Special Prognostic Phenomenon for Patients With Mid-Range Ejection Fraction Heart Failure: A Systematic Review and Meta-Analysis
Heart failure (HF) affects over 64 million people worldwide, making it a top driver of hospital stays and healthcare costs. For decades, doctors have classified HF using left ventricular ejection fraction (LVEF)—a measure of how well the heart’s main pumping chamber (left ventricle) pushes blood out. The two traditional groups are HF with reduced ejection fraction (HFrEF, LVEF <40%) (weak pumping) and HF with preserved ejection fraction (HFpEF, LVEF ≥50%) (stiff heart, normal pumping). But in 2016, the European Society of Cardiology added a third category: HF with mid-range ejection fraction (HFmrEF, LVEF 41–49%).
Despite this update, HFmrEF remains a puzzle. Is it a milder form of HFrEF? A subtype of HFpEF? Or something entirely unique? A 2020 systematic review and meta-analysis by Pan Guo (Tianjin Chest Hospital, Tianjin Medical University) and colleagues sought answers—by analyzing data from 19 studies involving 164,678 patients. Here’s what they found, and why it matters for anyone touched by HF.
What Is HFmrEF, and Why Does It Matter?
HFmrEF sits between HFpEF and HFrEF, accounting for 12–24% of all HF cases. Patients often have mild systolic dysfunction (reduced pumping ability) plus diastolic dysfunction (stiffness). But until now, its prognosis—how long patients live or how often they’re readmitted to the hospital—was unclear.
Guo’s team focused on four key outcomes:
- Long-term all-cause mortality (LAM): Death from any cause over ≥1 year.
- Short-term all-cause mortality (SAM): Death within 30 days.
- Long-term cardiovascular death (LCD): Death from heart-related causes.
- Long-term HF rehospitalization (LHR): Repeat hospital stays for HF.
Their goal? Compare HFmrEF’s risk to HFpEF and HFrEF—after adjusting for confounders like age, diabetes, and kidney disease.
The Study: What They Did
The team searched three major databases (PubMed, Embase, Web of Science) for cohort studies published by April 2019. They included only high-quality studies (rated 5–8 stars on the Newcastle-Ottawa Scale) that reported adjusted hazard ratios (HRs)—a statistic that measures how much one group’s risk of an outcome differs from another, after accounting for other factors.
For example, an HR of 1.0 means equal risk. An HR of 1.07 means a 7% higher risk; 0.80 means a 20% lower risk.
Key Findings: The “Separation Phenomenon”
The results were surprising. At first glance, HFmrEF patients seemed to have the best outcomes:
- 31% died from any cause long-term (LAM), vs. 40% for HFpEF and 40% for HFrEF.
- 2.7% died short-term (SAM), vs. 4.2% for HFpEF and 3.4% for HFrEF.
- 26% were readmitted for HF (LHR), vs. 29% for HFpEF and 36% for HFrEF.
But when the team adjusted for differences between groups—like HFpEF patients being older (76.6 vs. 72.4 years) and having more chronic obstructive pulmonary disease (COPD)—the risk picture flipped. HFmrEF patients had a higher adjusted risk of poor outcomes than HFpEF, but a lower risk than HFrEF.
For long-term all-cause mortality (the study’s main focus):
- HFmrEF vs. HFpEF: HR = 1.07 (7% higher risk).
- HFmrEF vs. HFrEF: HR = 0.80 (20% lower risk).
This mismatch—lower raw event rates but higher adjusted risk—is what the authors call the “separation phenomenon.” It means HFmrEF is not just a “middle ground” between HFpEF and HFrEF—it’s a unique subtype with its own risks.
Why Does This Happen?
The separation phenomenon boils down to confounders—factors that make HFpEF patients look “healthier” on paper but actually have higher underlying risks. For example:
- HFpEF patients are older, so their raw death rates are higher—but age is a strong driver of mortality. When the team adjusted for age, HFmrEF’s relative risk became clearer.
- HFpEF patients have more non-cardiac conditions (like COPD), which can mask the true risk of their heart failure.
Another key factor: ischemic heart disease (IHD)—blocked heart arteries. HFmrEF patients had almost the same rate of IHD as HFrEF (53.5% vs. 54.7%)—far higher than HFpEF (42.3%). IHD is a major driver of HF progression: HFmrEF patients with IHD are more likely to develop HFrEF (a worse prognosis), while those without IHD often shift to HFpEF.
What Does This Mean for Patients?
The study has big implications for how doctors treat HFmrEF:
- HFmrEF patients need aggressive cardiovascular care: Because of their high IHD rates and risk of progressing to HFrEF, treatments like statins, beta-blockers, or coronary stents (PCI) may be more beneficial than in HFpEF.
- HFpEF patients need comprehensive care: Their higher raw death rates come from non-cardiac issues (like COPD or kidney disease). Managing these comorbidities is just as important as treating their heart failure.
- HFmrEF is dynamic: LVEF can change over time. Patients with HFmrEF should have regular follow-ups to monitor for shifts to HFrEF or HFpEF.
For patients, the takeaway is clear: Not all heart failure is the same. If you have HFmrEF, ask your doctor about screening for IHD and adjusting treatments to prevent progression.
Limitations and Future Research
Like all studies, this one has gaps:
- Most included studies were observational (not randomized trials), so they can’t prove causation—only correlation.
- Follow-up times varied (1–5 years), which may affect results.
- Few studies reported long-term cardiovascular death (LCD), so those results are less robust.
The authors call for more research into:
- Why HFmrEF patients convert to other subtypes.
- Which treatments work best for HFmrEF (e.g., ACE inhibitors vs. ARBs).
- How to tailor care to HFmrEF’s unique risks.
Conclusion
Heart failure with mid-range ejection fraction (HFmrEF) is more than just a “gap filler” between HFpEF and HFrEF. It’s a distinct subtype with its own clinical features, risks, and treatment needs. The “separation phenomenon”—lower raw event rates but higher adjusted risk—highlights why doctors can’t rely on LVEF alone to guide care.
For patients, this means personalized treatment: HFmrEF patients may need more focus on their heart arteries, while HFpEF patients benefit from managing all their chronic conditions. For researchers, it means HFmrEF deserves more attention—because solving its mysteries could save thousands of lives.
The original study was published in the Chinese Medical Journal in 2020 by Pan Guo, Jian-Feng Dai, Chao Feng, Shu-Tao Chen, and Jin-Ping Feng (Department of Cardiology, Tianjin Chest Hospital, and Graduate School of Medicine, Tianjin Medical University).
doi:10.1097/CM9.0000000000000653
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