Heart Failure: A Look at Low Ejection Fraction

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Failure of the heart to effectively pump oxygenated blood through the left ventricle out to the rest of the body, or less commonly, to push it toward the lungs for oxygenation, can arise from any one of a number of causes. However, the impact of heart failure (HF) on patients typically follows a similar progressive trajectory.

At-risk, or so-called stage A, HF comprises a large proportion of the population. Common risk factors for HF affect hundreds of millions of people in the United States alone: some 115 million people have hypertension, 100 million have obesity, 92 million have prediabetes, 26 million have diabetes, and 125 million have atherosclerotic cardiovascular disease.

Pooling together the cardiometabolic risk factors of coronary heart disease, hypertension, diabetes, obesity, and smoking, accounted for 52% of incident HF in one study. Optimal health on at least five of seven components emphasized by the American Heart Association -- smoking, body mass index, physical activity, diet, cholesterol, blood pressure, and glucose -- was associated with 12% lifetime incidence of HF, compared with 45% among those who had less optimal status on all seven counts.

These factors contribute to the most common causes of HF: ischemic heart disease and myocardial infarction (MI), hypertension, and valvular heart disease.

Ischemia in the heart leads to hypoxia, fibrosis, and tissue death that impairs function. Coronary microvascular dysfunction may have similar effects. Ischemic heart disease raises the risk of heart failure by eight-fold, with a population-attributable risk of 65% in men and 48% in women, according to one review.

Hypertension over time can lead to left ventricular hypertrophy and diastolic dysfunction that makes the heart less compliant to preload, afterload, and sympathetic tone, resulting in progression to overt heart failure, as a review in Clinical Hypertension notes. Hypertension is also a risk factor for ischemic heart disease.

Chronic valvular heart disease imposes both excess preload and afterload on the left ventricle (LV), which ultimately leads to progressive LV dilation and systolic dysfunction as a result. Left untreated as aortic stenosis severity progresses, some 50% of patients develop HF. Primary mitral regurgitation can also cause HF.

"Other causes can include familial or genetic cardiomyopathies; amyloidosis; cardiotoxicity with cancer or other treatments or substance abuse such as alcohol, cocaine, or methamphetamine; tachycardia, right ventricular (RV) pacing or stress-induced cardiomyopathies; peripartum cardiomyopathy; myocarditis; autoimmune causes, sarcoidosis; iron overload, including hemochromatosis; and thyroid disease and other endocrine metabolic and nutritional causes," as the HF guidelines note.

The familial and genetic contribution to HF was emphasized by the multigenerational Framingham Heart Study, in which people with at least one parent impacted by HF had a 5.7% rate of asymptomatic LV systolic dysfunction compared with 3.1% among those without a parent with HF and a relative 72% higher incidence of HF, both of which were significant differences adjusted for age, sex, and height. Genome-wide association studies have identified dozens of potentially impactful loci.

Stage B, presymptomatic, HF can be detected with cardiac imaging and biomarkers of myocardial injury or cardiac maladaptive structural changes even without gross LV dysfunction or symptoms. This group is expected to grow with increasing sensitivity of such tests and other factors, like the COVID-19 pandemic.

Epidemiology

With an aging population, HF prevalence is rising in the United States.

National Health and Nutrition Examination Survey (NHANES) data showed an increase from about 5.7 million U.S. adults with HF in 2009-2012 to about 6.0 million in 2015-2018, representing 2.1% of the population. That number is expected to rise by 46%, compared with 2012, to reach a prevalence of more than eight million adults by 2030, representing 3.0% of the total population, according to projections from the American Heart Association (AHA).

Incidence, on the other hand, has been declining overall. In a study of Medicare data, HF incidence declined from 36 cases per 1,000 beneficiaries in 2011 to 26.5 per 1,000 in 2016.

Interestingly, incidence trends have diverged between HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF). In a study from Olmsted County, Minnesota, (near the Mayo Clinic there) age- and sex-adjusted incidence of HF declined in both groups from 2000-2010, but by 45% for HFrEF (−33% to −55%) compared with 27.9% for HFpEF (95% CI −12.9% to −40.3%).

In pooled data from the Framingham Heart Study and the Cardiovascular Health Study, the incidence of HFrEF dropped from 6.6 to 6.2 per 1,000 from 1990-1999 to 2000-2009, while the rate rose from 4.7 to 6.8 per 1,000 for HFpEF over the same timeframe.

"The lifetime risk of HF remains high, with variation across racial and ethnic groups ranging from 20% to 45% after 45 years of age," according to AHA statistics for 2022. The AHA pointed to data from the Southern Community Cohort Study, in which estimated age-standardized HF incidence rates were 34.8, 37.3, 34.9, and 35.6 per 1,000 person-years in white females, white males, Black males, and Black females, respectively. In the somewhat older MESA study, African Americans had the highest incidence rate, followed by Hispanic, white, and Chinese American participants (4.6, 3.5, 2.4, and 1.0 per 1,000 person-years, respectively).

The slight predominance in males with the condition yielded population prevalence rates of 2.5% in males and 1.7% in females overall. Women are more prone to develop HFpEF than HFrEF.

Estimates vary by age as well, with prevalence rising to more than 10% among people over age 70 and an incidence of nearly 21 per 1,000 persons after age 65, compared with 6.0 to 7.9 per 1,000 after age 45.

However, a review in Current Heart Failure Reports cautioned that these numbers "may underestimate the true scale of disease as the estimated prevalence of those with asymptomatic left ventricular (LV) systolic dysfunction in those aged over 65 years is 5.5%. One study estimates that the overall lifetime risk of developing HF is 33% for men and 28% for women."

HF With Mildly Reduced EF (HFmrEF)

This category was introduced as HF with "mid-range" ejection fraction -- 40-49% -- in the 2016 European Society of Cardiology heart failure guidelines before being christened HF with mildly reduced EF in the 2022 American College of Cardiology/AHA guidelines. A review by Lars Lund, MD, PhD, of Karolinska University Hospital in Stockholm, and colleagues noted it as a fairly unexplored category that accounts for some 10-25% of HF cases.

While the category shares the most important clinical features with HFrEF, it varies in other aspects, Lund's group noted.

"HFmrEF seems to be an intermediate clinical entity between HFrEF and HFpEF in some respects, but more similar to HFrEF in others, in particular with regard to the high prevalence of ischemic heart disease in these patients," the authors wrote. "HFmrEF is milder than HFrEF, and the risk of cardiovascular events is lower in patients with HFmrEF or HFpEF than in those with HFrEF. By contrast, the risk of non-cardiovascular adverse events is similar or greater in patients with HFmrEF or HFpEF than in those with HFrEF."

In one study from Sweden, HFmrEF had virtually the same association with ischemic heart disease as did HFrEF, whereas ischemia was a less common precursor for HFpEF. Adjusted risk of new ischemic heart disease events were marginally less common in HFmrEF patients than in those with HFrEF (HR 0.95, 95% CI 0.90-1.00), whereas they were more common than with HFpEF.

Part of the reason for these similarities, as the 2022 guidelines note: "Patients with HFmrEF are usually in a dynamic trajectory to improvement from HFrEF or to deterioration to HFrEF. Therefore, for patients whose EF falls into this mildly reduced category, 1 EF measurement at 1 time point may not be adequate, and the trajectory of LVEF over time and the cause is important to evaluate."

Risk factors differ by HF subtype as well, with pooled analysis of four large community-based studies showing that HFrEF incidence was significantly more strongly associated with male sex, prior MI, left ventricular hypertrophy, and left bundle-branch block but less strongly associated with older age compared with HFpEF.

HF With Improved EF (HFimpEF)

Terminology for this group has shifted over time, called HFpEF-improved in the 2013 guidelines (those whose EF improved to cross the 40% threshold) or HF-recovered EF (baseline LVEF ≤40%, then a ≥10% increase and a second measurement of LVEF >40%). The 2022 HF guidelines settled on HFimpEF (LVEF previously ≤40% but >40% on follow-up), as the writing committee emphasized that this group isn't the same as patients who start out with HFpEF, even if their EF returns to greater than 50%.

"Although associated with better outcomes, improvement in LVEF does not mean full myocardial recovery or normalization of LV function," the guidelines cautioned. "In most patients, cardiac structural abnormalities, such as LV chamber dilatation and ventricular systolic and diastolic dysfunction, may persist."

A meta-analysis of nine studies showed that 22.6% of HFrEF patients moved into the HFimpEF category with treatment over a follow-up period of 3.8 years. This group had a relative 56% lower risk of mortality than patients who stayed in the HFrEF category and 60% lower risk of hospitalization as well. They also had a relative 58% lower risk of mortality and 27% lower likelihood of hospitalization compared with HFpEF patients.

"However, the change of LVEF might not be linear and unidirectional that a patient may have improvement followed by a decline in EF or vice versa, depending on the underlying etiology, duration of disease, adherence to the medications, comorbidities, or reexposure to cardiotoxins," those authors cautioned.

The natural history of this newly defined group is still being determined, as is evidence to guide treatment.

Up next: Exploring Heart Failure With Preserved Ejection Fraction