysrhythmias, acquired valvular heart disease, congenital heart disease, myocardial deposition disorder, pulmonary hypertension, cerebrovascular accident (CVA), and Coronavirus disease 2019 disease (COVID-19). We utilized Microsoft Excel (2016, Redmond, Washington, USA) spreadsheet to record all the data.

Data Source

The Institutional Review Board approved this study and granted authorization to collect data for research purposes. Being a retrospective data collection, informed consents were not required. The data was accessible to all investigators from the hospital’s electronic medical records in the Epic healthcare software (Epic Systems Corporation, Wisconsin, USA).

Sample Study Size

We included the entire population of a total of 1207 patients in our healthcare system who were diagnosed with either HFpEF or HFrEF, out of which 1193 patient records accurately documented the diagnosis of HFpEF or HFrEF and had all pertinent data variables available. Hence, we included 1193 patients.

Statistical Methods

We used the SPSS (Statistical Package for the Social Sciences, version 15.01, IBM, Armonk, New York, USA) software for statistical analysis. We divided our cohort of patients into 4 groups: women with HFpEF (WHFpEF), men with HFpEF (MHFpEF), women with HFrEF (WHFrEF), and men with HFrEF (MHFrEF). We compared WHFpEF group with MHFpEF group, and WHFrEF group with MHFrEF group. For continuous variables, we ran a test of skewness to determine whether the data was normally distributed or nonparametric. Independent t-test was performed on normally distributed data and Mann-Whitney U test was performed on the non-parametric data. For the categorical variables, Pearson chi square tests were used. Additionally, in women with HF, we used logistic regression models in which women with HFpEF (WHFpEF), or women with HFrEF (WHFrEF) were the outcome variables. The model for WHFpEF included variables, such as age, race, BMI, smoking, rheumatological disorders, mental health disorders, CAD, asthma, hypothyroidism, and CKD. Similarly, the model for WHFrEF included age, race, BMI, smoking, rheumatological disorders, mental health disorders, CAD, asthma, hypothyroidism, and CKD. We defined statistical significance as a P value of <.05.

Results

Women With HFpEF Versus Men With HFpEF

The mean age was significantly greater in the WHFpEF group (n = 460) compared to the MHFpEF (n = 258; 82.2 ± 9.5 vs 80.6 ± 9.6 years; P = .029; Table 1). In both the groups, majority of the patients identified as of White race followed by Black and other races; however, the difference was not significant (Table 1). Tobacco, alcohol and recreational drug use were significantly lower in the WHFpEF group compared to the MHFpEF group (Table 1). There were no significant differences between the 2 groups in the family history of heart failure, mean BMI, mean systolic and diastolic blood pressures (Table 1).

Table 1.

Baseline Characteristics of Patients With HFpEF.

Variable	Variable	Women with HFpEF (n = 460)	Men with HFpEF (n = 258)	P-value
Age	Years, mean (SD)	82.2 (9.5)	80.6 (9.6)	.029
Race	White, n (%)	288 (62.6)	168 (65.1)	.252
	Black, n (%)	110 (23.9)	66 (25.6)
	Other, n (%)	62 (13.5)	24 (9.3)
Social	Tobacco use, n (%)	237 (51.5)	169 (60.1)	.001
	Alcohol use, n (%)	133 (28.9)	95 (36.8)	<.029
	Recreational drug use, n (%)	14 (3.0)	16 (6.2)	.042
Family history	Heart failure/CAD, n (%)	257 (55.9)	129 (50.0)	.130
Biometric values	BMI (kg/m²), mean (SD)	30.8 (8.7)	30.3 (6.9)	.397
	SBP (mmHg), mean (SD)	132 (52)	128 (21)	.228
	DBP (mmHg), mean (SD)	71 (12)	71 (13)	.980

Abbreviatons: BMI, Body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; HFpEF, heart failure with preserved ejection fraction; n, number of patients; SBP, systolic blood pressure; SD, standard deviation.

Analysis of associations with comorbid medical diagnoses revealed greater prevalence of several comorbidities with WHFpEF group compared to the MHFpEF group, such as asthma (34.3 vs 20.2%; P < .001), osteoarthritis (66.5 vs 50.0%; P < .001), depression (39.6 vs 23.6%; P < .001), hypothyroidism (38.0 vs 17.1%; P < .001), and anxiety (43.0 vs 20.9%; P < .001; Table 2). Additionally, we found significantly lower prevalence of some comorbidities with WHFpEF group compared to the MHFpEF group, such as CKD (50.0 vs 63.6%; P < .001), and CAD (50.0 vs 64.3%; P < .001; Table 2). We did not find significant differences in the prevalences of other comorbidities, such as hypertension, DM, dyslipidemia, PAD, carotid artery disorder, COPD, obstructive sleep apnea, chronic liver disease, bipolar disorder, hyperthyroidism, anemia, schizophrenia, cancer, atrial fibrillation, other cardiac dysrhythmias, acquired valvular heart disease, congenital heart disease, myocardial deposition disorder, pulmonary hypertension, CVA, COVID-19 disease, or prior use of chemotherapy (Table 2).

Table 2.

Comparative Associations of Comorbidities in Patients With HFpEF.

Variable	Women with HFpEF (n = 460)	Men with HFpEF (n = 258)	P-value
Hypertension, n (%)	443 (96.3)	243 (94.2)	.187
Dyslipidemia, n (%)	406 (88.3)	232 (89.9)	.497
Diabetes mellitus, n (%)	233 (50.7)	142 (55.0)	.259
CKD, n (%)	230 (50.0)	164 (63.6)	<.001
CAD, n (%)	230 (50.0)	166 (64.3)	<.001
PAD, n (%)	102 (22.2)	58 (22.5)	.925
Carotid artery disease, n (%)	88 (19.1)	38 (14.7)	.137
COPD, n (%)	147 (32.0)	75 (29.1)	.422
Asthma, n (%)	158 (34.3)	52 (20.2)	<.001
Obstructive sleep apnea, n (%)	155 (33.7)	104 (40.3)	.077
Osteoarthritis, n (%)	306 (66.5)	129 (50.0)	<.001
Other rheumatological disorders, n (%)	101 (21.9)	48 (18.6)	.288
Chronic liver disease, n (%)	55 (12.0)	34 (13.2)	.634
Depression, n (%)	182 (39.6)	61 (23.6)	<.001
Bipolar disorder, n (%)	10 (2.2)	5 (1.9)	.832
Hypothyroidism, n (%)	175 (38.0)	44 (17.1)	<.001
Hyperthyroidism, n (%)	17 (3.7)	8 (3.1)	.677
Anemia, n (%)	277 (60.2)	149 (57.8)	.519
Anxiety, n (%)	198 (43.0)	54 (20.9)	<.001
Schizophrenia, n (%)	8 (1.7)	3 (1.2)	.754
Cancer, n (%)	155 (33.7)	95 (36.8)	.399
Atrial fibrillation, n (%)	225 (49.0)	136 (52.7)	.342
Other cardiac dysrhythmias, n (%)	119 (26.9)	68 (26.4)	.887
Acquired valvular heart disease, n (%)	300 (65.2)	159 (61.6)	.337
Congenital heart disease, n (%)	11 (2.4)	10 (3.9)	.257
Myocardial deposition disorder, n (%)	6 (1.3)	2 (0.8)	.718
Pulmonary hypertension, n (%)	125 (27.2)	57 (22.1)	.133
CVA, n (%)	118 (25.7)	56 (21.7)	.236
COVID-19 disease, n (%)	127 (27.6)	79 (30.6)	.392
Post chemotherapy, n (%)	41 (8.9)	22 (8.5)	.861

Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; COVID-19, Coronavirus disease 2019; CVA, cerebrovascular accident; HFpEF, heart failure with preserved ejection fraction; n, number of patients; PAD, peripheral artery disease; SD, standard deviation.

A logistic regression model demonstrated greater odds of HFpEF in women with increasing age per year (OR = 1.043, 95% CI = 1.027-1.059; P < .001), increasing BMI (OR = 1.037, 95% CI = 1.018-1.056; P < .001), having a rheumatological disorder (OR = 1.920, 95% CI = 1.457-2.530; P < .001), having a mental health disorder, such as depression or anxiety (OR = 1.898, 95% CI = 1.459-2.470; P < .001), having asthma (OR = 1.807, 95% CI = 1.350-2.420; P < .001), and having hypothyroidism (OR = 1.973, 95% CI = 1.486-2.618; P < .001; Table 3).

Table 3.

Influence of Variables in Women With HFpEF.

Variable	B	P	Exp(B)	95% C.I. for Exp(B)
Variable	B	P	Exp(B)	Lower	Upper
Age (years)	0.042	<.001	1.043	1.027	1.059
Body mass index	0.036	<.001	1.037	1.018	1.056
Race—White vs Black	0.211	.193	1.234	0.899	1.695
Race—White vs Other	−0.120	.551	0.887	0.599	1.314
Hypothyroid	0.679	<.001	1.973	1.486	2.618
Rheumatological disorder	0.652	<.001	1.920	1.457	2.530
Mental health disease	0.641	<.001	1.898	1.459	2.470
Chronic kidney disease	−0.390	.003	0.677	0.522	0.879
Coronary artery disease	−0.784	<.001	0.457	0.352	0.539
Asthma	0.592	<.001	1.807	1.350	2.420

Women With HFrEF Versus Men With HFrEF

The mean age and race distribution were comparable between the WHFrEF group (n = 225) and MHFrEF group (n = 250; Table 4). In both the groups, majority of the patients identified as of White race followed by Black and other races; however, the difference was not significant (Table 4). Use of tobacco and alcohol were significantly lower in the WHFrEF group compared to the MHFrEF group, while we found no difference in the use of recreational drugs (Table 4). There were no differences in the frequencies of family history of heart failure, mean BMI, and mean SBP and mean DBP between the 2 groups (Table 4).

Table 4.

Baseline Characteristics of Patients With HFrEF.

Variable	Variable	Women with HFrEF (n = 225)	Men with HFrEF (n = 250)	P-value
Age	Years, mean (SD)	80.9 (9.1)	79.7 (8.6)	.127
Race	White, n (%)	130 (57.8)	155 (62.0)	.261
	Black, n (%)	63 (28.0)	54 (21.6)
	Other, n (%)	32 (14.2)	41 (16.4)
Social	Tobacco use, n (%)	116 (51.6)	133 (53.2)	.001
	Alcohol use, n (%)	54 (24.0)	109 (43.6)	<.001
	Recreational drug use, n (%)	6 (2.7)	13 (5.2)	.159
Family history	Heart failure/CAD, n (%)	120 (53.3)	143 (57.2)	.130
Biometric values	BMI (kg/m²), mean (SD)	29.0 (7.2)	28.2 (5.7)	.218
	SBP (mmHg), mean (SD)	122 (21)	123 (18)	.697
	DBP (mmHg), mean (SD)	69 (11)	71 (10)	.175

Abbreviations: BMI, Body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; HFpEF, heart failure with preserved ejection fraction; n, number of patients; SBP, systolic blood pressure; SD, standard deviation.

Analysis of associations with comorbid medical diagnoses in the WHFrEF group compared to the MHFrEF group revealed higher prevalence of asthma (26.7 vs 16.8%; P = .009), depression (40.0 vs 22.0%; P < .001), hypothyroidism (32.0 vs 20.0%; P = .003), and anxiety (32.9 vs 21.6%; P = .006; Table 5). Additionally, we found significantly lower prevalence of some comorbidities with WHFrEF group compared to the MHFrEF group, such as CKD (47.6 vs 58.8%; P = .014), CAD (60.0 vs 77.2%; P < .001), OSA (21.3 vs 29.2%; P = .049), atrial fibrillation (47.1 vs 56.8%; P = .035), and other cardiac dysrhythmias (32.4 vs 41.2%; P = .049; Table 5). We did not find significant differences in the prevalences of hypertension, DM, dyslipidemia, PAD, carotid artery disorder, COPD, osteoarthritis, other rheumatological disorders, chronic liver disease, bipolar disorder, hyperthyroidism, anemia, schizophrenia, cancer, acquired valvular heart disease, congenital heart disease, myocardial deposition disorder, pulmonary hypertension, CVA, COVID-19 disease, or prior use of chemotherapy (Table 5).

Table 5.

Comparative Associations of Comorbidities in Patients With HFrEF.

Variable	Women with HFrEF (n = 225)	Men with HFrEF (n = 250)	P-value
Hypertension, n (%)	213 (94.7)	241 (96.4)	.359
Dyslipidemia, n (%)	200 (88.9)	224 (89.6)	.803
Diabetes mellitus, n (%)	117 (52.0)	137 (54.8)	.541
CKD, n (%)	107 (47.6)	147 (58.8)	.014
CAD, n (%)	135 (60.0)	193 (77.2)	<.001
PAD, n (%)	53 (23.6)	61 (24.4)	.830
Carotid artery disease, n (%)	38 (16.9)	38 (15.2)	.616
COPD, n (%)	66 (29.3)	66 (26.4)	.476
Asthma, n (%)	60 (26.7)	42 (16.8)	.009
Obstructive sleep apnea, n (%)	48 (21.3)	73 (29.2)	.049
Osteoarthritis, n (%)	114 (50.7)	105 (42.0)	.058
Other rheumatological disorders, n (%)	52 (23.1)	44 (17.6)	.135
Chronic liver disease, n (%)	32 (14.2)	27 (10.8)	.259
Depression, n (%)	90 (40.0)	55 (22.0)	<.001
Bipolar disorder, n (%)	4 (1.8)	5 (2.0)	1.000
Hypothyroidism, n (%)	72 (32.0)	50 (20.0)	.003
Hyperthyroidism, n (%)	8 (3.6)	8 (3.2)	.830
Anemia, n (%)	118 (52.4)	128 (51.2)	.786
Anxiety, n (%)	74 (32.9)	54 (21.6)	.006
Schizophrenia, n (%)	4 (1.8)	2 (0.8)	.429
Cancer, n (%)	17 (33.6)	17 (7.6)	.951
Atrial fibrillation, n (%)	106 (47.1)	142 (56.8)	.035
Other cardiac dysrhythmias, n (%)	73 (32.4)	103 (41.2)	.049
Acquired valvular heart disease, n (%)	123 (54.7)	151 (60.4)	.207
Congenital heart disease, n (%)	10 (4.4)	11 (4.4)	.981
Myocardial deposition disorder, n (%)	3 (1.3)	7 (2.8)	.345
Pulmonary hypertension, n (%)	53 (23.6)	57 (22.8)	.845
CVA, n (%)	57 (25.3)	57 (22.8)	.519
COVID-19 disease, n (%)	56 (24.9)	56 (22.4)	.523
Post chemotherapy, n (%)	27 (12.0)	22 (8.8)	.252

Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CVA, cerebrovascular accident; HFpEF, heart failure with preserved ejection fraction; n, number of patients; PAD, peripheral artery disease; SD, standard deviation.

Greater odds of HFrEF in women was noted for Black race (OR = 1.455, 95% CI = 1.018-2.080; P = .039; Table 6).

Table 6.

Influence of Variables in Women With HFrEF.

Variable	B	P	Exp(B)	95% C.I. for Exp(B)
Variable	B	P	Exp(B)	Lower	Upper
Age (years)	−0.003	.753	0.997	0.980	1.015
Body mass index	−0.022	.050	0.979	0.958	1.000
Race—White vs Black	0.375	.039	1.455	1.018	2.080
Race—White vs Other	0.167	.460	1.181	0.759	1.839
Hypothyroid	0.291	.081	1.338	0.965	1.855
Rheumatological Disorder	0.377	.167	1.458	0.854	2.491
Mental health disease	0.172	.265	1.187	0.878	1.605
Chronic kidney disease	−0.396	.009	0.673	0.499	0.908
Coronary artery disease	0.021	.893	1.021	0.755	1.380
Asthma	0.027	.875	1.028	0.730	1.447

Discussion

We found that compared to men, women with HFpEF had higher prevalence of old age, elevated BMI, asthma, osteoarthritis, depression, anxiety, and hypothyroidism; while women with HFrEF had higher prevalence of Black race, asthma, depression, anxiety, and hypothyroidism.

In our population of patients, women with HFpEF were older in age compared to the men with HFpEF. Although, there happens to be a similar lifetime risk of HF in both men and women; nevertheless, reported studies showed increased prevalence of HFpEF in women, when compared to men and the prevalence increased with age.^7,13,14 A study that analyzed 3, large HFpEF trials revealed that patients who were younger were mostly men who were obese, while patients who were older comprised of women with comorbid medical conditions.¹⁵ Although there is no clear mechanism which explains this phenomenon, there are several proposed hypotheses: (1) greater inflammation of the myocardial muscles in women associated with microvascular dysfunction; (2) presence of risk factors that were sex-specific, such as adverse pregnancy outcomes, reproductive factors and early menopause; and (3) the fact that traditional HF risk factors, such as CAD, DM, obesity, and hypertension tend to contribute to the development of HFpEF preferentially in women.¹³ Moreover, estradiol regulates inflammatory factors, hence a declining level of estradiol during menopause leads to changes in blood pressure, lipid content, and body fat, which are all known risk factors in the development of HFpEF.¹⁶ Although, older age has been reported as a risk factor for HFpEF in both men and women; however, there are no reports that suggest a predilection toward women more than men. Our study underscores a greater association of older age with women who had HFpEF compared to men with HFpEF.

It has been reported that up to 80% of all individuals with HFpEF, irrespective of sex, tend to be either overweight or obese. Obesity-related pathophysiological changes include increased plasma volume, right ventricular dysfunction, and concentric left ventricular remodeling in such population.^17-19 In our study, we found that when compared to men, women with HFpEF had a higher association with elevated BMI which has not been explicitly reported. Women with HFpEF and elevated BMI tend to exhibit greater visceral adipose tissue (VAT) accumulation, which has been implicated with severe hemodynamic abnormalities during exercise, including higher pulmonary capillary wedge pressure (PCWP).²⁰ This suggests that VAT might play a distinct role in the pathophysiology of HFpEF in women, contributing to decreased exercise capacity and higher filling pressures.^20,21 We also found that higher BMI was more strongly linked to HFpEF in women than HFrEF. This association underscores the importance of managing obesity and its related conditions to mitigate the risk and severity of HFpEF in women.

We found that osteoarthritis was strongly associated with HFpEF in women which has not been reported so far. One study reported that osteoarthritis was linked to increased cardiovascular risk factors such as obesity, hypertension, and systemic inflammation, which happen to be the risk factors for HFpEF.²² This association was believed to be due to the higher prevalence of systemic inflammation and metabolic syndrome in women with osteoarthritis, which could exacerbate the pathophysiological mechanisms underlying HFpEF.²³

It has been reported that HFrEF happens to be more prevalent in individuals who identify as of the Black race when compared to other racial groups.²⁴ In the Multi-Ethnic Study of Atherosclerosis (MESA) regarding individuals without baseline cardiovascular disease, individuals identified as of Black race had the highest risk of developing HF, followed by individuals of Hispanic, White, and Chinese race categories.²⁵ Similar findings were observed in the Atherosclerosis Risk in Communities (ARIC) study, in which Black American men and women had a higher burden of new-onset HF compared to White men and women.²⁶ Multiple studies have shown that HFrEF is more prevalent in Black men than in Black women, with Black women having higher rates than White women but still lower than Black men.^6,7,27-32 However, in our study, we found that Black race had a stronger association with women with HFrEF compared to HFrEF in men and women of any other race. Several factors might contribute to this association in Black race and women with HFrEF, such as a higher burden of modifiable risk factors, including DM, hypertension, obesity, and other non-ischemia related causes.³³

Asthma has been reported to be associated with an increased risk of developing cardiovascular disease, especially in women.^34,35 A prospective study of over 200 000 patients found that asthma was associated with a 2.14-fold increased hazard of HF (HFpEF and HFrEF), with stronger associations observed with women compared to men.³⁶ A meta-analysis of 18 cohort studies reported a pooled risk ratio of 2.1 for HF in individuals with asthma compared to non-asthmatics, and noted that women with asthma had a higher risk, suggesting a possible sex-specific effect for cardiovascular risk.³⁷ There are other epidemiological reviews that have supported the link between asthma and increased cardiovascular risk, including HF, and have highlighted the role of systemic inflammation.^38,39 Our observation of association of asthma with HF in women aligns with the existing literature.

We found a strong association of depression and anxiety disorder in women with HF (both HFpEF and HFrEF). Several studies have reported that depression and anxiety were common in women with HF and were associated with poor outcomes, including increased morbidity, mortality, and reduced quality of life.^40,41 One study reported that compared to men with HF, women with HF were more likely to develop depression, and depressive symptoms in women were strongly linked to higher risk of cardiovascular death.⁴² Changes in depression severity over time also impacted the prognosis.⁴² It has also been observed that in women with HFrEF, association of depression at baseline had a stronger association with cardiovascular death.³⁴ Another prospective cohort study reported that among individuals with anxiety disorder only, depression only, and individuals with both conditions, the risk of HF was greater than in the individuals without these conditions.⁴³ A large cohort Veteran’s Administration study concluded that anxiety disorder, depression, and co-occurring anxiety with depression were associated with HF in patients who were free of cardiovascular disease at baseline.⁴⁴ The investigators also found that the risk of HF was greater after accounting for the protective effects of psychotropic medications.⁴⁴ Despite their impact, depression and anxiety are often underdiagnosed and undertreated in HF, highlighting the need for routine screening and targeted psychosocial interventions, particularly in women.

Hypothyroidism has been reported to be associated with an increased risk of HF, with women being at a higher risk than men for developing HF after hypothyroidism.^45-51 Both subclinical and overt hypothyroidism have been reported to be linked to adverse cardiac changes, such as diastolic dysfunction, increased systemic vascular resistance, and progression to HFpEF and HFrEF.⁴⁶ We found a similar association. Women with hypothyroidism, particularly after iodine exposure, were found to have a significantly higher risk of developing HF compared to men.⁴⁷ While thyroid hormone replacement improved cardiac function in some cases, evidence has been mixed regarding whether treating subclinical hypothyroidism might reduce HF risk, or not.^49,50 Further research is needed to clarify sex-specific risks and treatment benefits.

Being a retrospective study, our study had a few limitations. We had to solely rely on the documentation of the clinical care team regarding the onset of HF and the onset of the comorbidities, while inadequate or duplication of HF diagnosis in the medical records forced us to exclude several patients who had no concurring supportive echocardiogram evidence. Since the study patients belonged to the medical offices in urban settings, our results cannot be generalized. Moreover, diet, physical activity, and socioeconomic status could not be included in the study which might have influenced the sex-specific risk of HF. However, in this study, we could review a large database of existing patients who received their medical care in the offices of a single healthcare institution which allowed the care teams to document events and comorbidities in a chronological order over a long duration of follow up.

Conclusion

We provide a comprehensive list of risk factors associated with HF in women and conclude that in women with HF, old age, elevated BMI, and osteoarthritis are associated with HFpEF; Black race is associated with HFrEF; while asthma, depression, anxiety, and hypothyroidism are associated with both HFpEF and HFrEF when compared to men with HF. Further research in different settings may allow clinicians to identify, modify, and optimize the sex specific risk factors associated with HF in women.

Footnotes

ORCID iDs

Anika Pruthi

Sarah Kim

Joseph Ragan

Krystal Hunter

Satyajeet Roy

Consent to Participate

Not applicable. Being a retrospective chart review study, the Institutional Review Board waived the need for informed consent.

Author Contributions

KY and SR made substantial contributions to the study design, drafting, data acquisition, data analysis, and manuscript writing. All authors contributed to data collection and manuscript writing. KH analyzed the data. SR contributed by revising the manuscript critically for improved intellectual content, and final approval for the version to be published.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The authors declare that data supporting the findings of this study are available within the article.

References

Bozkurt

Ahmad

Alexander

, et al.; Writing Committee Members. Heart failure epidemiology and outcomes statistics: a report of the Heart Failure Society of America. J Card Fail. 2023;29(10):1412-1451.

Tahhan

Vaduganathan

Greene

, et al. Enrollment of older patients, women, and racial and ethnic minorities in contemporary heart failure clinical trials: a systematic review. JAMA Cardiol. 2018;3(10):1011-1019.

Morgan

Sinha

Mcentegart

, et al. Evaluation of the causes of sex disparity in heart failure trials. Heart. 2022;108(19):1547-1552.

Whitelaw

Sullivan

Eliya

, et al. Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review. Eur J Heart Fail. 2021;23(1):15-24.

Wang

Evans

Sawant

, et al. Sex-specific differences in the efficacy of heart failure therapies: a meta-analysis of 84,818 patients. Heart Fail Rev. 2023;28(4):949-959.

Heidenreich

Bozkurt

Aguilar

, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421.

Lam

CSP

Arnott

Beale

, et al. Sex differences in heart failure. Eur Heart J. 2019;40(47):3859-3868c.

Simmonds

Cuijpers

Heymans

, et al. Cellular and molecular differences between HFpEF and HFrEF: a step ahead in an improved pathological understanding. Cells. 2020;9(1):242.

Regitz-Zagrosek

Sex and gender differences in heart failure. Int J Heart Fail. 2020;2(3):157-181.

10.

Lee

Glynn

Schneeweiss

, et al. Risk factors for heart failure with preserved or reduced ejection fraction among medicare beneficiaries: application of competing risks analysis and gradient boosted model. Clin Epidemiol. 2020;12:607-616.

11.

Khan

Beach

Yancy

CW.

Sex-based differences in heart failure: JACC focus seminar 7/7. J Am Coll Cardiol. 2022;79(15):1530-1541.

12.

Savarese

D’Amario

Sex differences in heart failure. Adv Exp Med Biol. 2018;1065:529-544.

13.

Kaur

Lau

Sex differences in heart failure with preserved ejection fraction: from traditional risk factors to sex-specific risk factors. Womens Health. 2022;18:17455057221140209.

14.

Ceia

Fonseca

Mota

, et al. Prevalence of chronic heart failure in Southwestern Europe: the EPICA study. Eur J Heart Fail. 2002;4(4):531-539.

15.

Tromp

Shen

Jhund

, et al. Age-related characteristics and outcomes of patients with heart failure with preserved ejection fraction. J Am Coll Cardiol. 2019;74:601-612.

16.

Sabbatini

Kararigas

Menopause-related estrogen decrease and the pathogenesis of HFpEF: JACC review topic of the week. J Am Coll Cardiol. 2020;75:1074-1082.

17.

Powell-Wiley

Poirier

Burke

, et al.; American Heart Association Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and Stroke Council. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143(21):e984-e1010.

18.

Bozkurt

Aguilar

Deswal

, et al.; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; and Council on Quality and Outcomes Research. Contributory risk and management of comorbidities of hypertension, obesity, diabetes mellitus, hyperlipidemia, and metabolic syndrome in chronic heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134(23):e535-e578.

19.

Kittleson

Panjrath

Amancherla

, et al. 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;81(18):1835-1878.

20.

Sorimachi

Obokata

Takahashi

, et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur Heart J. 2021;42(16):1595-1605.

21.

Sorimachi

Omote

Omar

, et al. Sex and central obesity in heart failure with preserved ejection fraction. Eur J Heart Fail. 2022;24(8):1359-1370.

22.

Veronese

Trevisan

De Rui

, et al. Association of osteoarthritis with increased risk of cardiovascular diseases in the elderly: findings from the Progetto Veneto Anziano Study Cohort. Arthritis Rheumatol. 2016;68(5):1136-1144.

23.

Packer

Lam

CSP

Lund

, et al. Characterization of the inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction: a hypothesis to explain influence of sex on the evolution and potential treatment of the disease. Eur J Heart Fail. 2020;22(9):1551-1567.

24.

Piña

Jimenez

Lewis

, et al. Race and ethnicity in heart failure: JACC focus seminar 8/9. J Am Coll Cardiol. 2021;78(25):2589-2598.

25.

Bahrami

Kronmal

Bluemke

, et al. Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atherosclerosis. Arch Intern Med. 2008;168(19):2138-2145.

26.

Loehr

Rosamond

Chang

, et al. Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). Am J Cardiol. 2008;101(7):1016-1022.

27.

Chandra

Skali

Claggett

, et al. Race- and gender-based differences in cardiac structure and function and risk of heart failure. J Am Coll Cardiol. 2022;79(4):355-368.

28.

Pandey

Omar

Ayers

, et al. Sex and race differences in lifetime risk of heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Circulation. 2018;137(17):1814-1823.

29.

Heredia-Campos

Rodríguez-Gómez

Perea-Armijo

, et al. Heart failure with reduced ejection fraction: influence of gender on clinical characteristics, cardiac remodeling and neurohormonal response. Med Clin (Barc). 2025;164(12):106962.

30.

Eaton

Abdulbaki

Margolis

, et al. Racial and ethnic differences in incident hospitalized heart failure in postmenopausal women: the Women’s Health Initiative. Circulation. 2012;126(6):688-696.

31.

Mehta

Velarde

Lewey

, et al.; American Heart Association Cardiovascular Disease and Stroke in Women and Underrepresented Populations Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council. Cardiovascular disease risk factors in women: the impact of race and ethnicity: a scientific statement from the American Heart Association. Circulation. 2023;147(19):1471-1487.

32.

Chang

Wruck

Shahar

, et al. Trends in hospitalizations and survival of acute decompensated heart failure in four US Communities (2005-2014): ARIC study community surveillance. Circulation. 2018;138(1):12-24.

33.

Lewsey

Breathett

Racial and ethnic disparities in heart failure: current state and future directions. Curr Opin Cardiol. 2021;36(3):320-328.

34.

Pollevick

Mhango

, et al. The relationship between asthma and cardiovascular disease: an examination of the Framingham offspring study. Chest. 2021;159(4):1338-1345.

35.

Tattersall

Dasiewicz

McClelland

, et al. Persistent asthma is associated with carotid plaque in MESA. J Am Heart Assoc. 2022;11(23):e026644.

36.

Iribarren

Tolstykh

Miller

, et al. Adult asthma and risk of coronary heart disease, cerebrovascular disease, and heart failure: a prospective study of 2 matched cohorts. Am J Epidemiol. 2012;176(11):1014-1024.

37.

Hua

Diao

LL.

Bronchial asthma and risk of 4 specific cardiovascular diseases and cardiovascular mortality: a meta-analysis of cohort studies. Eur Rev Med Pharmacol Sci. 2022;26(14):5081-5091.

38.

Tattersall

MC.

Asthma as a systemic disease: cardiovascular effects associated with asthma. Adv Exp Med Biol. 2023;1426:77-100.

39.

Tattersall

Guo

Korcarz

, et al. Asthma predicts cardiovascular disease events: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35(6):1520-1525.

40.

Manolis

Melita

, et al. Neuropsychiatric disorders in patients with heart failure: not to be ignored. Heart Fail Rev. 2023;28(4):821-858.

41.

Celano

Villegas

Albanese

, et al. Depression and anxiety in heart failure: a review. Harv Rev Psychiatry. 2018;26(4):175-184.

42.

Zhao

Jiang

Zhong

, et al. Prognostic value of depressive symptoms for cardiovascular events in female patients with heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. J Am Heart Assoc. 2024;13(9):e032961.

43.

Nakada

Celis-Morales

, et al. Individual and joint associations of anxiety disorder and depression with cardiovascular disease: a UK Biobank prospective cohort study. Eur Psychiatry. 2023;66(1):e54.

44.

Garfield

Scherrer

Hauptman

, et al. Association of anxiety disorders and depression with incident heart failure. Psychosom Med. 2014;76(2):128-136.

45.

Peeters

RP.

Subclinical hypothyroidism. N Engl J Med. 2017;376(26):2556-2565.

46.

Rodondi

Bauer

Cappola

, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. J Am Coll Cardiol. 2008;52(14):1152-1159.

47.

Inoue

Guo

Lee

, et al. Iodine-induced hypothyroidism and long-term risks of incident heart failure. J Am Heart Assoc. 2023;12(20):e030511.

48.

Gencer

Collet

Virgini

, et al.; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012;126(9):1040-1049.

49.

Bielecka-Dabrowa

Godoy

Suzuki

Banach

, et al. Subclinical hypothyroidism and the development of heart failure: an overview of risk and effects on cardiac function. Clin Res Cardiol. 2019;108(3):225-233.

50.

Rizzo

Gioia

Parisi

, et al. Dysthyroidism and chronic heart failure: pathophysiological mechanisms and therapeutic approaches. Adv Exp Med Biol. 2018;1067:239-253.

51.

Ning

Gao

Triggiani

, et al. Prognostic role of hypothyroidism in heart failure: a meta-analysis. Medicine (Baltimore). 2015;94(30):e1159.