7.2 Management of Heart Failure with Preserved (HFpEF), Mildly Reduced (HFmrEF), and Improved Ejection Fraction (HFimpEF)

The Spectrum of Heart Failure Beyond Reduced Ejection Fraction

Heart failure encompasses a heterogeneous clinical continuum classified by left ventricular ejection fraction (LVEF). While Chapter 6 examined HFrEF (LVEF ≤40%), over half of all heart failure patients evaluated in contemporary practice possess an LVEF >40%. The 2022 AHA/ACC/HFSA guidelines formally codify three distinct categories within this spectrum:

1. Heart Failure with Preserved Ejection Fraction (HFpEF): LVEF ≥50% with evidence of spontaneous or provokable increased LV filling pressures.
2. Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF): LVEF 41% to 49% with evidence of elevated LV filling pressures.
3. Heart Failure with Improved Ejection Fraction (HFimpEF): A previous LVEF ≤40% with a follow-up measurement >40% (the 2021 Universal Definition adds a ≥10-point increase).

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Phenotypic Characterization and Pathophysiology of HFpEF

HFpEF is a complex systemic syndrome driven by systemic pro-inflammatory comorbidities rather than isolated cardiomyocyte loss. Comorbidities such as visceral obesity, longstanding arterial hypertension, Type 2 diabetes, chronic kidney disease, and aging induce widespread coronary microvascular endothelial inflammation.

• Endothelial-Cardiomyocyte Signaling: Microvascular inflammation stimulates reactive oxygen species (ROS) production and blunts endothelial nitric oxide synthase (eNOS), depleting bioavailable nitric oxide (NO). This reduces protein kinase G (PKG) activity in adjacent cardiomyocytes, causing hypophosphorylation of the giant sarcomeric spring protein titin. Hypophosphorylated titin stiffens cardiomyocytes. Concurrently, activated cardiac fibroblasts deposit excess cross-linked interstitial collagen.
• Diastolic Dysfunction: The physiological hallmark of HFpEF is impaired active early LV diastolic relaxation and increased passive late diastolic myocardial stiffness. Because the thick, concentric left ventricle cannot distend adequately during diastole, filling pressures (left ventricular end-diastolic pressure [LVEDP] and pulmonary capillary wedge pressure [PCWP]) skyrocket precipitously with small increases in intravascular volume or during exertion, precipitating acute pulmonary venous congestion and dyspnea.

                  PATHOGENIC CASCADE OF HFpEF
 ┌────────────────────────────────────────────────────────────────────────┐
 │ Comorbidities: Visceral Obesity, Hypertension, Diabetes, Aging, CKD    │
 └───────────────────────────────────┬────────────────────────────────────┘
                                     │
                                     ▼
 ┌────────────────────────────────────────────────────────────────────────┐
 │ Systemic Microvascular Endothelial Inflammation & Oxidative Stress     │
 └───────────────────────────────────┬────────────────────────────────────┘
                                     │
                                     ▼
 ┌────────────────────────────────────────────────────────────────────────┐
 │ ↓ Nitric Oxide (NO) Bioavailability ──► ↓ Cyclic GMP ──► ↓ PKG Activity│
 └───────────────────────────────────┬────────────────────────────────────┘
                                     │
                                     ▼
 ┌────────────────────────────────────────────────────────────────────────┐
 │ • Titin Hypophosphorylation (Sarcomeric Stiffening)                    │
 │ • Interstitial Collagen Deposition & Fibrosis                          │
 │ • Concentric LV Hypertrophy & Left Atrial Enlargement                  │
 └───────────────────────────────────┬────────────────────────────────────┘
                                     │
                                     ▼
 ┌────────────────────────────────────────────────────────────────────────┐
 │ Impaired Diastolic Filling & Explosive Exertional PCWP Surges ──► HFpEF│
 └────────────────────────────────────────────────────────────────────────┘

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SGLT2 Inhibitors: The Strongest HFpEF Recommendation

For decades, HFpEF lacked proven disease-modifying pharmacotherapy. This paradigm was shattered by two landmark randomized controlled clinical trials that established Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors as the first drug class with a Class 2a (Level of Evidence B-R) recommendation for HFmrEF and HFpEF in the 2022 AHA/ACC/HFSA guideline (the 2023 ESC focused update later made them Class I):

• EMPEROR-Preserved (Empagliflozin): Randomized 5,988 patients with HF and LVEF >40% (average LVEF 54%) to empagliflozin 10 mg daily vs. placebo. Empagliflozin produced a 21% relative risk reduction in the primary composite endpoint of cardiovascular death or hospitalization for heart failure (p < 0.001), driven primarily by a 29% reduction in HF hospitalizations. Benefits were consistent across diabetic and non-diabetic cohorts.
• DELIVER (Dapagliflozin): Randomized 6,263 patients with HF and LVEF >40% (including patients with previously reduced EF that improved to >40%) to dapagliflozin 10 mg daily vs. placebo. Dapagliflozin produced an 18% relative risk reduction in cardiovascular death or worsening heart failure (p < 0.001).
• Clinical Practice: Unless contraindicated, empagliflozin 10 mg or dapagliflozin 10 mg once daily is a reasonable first addition for patients with HFpEF and an eGFR ≥20–25 mL/min/1.73m², with no dose titration needed.

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Targeted Neurohormonal Blockade: MRA and ARNI in HFpEF

While neurohormonal antagonists do not demonstrate uniform, across-the-board mortality reductions in high-ejection fraction phenotypes, rich clinical trial data support their targeted deployment in selected subgroups:

1. Mineralocorticoid Receptor Antagonists (TOPCAT Trial)

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial randomized 3,445 patients with symptomatic HFpEF (LVEF ≥45%) to spironolactone (15 to 45 mg daily) vs. placebo.

• The Geographic Discordance: Overall global results narrowly missed statistical significance (p = 0.14). However, a post hoc regional analysis revealed profound geographic heterogeneity between patients enrolled in the Americas (United States, Canada, Argentina, Brazil) versus those in Eastern Europe (Russia, Georgia).
• Americas Cohort Findings: Patients in Russia and Georgia had vanishingly low event rates and undetectable spironolactone metabolite levels, indicating non-adherence or misdiagnosis. In contrast, in the Americas cohort, spironolactone was associated with an 18% lower rate of the primary composite (HR 0.82), with lower cardiovascular death and HF hospitalization.
• Guideline Status: Class 2b recommendation (2022 AHA/ACC/HFSA) for MRAs in selected HFpEF, particularly in patients with elevated natriuretic peptides, lower-range LVEF (45%–57%), and uncontrolled hypertension.

2. Angiotensin Receptor-Neprilysin Inhibitors (PARAGON-HF Trial)

The PARAGON-HF trial evaluated sacubitril/valsartan vs. valsartan in 4,796 patients with HFpEF (LVEF ≥45%).

• Efficacy in Lower-Spectrum EF and Women: The overall composite primary outcome missed conventional statistical significance by the slimmest margin (rate ratio 0.87, p = 0.059). However, prespecified subgroup analyses revealed striking heterogeneity:
  • Patients with lower LVEF (below the median of 57%, specifically 45% to 57%) had a 22% lower rate of the primary composite (total HF hospitalizations and cardiovascular death).
  • Women had a 27% lower rate of primary composite events in a prespecified subgroup analysis.
• FDA Indication & Guideline Status: The FDA expanded the indication for sacubitril/valsartan to include heart failure in adult patients with "below normal" LVEF. Guidelines grant a Class 2b recommendation for ARNI in HFpEF, with the most plausible benefit toward the lower end of the LVEF range.

3. Angiotensin Receptor Blockers (CHARM-Preserved)

In CHARM-Preserved (LVEF >40%), candesartan did not significantly reduce cardiovascular death but was associated with fewer HF hospitalizations. The 2022 guideline therefore rates an ARB as Class 2b in HFpEF to decrease hospitalizations, particularly toward the lower end of the LVEF spectrum. ARBs are also a reasonable way to treat coexisting hypertension.

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Multidimensional Comorbidity Management in HFpEF

Because myocardial stiffness in HFpEF is perpetuated by extracardiac pathologies, aggressive comorbidity management is mandatory:

1. Strict Blood Pressure Control: Uncontrolled hypertension increases left ventricular afterload, accelerates myocardial concentric remodeling, and worsens diastolic stiffness. The 2022 guideline recommends titrating blood pressure to published hypertension targets (Class 1), generally <130/80 mmHg, often using neurohormonal agents (ARNI, ACEi, ARB, MRA).
2. Obesity & Metabolic Weight Loss: Visceral adiposity expands plasma volume, promotes systemic inflammation, and constrains pericardial reserve. The landmark STEP-HFpEF trial demonstrated that once-weekly semaglutide (a GLP-1 receptor agonist) produced substantial weight loss, markedly improved Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, increased 6-minute walk distance, and reduced systemic inflammation (hs-CRP) in obese HFpEF patients.
3. Atrial Fibrillation Management: Loss of the active atrial "kick" in a non-compliant, stiff ventricle precipitates catastrophic decreases in cardiac output and acute pulmonary edema. Restoration of sinus rhythm (catheter ablation or antiarrhythmic drugs) or aggressive rate control is prioritized.

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Management of Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

Patients with an LVEF of 41% to 49% occupy the intermediate "gray zone" known as HFmrEF. Secondary analyses of trials (such as CHARM, TOPCAT, PARAGON-HF, DELIVER, and pooled beta-blocker trials) suggest that HFmrEF, especially near 41%, often behaves more like HFrEF than HFpEF.

• Guideline Recommendations for HFmrEF:
  • SGLT2 Inhibitors: Class 2a recommendation (dapagliflozin, empagliflozin).
  • ARNI / ACEi / ARB: Class 2b recommendation.
  • Evidence-Based Beta-Blockers: Class 2b recommendation (carvedilol, metoprolol succinate, bisoprolol).
  • Mineralocorticoid Receptor Antagonists: Class 2b recommendation (spironolactone, eplerenone).
• Core Clinical Teaching: In HFmrEF an SGLT2 inhibitor is reasonable, and the other HFrEF pillars may be considered, particularly when LVEF is near 41%. Repeat LVEF measurement matters because many patients in this range are recovering HFrEF (HFimpEF), in which all GDMT should continue.

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Management of HFimpEF: The Mandate of the TRED-HF Trial

One of the most heavily tested topics on the CHFN exam is Heart Failure with Improved Ejection Fraction (HFimpEF). When a patient with HFrEF (e.g., initial LVEF 25%) undergoes dramatic reverse remodeling on quadruple GDMT and their repeat echocardiogram shows a normalized LVEF (e.g., 55%), both patients and clinicians frequently wonder: Can we stop the medications?

                     THE TRED-HF TRIAL WARNING
 ┌────────────────────────────────────────────────────────────────────────┐
 │ Recovered Dilated Cardiomyopathy (Baseline EF ≤40% improved to >40%)   │
 └───────────────────────────────────┬────────────────────────────────────┘
                                     │
                    ┌────────────────┴────────────────┐
                    ▼                                 ▼
       ┌────────────────────────┐        ┌────────────────────────┐
       │ Continue Quadruple     │        │ Withdraw / Taper       │
       │ GDMT Indefinitely      │        │ GDMT Medications       │
       └────────────┬───────────┘        └────────────┬───────────┘
                    │                                 │
                    ▼                                 ▼
       ┌────────────────────────┐        ┌────────────────────────┐
       │ Sustained Remission:   │        │ Rapid Disease Relapse: │
       │ • Preserved LVEF       │        │ • >40% Relapse within  │
       │ • Normal LV Dimensions │        │   6 Months             │
       │ • Low Natriuretic      │        │ • Precipitous EF Drop  │
       │   Peptides             │        │ • Recurrent Congestion │
       │ • Long-Term Survival   │        │ • Increased Mortality  │
       └────────────────────────┘        └────────────────────────┘

The TRED-HF Trial Evidence:

The TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy) randomized controlled trial enrolled patients with previously diagnosed dilated cardiomyopathy who had "recovered" (LVEF improved from <40% to ≥50% with normal LV volumes and normal NT-proBNP). Patients were randomized to phased medication withdrawal versus continuing therapy.

• The Outcome: Within just 6 months, 44% of patients in the medication withdrawal group relapsed (defined by a drop in LVEF >10%, an increase in LV end-diastolic volume, or a surge in NT-proBNP).
• The Clinical Paradigm: Heart failure with improved ejection fraction represents disease remission, NOT disease cure! The underlying genetic, microvascular, or cellular vulnerability remains permanently imprinted in the myocardium.
• Guideline Recommendation: In patients with HFimpEF, GDMT should be continued (Class 1) at maximally tolerated doses to prevent relapse, even when the patient is asymptomatic.

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Spectrum of Heart Failure by Ejection Fraction: Clinical Summary

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Clinical Case Scenario: HFimpEF Counseling

A 52-year-old male with a history of alcohol-induced non-ischemic cardiomyopathy presents to the clinic for an annual checkup. Two years ago, his LVEF was 22% with severe LV dilation (LVEDD 68 mm). Following complete alcohol cessation and escalation to target quadruple GDMT (carvedilol 25 mg BID, sacubitril/valsartan 97/103 mg BID, spironolactone 25 mg daily, empagliflozin 10 mg daily), a surveillance echocardiogram today reveals an LVEF of 52% with normalized chamber dimensions (LVEDD 50 mm). The patient states: "My heart is completely cured! Since I am fully back to normal and money is tight, I want to stop taking these heart medications."

• Nurse Response & Counseling: The heart failure nurse provides vital education based on the TRED-HF trial:
  1. Congratulate the patient on phenomenal reverse remodeling, but clarify that his heart muscle is in remission, not cured.
  2. Explain that heart medications act like an external structural scaffold holding the cardiac architecture in shape.
  3. Inform the patient that clinical trials show that more than 40% of patients who stop their medications suffer a rapid drop in heart function, severe fluid backup, and repeat hospitalization within 6 months.
  4. Work with pharmacy assistance programs to reduce copays, firmly reinforcing that all four medications must be continued indefinitely.

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CHFN Exam Traps & Clinical Pearls

[!WARNING] Exam Trap: Beware of questions suggesting medication cessation when an echocardiogram shows an LVEF improving from 30% to 55%! The correct answer is ALWAYS to continue all GDMT indefinitely. Stopping therapy leads to a high rate of severe relapse (TRED-HF).

[!IMPORTANT] Clinical Pearl: SGLT2 inhibitors are the only drug class recommended across the entire LVEF spectrum in the 2022 AHA/ACC/HFSA guideline: Class 1 in HFrEF and Class 2a in HFmrEF and HFpEF.

[!TIP] Clinical Pearl: In HFpEF, the greatest benefit from sacubitril/valsartan (PARAGON-HF) and spironolactone (TOPCAT Americas) is consistently found in patients at the lower end of the preserved spectrum (LVEF 45% to 57%) and in women.