What causes heart failure with preserved ejection fraction (HFpEF)?

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial and multisystemic disorder that represents more than 50% of all heart failure cases.[1]

Epidemiologic data from the Framingham Study, an international cohort study, shows a rapid increase in the prevalence of HFpEF over the past three decades, from 41% to 56% and, conversely, a decrease in the prevalence of HFrEF from 44% to 31%. [2]

Because of its complex pathophysiology, increasing prevalence, high mortality and morbidity, and very limited therapeutic options, HFpEF is considered one of the greatest unmet medical needs in cardiovascular medicine.[1] 

Patients with HFpEF have higher morbidity, mortality, and rehospitalization. Quality of life in patients with HFpEF is worse than in those with heart failure with reduced ejection fraction (HFrEF).[3]

While HFrEF is dominated by left ventricular (LV) impairment, HFpEF results from a complex interplay of cardiac remodeling, peripheral circulation, and concomitant features including age, hypertension, obesity, and diabetes.[4]

Gaining a better understanding of HFpEF’s complex pathophysiology and its relationship between underlying age-related changes and frequent comorbidities may help us better understand the biology, diagnosis, and treatment of these patients.

What causes HFpEF?

HFpEF affects the left and right ventricles, diastolic and systolic function, atrial reserve, heart rate and rhythm, autonomic control, vasculature and microcirculation, and the periphery.[5]

While dominant contributors can vary from patient to patient, HFpEF is typically displayed as a conglomeration of several reserve impairments that combine to cause symptomatic heart failure (HF).

A great number of studies have attempted to uncover the cellular and molecular basis of HFpEF development, however, its pathophysiology remains complex.[1]

Though the processes leading to the cardiac, vascular, and peripheral limitations that cause HFpEF remain relatively unclear, epidemiological studies have found some leading risk factors for the development of the condition. [5]   

What are the comorbidities and risk factors for HFpEF?

There is a strong association between HFpEF, older age, and comorbidities. HFpEF patients are likely to have a high prevalence of cardiovascular and non-cardiovascular comorbidities, such as obesity, metabolic syndrome, diabetes mellitus type 2, salt-sensitive hypertension, atrial fibrillation (AF), chronic obstructive pulmonary disease, anaemia, and renal dysfunction.[6.7,8]

As life expectancy and comorbidity rates rise, the proportion of HF patients with HFpEF and the impact HFpEF has on healthcare services is projected to increase and become a greater health burden.

The importance of risk factors and comorbidities in HFpEF is recognized in the strong (Class I) recommendation in 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.[9] Except for comorbidity-specific guidelines, no HFpEF-specific treatment for comorbidities currently exist at this time.

Here’s what we know so far about some of these risk factors and their involvement in the progression to HFpEF: Aging

Structural and functional changes related to aging are believed to be significant risk factors of HFpEF, for example, ventricular arterial stiffening, vascular dysfunction, impaired Ca2+ regulation, and physical deconditioning. [5]

HFpEF has traditionally been perceived as a disease of the elderly. The PREVEND study showed that older age was strongly associated with new onset of HFpEF (HR 2.53; 95% CI [1.93–3.30], per 10 years).[10].

The high comorbidity burden in the elderly is postulated to play a central role in HFpEF’s pathology. Comorbidities have a cumulative and synergistic effect on cardiac function and outcomes. [11] The elderly with HFpEF have 5.5 noncardiac comorbidities on average. [12]

Aging promotes coronary microvascular endothelial abnormalities, myocardial remodeling, and dysfunction in HFpEF [13,14,15]. It contributes independently to the deterioration of diastolic function. [16,17].

Recent studies highlight the unique risk factors of younger patients with HFpEF. An analysis by the PREVEND, Framingham Heart Study and the MESA cohort Study explained hypertension, smoking and obesity in the young promote a greater risk for future HFpEF in younger than older individuals.[18] TOPCAT, I-Preserve and CHARM-Preserved showed a higher risk of cardiovascular death, particularly from sudden death in younger patients, despite fewer comorbidities.[19]

Preventative measures early in life in high-risk individuals might prove beneficial to reduce the burden of HFpEF.

Hypertension

Hypertension is the most common co-morbidity in HFpEF patients. Research suggests the prevalence of hypertension ranges between 55% and 90% in HFpEF patients[20,21,22], and that hypertension carries a sixfold increase in HF risk as compared to non-hypertensive individuals.[23]

Hypertension is not only a risk factor for increased LV afterload and pressure-induced hypertrophy, but it is also associated with a chronic proinflammatory state, arterial stiffness, and titin-dependent stiffness, which are central and peripheral mechanisms involved in the progression to HFpEF. [24]

Chronic arterial hypertension is also a known risk factor for renal impairment, which can lead to a poorer prognosis in HFpEF patients. [24]

There are multiple ways in which hypertension interacts with other comorbidities, the vasculature, and the heart to predispose to HFpEF, contributing to HFpEF’s complex pathophysiology. [25]

Despite it being challenging, it’s widely agreed that blood pressure control remains central in the clinical management of hypertensive patients with HFpEF.

Atrial Fibrillation

Atrial Fibrillation (AF) is a well-known risk factor and prognostic indicator in HFpEF. The prevalence of AF in HFpEF ranges from 15% to 40%,[26,27,28,29] and it seems to implicate a worse prognosis in patients with HFpEF than HFrEF.[30]

If both heart failure and AF coexist, the risk for worse outcomes and hospitalizations increases significantly, with a two-fold increase in mortality.[31]

AF and HFpEF appear to both be manifestations of a common underlying atrial and ventricular myopathy that is triggered when a systemic inflammatory or metabolic disorder causes coronary microvascular dysfunction and fibrosis of the atrial and ventricular myocardium, a process that may be mediated or exacerbated by inflammation in the adjoining epicardial adipose tissue.[32]

The diagnosis of HF can be complicated in the presence of AF because both conditions share common clinical manifestations, such as similar symptoms and elevated B-type natriuretic peptides.[33] Regardless of which disorder presents first, both are or will soon become evident in the same patients.[32]

Obesity

More than 80% of HFpEF patients are overweight or obese, and obesity is a major risk factor for incidents of HFpEF.[33]

Obesity and its related comorbidities – such as metabolic syndrome, sedentary lifestyle, and hypertension – have been commonly observed alongside HFpEF. They may interact with aging to further increase the risk of developing the condition. [5]

Obesity is often accompanied by increased epicardial adipose tissue volume, which transduces the effects of these diseases on cardiac function and structure. It has been additionally found to cause systemic inflammation, oxidative stress, and depressed nitric oxide availability that can lead to the manifestation of HFpEF.[5]

A consortium of four large community cohorts (the Cardiovascular Health Study, PREVEND, Framingham Heart Study and MESA) assessing 22,681 individuals showed that every 1 standard deviation increase in BMI was associated with 34% increase in incident HFpEF, consistent with other community studies.[34,35,36]

Diabetes

Diabetes is another major risk factor in patients with HFpEF. At least one-third of patients with HFpEF have a diagnosis of diabetes[37].

In the CHARM programme, 40% of patients with HFpEF had a diagnosis of diabetes at enrolment and another 22% were prediabetic with hemoglobin A1c between 6.0% and 6.4%.[38]

Like obesity, diabetes is accompanied by increased epicardial adipose tissue volume, which affects cardiac function [39] and can lead to inflammatory and fibrotic atrial and ventricular myopathy, the two major elements of HFpEF [40].

In addition to diabetes’ effect on the systemic inflammatory state, the condition can also contribute to the development of HFpEF through other pathways, such as accelerating atherosclerosis, leading to myocardial ischemia. [41]

Volume overload can also result from the progressive renal dysfunction associated with diabetes. Hyperglycemia and insulin resistance can promote autonomic neuropathy, contributing to cardiac stiffness, hypertrophy, and fibrosis. [41]

Sex Differences

The higher occurrence of HFpEF in women suggests that sex-dependent mechanisms may be involved in HFpEF pathogenesis (Dunlay et al., 2017).[41] In general, women tend to show more concentric LV remodeling, with smaller LV volumes, higher EF, and increased diastolic LV and arterial stiffness. [41, 42].

While gender seems to play a role in HFpEF development and progression, the detailed mechanisms underlying the gender-related differences in HFpEF are not yet understood.

What we do know is that women display a higher left ventricular ejection fraction (LVEF), a worse diastolic function, and fewer co-morbid conditions when compared to men. [43]

That said, women with HFpEF are more likely to be obese and to have a history of hypertension or renal impairment. More concerning, having hypertension increases the risk of heart failure by 3 times in women, compared to by 2 times in men. [41,42]

The high prevalence of HFpEF in postmenopausal women also hints that menopause-related estrogen dysregulation and the related comorbidities, such as obesity, diabetes, hypertension, and renal dysfunction, may contribute to HFpEF development (Sabbatini and Kararigas, 2020).[44]

Clinical Indicators to Chart the Pathophysiology of HFpEF

Tracking the clinical indicators of HFpEF can help us gain a better understanding of the processes and dysfunctions that might lead to the disorder. 

Circulating biomarkers reflect cardiac as well as non-cardiac abnormalities, and their measurements often provide insights into pathophysiological processes associated with HF. The clinical uptake of biomarkers for diagnosing HFpEF has generally been poor, with only cardiac natriuretic peptides (NPs) having emerged as clinically relevant. [45]

Indicators can include:

• Lower laboratory parameters, including blood urea nitrogen, creatinine, N-terminal pro-B-type natriuretic peptide (NT-proBNP), potassium, uric acid, and ferritin levels, when compared to populations with heart failure with mid-range ejection fraction (HFmrEF).
• Smaller LV end-diastolic and end-systolic dimensions, a lower left atrial volume index and LV mass index, and a higher LVEF when compared to HFmrEF patients. 
• Cardiac inflammation
• Significantly higher levels of ST2 and cystatin C than HFmrEF patients. 
• Increased collagen content
• Cardiac myocytes that are thicker and shorter than normal 
• Reductions in myocardial capillary density 
• Concentric organ remodeling with or without hypertrophy.

Holistic schematic of biomarkers in heart failure with preserved ejection fraction (HFpEF) [45]

New direction needed for HFpEF

There have been great strides taken to understand the epidemiology of HFpEF, but knowledge gaps still exist. Compared with advances in the diagnosis and treatment of HFrEF, HFpEF continues to be a great enigma.

The development of HFpEF involves a complex and multi-system integration of dysfunction, which makes it difficult to succinctly track its causes.

We do know that risk factors such as aging, obesity, and diabetes can play a role in its progression, alongside clinical indicators of HFpEF such as chronic cardiac inflammation. However, there is a lack of precise indicators for diagnosing HFpEF and a high prevalence of comorbidities that may interfere with HFpEF diagnosis.

More research regarding sex/gender, racial/ethnic, geographical, and socioeconomic variations in the prevalence, incidence, and outcomes are needed to address the global burden of HFpEF.

Optimized care pathways and prevention through early diagnosis and treatment of risk factors is currently the best approach to reducing hospitalizations through a seamless inpatient and outpatient care structure.