Cardiovascular

Heart failure with mildly reduced ejection fraction

Clinical Overview and When to Suspect HFmrEF

— Replaces older "borderline" or "mid-range" terminology

— Distinct from HFrEF (≤40%), HFimpEF (previously ≤40%, now >40%), and HFpEF (≥50%)

— Many patients are transitioning either direction — toward recovery (HFimpEF) or toward worsening systolic dysfunction

— Cardiovascular mortality and HF hospitalization rates are intermediate but closer to HFpEF

— Dyspnea on exertion, orthopnea, PND, fatigue, lower extremity edema in a patient with prior MI, hypertension, diabetes, or atrial fibrillation

— Echo report shows "LVEF 45%" with diastolic dysfunction or LA enlargement

— Patient previously had HFrEF (EF 30%) and now improved to 45% on GDMT — this is HFimpEF, managed like HFrEF

— Ischemic heart disease (most common — always evaluate CAD)

— Hypertensive heart disease, valvular disease, tachycardia-mediated cardiomyopathy

— Recovering nonischemic cardiomyopathy (peripartum, alcohol, chemotherapy)

Definition (2022 AHA/ACC/HFSA): Heart failure with mildly reduced ejection fraction (HFmrEF) = symptomatic HF with LVEF 41–49% plus evidence of structural heart disease, elevated filling pressures, or elevated natriuretic peptides.

Epidemiology: Roughly 13–25% of all HF patients; intermediate phenotype between HFrEF and HFpEF.

When to suspect on Step 3:

Common etiologies:

Board pearl: A patient with EF 45% and exertional dyspnea who had an EF of 30% two years ago has HFimpEF, not HFmrEF — continue full HFrEF GDMT indefinitely; do not de-escalate even if asymptomatic. Stopping GDMT after EF recovery causes relapse in ~40% (TRED-HF trial).

Step 3 management: First outpatient visit for newly identified EF 45% — order ischemic workup (stress test or coronary CTA), optimize BP and rate control, initiate SGLT2 inhibitor, and document the trajectory of EF over time.

Presentation Patterns and Key History

— Progressive dyspnea on exertion over weeks to months

— Reduced exercise tolerance, often blamed on aging or deconditioning

— Orthopnea (number of pillows), paroxysmal nocturnal dyspnea, bendopnea (dyspnea bending forward)

— Lower extremity edema, weight gain (>2 lb/day or >5 lb/week is a red flag)

— Nocturnal cough, early satiety from hepatic/gut congestion

— Forgetting medications/dietary indiscretion (high Na, fluid)

— Arrhythmia (especially new AF with RVR)

— Ischemia/infarction

— Lifestyle (alcohol binge, cocaine)

— Upregulation (thyroid, pregnancy, anemia)

— Renal failure

— Embolism (PE) or Endocarditis

— Prior MI with partial LV recovery

— Long-standing hypertension with concentric remodeling now developing eccentric features

— Atrial fibrillation with rapid rates → tachycardia-mediated cardiomyopathy (EF often recovers fully with rate/rhythm control)

— Recent chemotherapy (anthracyclines, trastuzumab) with EF drop from 60% → 45%

— I: symptoms only with extraordinary activity

— II: symptoms with ordinary activity

— III: symptoms with less than ordinary activity

— IV: symptoms at rest

— Document at every visit — drives therapy escalation

Typical ambulatory presentation:

Acute decompensation triggers (FAILURE mnemonic):

Key historical clues pointing to HFmrEF specifically:

Functional class assessment (NYHA):

Key distinction: HFmrEF vs HFpEF — both can have preserved exercise capacity at rest, but HFmrEF more often has a clear ischemic or post-MI substrate, while HFpEF skews toward elderly women with HTN, obesity, AF, and CKD. The H2FPEF and HFA-PEFF scores help when EF is ≥50%, but in the 41–49% window, the workup pivots toward ischemia first.

Step 3 management: At every HF clinic visit, ask about weights, diuretic adherence, dietary sodium (<2–3 g/day), and alcohol — these drive 80% of preventable readmissions.

Physical Exam Findings and Hemodynamic Assessment

— JVP: Elevated >8 cm H₂O (measured as vertical height above sternal angle + 5 cm) indicates elevated RA pressure; correlates well with PCWP in ~80% of HF patients

— Hepatojugular reflux: sustained JVP rise >3 cm with 10 sec RUQ pressure = elevated filling pressures

— Peripheral edema (pitting), ascites, hepatomegaly with pulsatile liver (TR)

— Pulmonary rales: often absent in chronic HF due to lymphatic compensation — JVP is more sensitive

— Narrow pulse pressure (<25% of SBP), cool extremities, mottling, altered mentation

— Defines the Stevenson profiles: warm-dry (A), warm-wet (B, most common), cold-wet (C), cold-dry (L)

— Displaced, sustained PMI (LV dilation)

— S3 gallop: highly specific for elevated LVEDP and decompensation in adults >40

— S4 gallop: stiff ventricle, common in HTN/ischemic substrate

— Murmurs: functional MR from annular dilation; AS, AR as primary etiology

— Cheyne-Stokes respirations (advanced disease, sleep)

— Pulsus alternans (severe LV dysfunction)

— Cardiac cachexia in chronic advanced HF

— Cold + wet = needs inotropy + diuresis (Profile C — worst prognosis)

— Warm + wet = pure congestion → diurese

— Cold + dry = consider inotropes cautiously, fluid challenge

Volume status — the "wet vs dry" axis:

Perfusion — the "warm vs cold" axis:

Cardiac exam in HFmrEF:

Other clues:

Bedside hemodynamics (when Swan or echo not immediately available):

CCS pearl: On a CCS case with suspected HF, order JVP, lung exam, and weight in the initial physical, then echo + BNP + BMP + troponin + ECG. Don't forget daily weights as a standing order on admission — failure to track weights is a classic CCS scoring pitfall.

Board pearl: Elevated JVP + S3 in an adult is the most specific bedside combination for elevated LV filling pressures and predicts HF hospitalization independently of EF.

Diagnostic Workup — Initial Labs, Imaging, ECG, Biomarkers

— BNP >35 pg/mL or NT-proBNP >125 pg/mL in ambulatory setting supports HF

— Acute setting cutoffs: BNP >100, NT-proBNP age-adjusted (>450 if <50 y, >900 if 50–75 y, >1800 if >75 y)

— Falsely low: obesity (BMI >35 reduces BNP ~50%), flash pulmonary edema, constrictive pericarditis

— Falsely high: age, female sex, CKD, AF, sepsis, sacubitril (raises BNP but not NT-proBNP — use NT-proBNP if on ARNI)

— CBC (anemia worsens HF)

— CMP: Na (hyponatremia = poor prognosis), K, Mg, Cr/eGFR, LFTs (congestive hepatopathy)

— TSH (thyroid disease can cause or unmask HF)

— Fasting glucose/HbA1c, lipid panel

— Iron studies: ferritin and TSAT — iron deficiency (ferritin <100 or 100–299 with TSAT <20%) is present in ~50% of HF patients and treatable

— HIV in appropriate populations; consider HCV

— Prior MI (Q waves), LVH, LBBB (QRS ≥150 ms — future CRT candidacy), AF, ischemia

— A completely normal ECG has high NPV for systolic dysfunction

— Cardiomegaly, cephalization, Kerley B lines, pleural effusions (R > L classically)

— Rules out alternative causes (pneumonia, mass)

— LVEF (defines HFmrEF at 41–49%)

— Wall motion abnormalities (regional → ischemic)

— Diastolic function (E/e' >14), LA volume, RV function, valves, PASP

— Strain imaging detects subclinical dysfunction

Natriuretic peptides (cornerstone):

Initial labs (every new HF workup):

ECG (always):

Chest X-ray:

Echocardiogram — the diagnostic anchor:

Board pearl: In a patient on sacubitril/valsartan, BNP is artificially elevated because neprilysin normally degrades BNP — always use NT-proBNP for monitoring on ARNI therapy.

Step 3 management: Order TTE, BNP/NT-proBNP, CBC, CMP, TSH, iron studies, A1c, lipids, and ECG at first HFmrEF diagnosis — this single panel covers etiology + comorbidities + baseline for monitoring.

Diagnostic Workup — Advanced or Confirmatory Studies

— Low/intermediate pretest probability + interpretable ECG: stress echo or stress MPI

— High pretest probability, angina, prior CAD, or hemodynamic instability: coronary angiography

— Coronary CTA: increasingly first-line for new HF without prior CAD, low-to-intermediate risk, per 2021 chest pain guidelines

— Any patient with new HF and unknown coronary status warrants ischemic workup

— Gold standard for LVEF and volumes

— Late gadolinium enhancement (LGE) pattern identifies etiology:

— Subendocardial/transmural → ischemic

— Mid-wall striae → nonischemic dilated cardiomyopathy

— Subepicardial → myocarditis, sarcoid

— Diffuse → infiltrative (amyloid)

— T1/T2 mapping for amyloid, iron overload, edema

— Cardiac amyloid: elderly, low voltage on ECG with LVH on echo, carpal tunnel, neuropathy, HFpEF/HFmrEF — order pyrophosphate (PYP) scan for ATTR; SPEP/UPEP/free light chains for AL

— Sarcoidosis: AV block, VT, young patient — cardiac PET or MRI

— Hemochromatosis: ferritin >300 with TSAT >45% → genetic testing

— Hypertrophic cardiomyopathy: asymmetric septal hypertrophy, family history

— Indicated when noninvasive assessment ambiguous, suspected pulmonary hypertension, pre-transplant/LVAD evaluation, refractory symptoms

— Differentiates pre- vs post-capillary PH (PCWP >15 mmHg = post-capillary)

— First-degree relatives of patients with familial dilated cardiomyopathy

— Specific syndromes (HCM, ARVC, LMNA mutations with conduction disease)

Ischemic evaluation (essential in HFmrEF — CAD is leading cause):

Cardiac MRI (CMR):

When to suspect infiltrative/specific etiologies:

Right heart catheterization (RHC):

Genetic testing:

Key distinction: Ischemic vs nonischemic cardiomyopathy — ischemic etiology mandates revascularization assessment and aspirin/statin; nonischemic prompts a search for reversible causes (alcohol, tachycardia, toxins, thyroid, peripartum). CMR with LGE pattern often resolves this when coronaries are clean but suspicion remains.

Risk Stratification and First-Line Management Logic

— Stage A: at risk (HTN, DM, CAD) — no structural disease, no symptoms

— Stage B: structural disease (LVH, low EF), no symptoms

— Stage C: structural disease + current/prior symptoms ← most HFmrEF lives here

— Stage D: refractory, advanced HF

— Historically a therapeutic "gray zone" — recent trials extended HFrEF benefits down through this EF range

— Treat phenotypically like HFrEF — most class IIa/IIb recommendations

— Aggressive treatment of comorbidities (HTN, AF, CAD, DM, OSA, obesity)

1. ARNI/ACEi/ARB (IIb in HFmrEF, IIa if EF closer to 40%)

2. Beta-blocker (IIb — bisoprolol, carvedilol, metoprolol succinate)

3. MRA (IIb — spironolactone, eplerenone)

4. SGLT2 inhibitor (Class 2a recommendation across full EF spectrum — strongest evidence in HFmrEF/HFpEF from EMPEROR-Preserved and DELIVER)

— Loop diuretics (furosemide, torsemide, bumetanide) as needed for volume — Class I but symptomatic only, no mortality benefit

— MAGGIC, Seattle HF Model for prognosis

— Elevated troponin, persistently elevated BNP, hyponatremia, worsening renal function, anemia, frequent hospitalizations → high-risk markers

— Start empagliflozin or dapagliflozin first (strongest evidence, no titration)

— Add ACEi or ARNI + beta-blocker + MRA sequentially as tolerated

— Treat HTN to <130/80, treat ischemia, anticoagulate AF per CHA₂DS₂-VASc, screen/treat iron deficiency with IV ferric carboxymaltose

Staging (ACC/AHA):

HFmrEF-specific management philosophy (2022 guidelines):

The "Four Pillars" framework — adapted for HFmrEF:

Diuretics for congestion:

Risk stratification tools:

Step 3 management: For a newly diagnosed HFmrEF patient with NYHA II symptoms:

Board pearl: The SGLT2 inhibitor is the most evidence-based agent in HFmrEF — DELIVER and EMPEROR-Preserved showed reduced HF hospitalization across EF 41–49%. Start it even before fully titrating other agents.

Pharmacotherapy — First-Line Drug Regimen

— Dapagliflozin 10 mg daily or empagliflozin 10 mg daily

— Indicated regardless of diabetes status; works down to eGFR ~20–25

— Reduces HF hospitalization ~20% in HFmrEF (DELIVER, EMPEROR-Preserved)

— Side effects: genital mycotic infections, euglycemic DKA (hold during illness/surgery), volume depletion

— Hold for procedures 3–4 days preop

— Sacubitril/valsartan preferred (start 49/51 mg BID if no prior ACEi/ARB use; 24/26 mg BID if low BP/CKD)

— Washout ≥36 hours when switching from ACEi to ARNI (angioedema risk)

— ACEi alternatives: lisinopril, enalapril; ARB if ACEi cough (losartan, valsartan, candesartan)

— Monitor K, Cr 1–2 weeks after start/titration; tolerate up to 30% Cr rise

— Carvedilol 3.125 mg BID → up to 25 mg BID (50 mg BID if >85 kg)

— Metoprolol succinate 12.5–25 mg daily → 200 mg daily

— Bisoprolol 1.25 mg daily → 10 mg daily

— Do not initiate during acute decompensation; only when euvolemic

— Spironolactone 12.5–25 mg daily → 50 mg

— Eplerenone if gynecomastia

— Contraindicated if K >5.0 or eGFR <30; check K, Cr at 1 week, 1 month, then every 3 months

— TOPCAT signaled HFmrEF benefit

— Furosemide 20–40 mg PO daily, torsemide preferred for variable absorption (better bioavailability ~80–100%)

— Titrate to euvolemia; teach patient flexible diuretic dosing based on daily weight

— NSAIDs (sodium retention, AKI)

— Non-dihydropyridine CCBs (verapamil, diltiazem) — negative inotropy

— Thiazolidinediones (pioglitazone) — fluid retention

— Saxagliptin (HF hospitalization signal)

SGLT2 inhibitors (cornerstone in HFmrEF):

ARNI / ACEi / ARB:

Beta-blockers (evidence-based three only):

MRA:

Loop diuretics (symptomatic):

Avoid/use cautiously:

Step 3 management: Start GDMT sequentially. A reasonable cadence: visit 1 — SGLT2i + ARNI low dose; visit 2 (2 weeks) — add beta-blocker; visit 3 (2–4 weeks) — add MRA; titrate each every 2 weeks as BP/K/Cr allow. Reassess EF and symptoms at 3–6 months.

Board pearl: Sacubitril/valsartan + ACEi = angioedema — always 36-hour washout.

Procedures and Device Therapy

— Primary prevention: EF ≤35%, NYHA II–III on ≥3 months GDMT, life expectancy >1 year

— HFmrEF (EF 41–49%) does NOT meet criteria for primary prevention ICD by EF alone

— Exception: secondary prevention (prior sustained VT/VF, survived SCA) — regardless of EF

— If HFmrEF patient's EF declines to ≤35% despite optimized GDMT, reassess for ICD

— Class I: EF ≤35%, NYHA II–IV, sinus rhythm, LBBB with QRS ≥150 ms, on GDMT

— Not indicated in HFmrEF unless EF declines

— Greatest benefit: women, LBBB, non-ischemic etiology

— Critical decision point in HFmrEF given ischemic predominance

— CABG for multivessel CAD with LV dysfunction (STICH trial showed long-term mortality benefit even at EF 35%)

— PCI for focal disease, viable myocardium

— Assess viability (CMR with LGE, PET) before revascularizing dysfunctional segments

— Severe AS with HF → TAVR or SAVR

— Severe primary MR → mitral repair

— Severe secondary (functional) MR with persistent HF on GDMT → TEER (MitraClip) per COAPT criteria (EF 20–50%, includes HFmrEF range)

— Rhythm control increasingly favored in HF (CASTLE-AF, EAST-AFNET 4)

— Catheter ablation reduces HF hospitalization and mortality in AF + HF

— Rate control with beta-blocker or digoxin (avoid non-DHP CCBs); target <80 bpm at rest

— LVAD, transplant — reserved for stage D

ICD (implantable cardioverter-defibrillator):

CRT (cardiac resynchronization therapy):

Revascularization:

Valve interventions:

Atrial fibrillation management:

Advanced therapies (rarely needed in HFmrEF unless progression):

CCS pearl: Before placing an ICD or CRT, document ≥3 months of optimized GDMT with reassessed EF — Step 3 loves the patient whose EF improves from 30% to 45% on GDMT, who no longer needs an ICD (becomes HFimpEF — continue meds, defer ICD).

Board pearl: EF 45% post-MI + ventricular tachycardia on monitor = secondary prevention ICD indicated regardless of EF threshold.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher prevalence of HFmrEF and HFpEF

— Polypharmacy, frailty, cognitive impairment complicate adherence

— Start low, go slow — but do not withhold GDMT based on age alone

— Watch orthostasis on ARNI + diuretic + beta-blocker — fall risk

— Deprescribe non-essential medications; review at every visit

— Goal SBP often 130–140 (avoid <120 in frail elderly per SPRINT subgroup considerations)

— eGFR thresholds for GDMT:

— ACEi/ARB/ARNI: tolerate up to 30% Cr rise and K ≤5.5; pause if greater

— MRA: avoid if eGFR <30 or K >5.0; finerenone is alternative (FIDELIO-DKD, FIGARO-DKD show CV benefit in DKD)

— SGLT2i: initiate down to eGFR 20 (dapa) or 20 (empa); continue even as eGFR declines unless dialysis

— Loop diuretics: higher doses needed (furosemide 80–160 mg+); IV when oral fails

— Cardiorenal syndrome: worsening renal function during diuresis is acceptable if congestion improving

— Avoid contrast and nephrotoxins when feasible

— Elevated transaminases (acute, AST/ALT in thousands with cardiogenic shock)

— Elevated alk phos and bilirubin chronic congestion

— Adjust hepatically metabolized drugs (carvedilol, sacubitril)

— Avoid hepatotoxic drugs; cautious diuresis to avoid hypoperfusion

— Patiromer or sodium zirconium cyclosilicate to lower K and maintain RAAS/MRA therapy

— Dietary K education; loop diuretics promote K loss

— IV iron (ferric carboxymaltose, ferric derisomaltose) for ferritin <100 or 100–299 with TSAT <20% — improves symptoms and reduces HF hospitalization (AFFIRM-AHF, IRONMAN)

— Oral iron poorly absorbed in HF

Elderly (>75 years):

CKD:

Hepatic impairment / congestive hepatopathy:

Hyperkalemia management to enable GDMT:

Iron deficiency:

Step 3 management: In an 82-year-old with HFmrEF, eGFR 35, K 4.8: start dapagliflozin 10 mg daily (renal and CV benefit, no K rise), low-dose ARB, low-dose carvedilol; hold MRA initially; reassess K weekly. Add patiromer if K rises to enable MRA later.

Board pearl: Continue SGLT2 inhibitor even as eGFR drops below baseline — the initial 3–5 mL/min "dip" is hemodynamic and reverses; long-term renal protection persists.

Special Populations — Pregnancy, Peripartum, and Other Subgroups

— New HF with EF <45% in last month of pregnancy or within 5 months postpartum, no other cause

— Often presents in HFmrEF range as it improves

— Risk factors: multiparity, advanced maternal age, twin gestation, preeclampsia, Black race

— Bromocriptine controversial but used in Europe; suppresses lactation (which limits its use in mothers wishing to breastfeed)

— ~50% recover EF; future pregnancy contraindicated if EF does not normalize

— Contraindicated: ACEi, ARB, ARNI, MRA (spironolactone — antiandrogen, virilization), SGLT2 inhibitors, ivabradine, warfarin (1st trimester teratogenic)

— Safe: beta-blockers (metoprolol, labetalol preferred; avoid atenolol — IUGR), hydralazine + nitrates, loop diuretics (cautious, can reduce placental perfusion), digoxin

— Postpartum: resume full GDMT; if breastfeeding, beta-blockers and ACEi (enalapril, captopril) generally compatible

— Anthracyclines (doxorubicin): dose-dependent, can present as HFmrEF

— Trastuzumab: typically reversible; hold drug, start GDMT, often recovers

— Surveillance with serial echo/strain imaging; cardio-oncology referral

— Dexrazoxane for cardioprotection in high-dose anthracycline regimens

— Exclude genetic cardiomyopathy (HCM, ARVC, LMNA mutations)

— Family screening if hereditary form identified

— Standard GDMT; review ART for cardiotoxicity; check for opportunistic causes

— Alcohol cardiomyopathy: abstinence can fully reverse EF (becomes HFimpEF)

— Methamphetamine, cocaine: abstinence + GDMT

Peripartum cardiomyopathy (PPCM):

Pregnancy and HF medications:

Chemotherapy-induced cardiomyopathy:

Athletes and young adults:

HIV-associated cardiomyopathy:

Substance-related:

Key distinction: PPCM vs preexisting cardiomyopathy unmasked by pregnancy — PPCM presents late pregnancy/postpartum and may fully recover; preexisting often presents earlier and persists.

Step 3 management: Postpartum patient with EF 45%, recent PPCM diagnosis — continue beta-blocker and diuretic during breastfeeding, hold ACEi until weaning OR use enalapril/captopril (compatible), counsel against future pregnancy until EF normalizes and stable off therapy.

Complications and Adverse Outcomes

— Most common reason for HF hospitalization; 25% 30-day readmission rate nationally

— Triggers: medication nonadherence, dietary indiscretion, arrhythmia, ischemia, infection

— Treatment: IV loop diuretic (2.5× home dose IV), oxygen, nitrates if hypertensive, NIPPV for pulmonary edema

— Atrial fibrillation: 30–40% of HF patients; worsens symptoms, raises stroke risk

— Anticoagulate per CHA₂DS₂-VASc (HF = 1 point automatically)

— Rhythm control via ablation reduces mortality (CASTLE-AF)

— Ventricular arrhythmias: EF 41–49% lower SCD risk than HFrEF but not zero

— Address ischemia, electrolytes, QT-prolonging drugs

— Type 1: acute HF → AKI

— Type 2: chronic HF → CKD

— Management: gentle diuresis, vasodilators if hypertensive, ultrafiltration if diuretic-resistant

— Marker of severity (neurohormonal activation, free water retention)

— Fluid restriction <1.5 L/day; tolvaptan in select cases

— Stroke, DVT/PE — prophylaxis on admission; anticoagulate if AF, LV thrombus, or prior event

— Worsens functional capacity; treat with IV iron

— Late stage, >5% involuntary weight loss; poor prognosis

— Present in 20–40%; screen with PHQ-9; SSRIs (sertraline) preferred over TCAs

— Lower absolute risk in HFmrEF than HFrEF but still elevated vs general population

— Optimal GDMT, address ischemia, secondary prevention ICD if indicated

— ~25% of HFmrEF transitions to HFrEF over 1–2 years

— Another 25% improves to HFpEF range (HFimpEF) — continue GDMT

Acute decompensated heart failure (ADHF):

Arrhythmias:

Cardiorenal syndrome:

Hyponatremia:

Thromboembolism:

Iron deficiency and anemia:

Cardiac cachexia:

Depression and cognitive impairment:

Sudden cardiac death:

Progression:

Board pearl: Acute kidney injury during inpatient diuresis with improving congestion is acceptable — do not stop diuretics; the kidney recovers as filling pressures normalize. Stopping diuresis "to protect the kidney" worsens outcomes (ADHERE registry data).

CCS pearl: In ADHF on the CCS interface, advance the clock in 1–2 hour blocks initially; reassess weight, JVP, urine output, and creatinine before each dose escalation.

When to Escalate Care — ICU, Consult, Inpatient Triage

— Resting dyspnea, hypoxemia (SpO₂ <90%)

— New or worsening edema unresponsive to oral diuretic uptitration

— Hypotension, altered mental status

— Acute kidney injury, hyperkalemia

— Suspected ACS, new arrhythmia (AF with RVR, sustained VT)

— Weight gain >5 lb over a few days with symptoms

— Telemetry/step-down: most ADHF — continuous rhythm monitoring, IV diuresis, BNP trending

— ICU criteria:

— Cardiogenic shock (hypotension SBP <90 with end-organ hypoperfusion, lactate >2, cold extremities)

— Need for vasopressors or inotropes (dobutamine, milrinone)

— Mechanical ventilation or BiPAP failing

— Need for mechanical circulatory support (IABP, Impella, ECMO)

— Unstable ventricular arrhythmias

— Cardiology: all new HF diagnoses; ADHF admissions

— Advanced HF/transplant cardiology: refractory HF, recurrent admissions, EF declining despite GDMT, need for MCS evaluation (INTERMACS profile assessment)

— Electrophysiology: for ICD/CRT, AF ablation, VT management

— Interventional cardiology: revascularization, structural intervention

— Cardio-oncology: chemotherapy-related cardiomyopathy

— Nephrology: refractory cardiorenal syndrome, ultrafiltration

— Palliative care: advanced HF symptom management, goals of care

— A: at risk

— B: beginning (hypotension/tachycardia, no hypoperfusion)

— C: classic shock (hypoperfusion, needing intervention)

— D: deteriorating

— E: extremis

— Tertiary center capable of advanced MCS, transplant evaluation

— When local resources inadequate for refractory case

Outpatient → ED/admission criteria:

Floor vs telemetry vs ICU:

Specialty consultations:

Shock recognition (SCAI stages):

Transfer indications:

CCS pearl: A patient in profile C (cold + wet) on initial assessment needs ICU-level care — order dobutamine or milrinone (cautious in renal failure for milrinone), IV loop diuretic, arterial line, central access, Foley, and call cardiology stat. Do not start beta-blockers in this setting.

Step 3 management: In the outpatient clinic, a known HFmrEF patient with 8-lb weight gain and increasing orthopnea but normal vitals and no hypoxia → double home loop diuretic dose, recheck in 24–48 hours, daily weights — admit only if no response or vital sign instability.

Key Differentials — Same-Category (Cardiac) Causes

— Same management framework; stronger evidence for full GDMT and devices (ICD/CRT)

— Often advances from HFmrEF if untreated

— Elderly, female-predominant, HTN/obesity/AF/CKD/DM phenotype

— H₂FPEF or HFA-PEFF score for diagnosis when EF preserved

— Treatment: SGLT2 inhibitor (Class 1 in HFpEF per recent updates), diuretics, treat comorbidities, MRA (IIb)

— Prior EF ≤40% now improved to >40% with GDMT

— Continue full HFrEF GDMT indefinitely — do not de-escalate (TRED-HF)

— Anemia, thyrotoxicosis, AV fistula (including hemodialysis), beriberi (thiamine deficiency), Paget disease, pregnancy

— Wide pulse pressure, warm extremities, elevated cardiac output

— Treat underlying cause

— Pulmonary hypertension (any WHO group), RV infarct, ARVC, congenital heart disease

— Elevated JVP, hepatomegaly, edema with clear lungs

— Amyloid (AL, ATTR), sarcoid, hemochromatosis, endomyocardial fibrosis

— Echo: small/normal LV cavity, biatrial enlargement, restrictive filling pattern

— Often presents as HFpEF/HFmrEF

— Asymmetric septal hypertrophy, dynamic LVOT obstruction

— Family history, syncope, murmur changes with Valsalva

— Avoid pure vasodilators and high-dose diuretics

— Severe AS, AR, MR, MS can cause HF symptoms — evaluate carefully on echo

— Surgical/transcatheter correction reverses symptoms

— Prior cardiac surgery, radiation, TB

— Kussmaul sign, pericardial knock, square root sign on cath

— Pericardiectomy curative

— Sustained tachyarrhythmia (AF, atrial flutter, VT) → dilated CM

— EF recovers fully with rate/rhythm control

HFrEF (EF ≤40%):

HFpEF (EF ≥50%):

HFimpEF:

High-output heart failure:

Right heart failure (isolated):

Restrictive cardiomyopathy:

Hypertrophic cardiomyopathy:

Valvular heart disease:

Constrictive pericarditis:

Tachycardia-mediated cardiomyopathy:

Key distinction: HFmrEF that doesn't improve with standard GDMT → reconsider restrictive/infiltrative etiologies (especially amyloid) — order PYP scan, light chains, and consider CMR. ATTR amyloid now treatable with tafamidis.

Key Differentials — Other-Category (Non-Cardiac) Causes

— COPD exacerbation: wheezing, prolonged expiration, smoking history; BNP often mildly elevated

— Pulmonary embolism: acute dyspnea, pleuritic chest pain, tachycardia, hypoxia — D-dimer, CTPA

— Pulmonary hypertension (groups 1, 3, 4, 5): primary lung disease; right heart strain

— Interstitial lung disease: fine crackles, fibrosis on CT, restrictive PFTs

— Nephrotic syndrome, ESRD with volume overload → edema, dyspnea

— Distinguish by urinalysis (proteinuria), eGFR, BNP often elevated from CKD

— Cirrhosis with ascites, peripheral edema, hypoalbuminemia

— JVP usually low/normal (unlike HF); look for stigmata of liver disease

— Thyrotoxicosis: high-output state, AF, weight loss, tremor

— Hypothyroidism (myxedema): can cause low-output HF, pericardial effusion, bradycardia

— Pheochromocytoma: episodic HTN, catecholamine cardiomyopathy

— Acromegaly: cardiomyopathy from GH excess

— Severe anemia (Hb <8) → high-output HF

— Hemochromatosis → restrictive/dilated CM with diabetes, skin hyperpigmentation, arthropathy

— Alcohol, cocaine, methamphetamine

— Doxorubicin, trastuzumab, sunitinib, immune checkpoint inhibitors (myocarditis)

— Clozapine (myocarditis), hydroxychloroquine (rare CM)

— Amyloid (AL, ATTR), sarcoid, hemochromatosis, Fabry disease

— Acute myocarditis (viral, autoimmune, checkpoint inhibitor)

— Giant cell myocarditis (rapidly progressive, biopsy + immunosuppression)

— Tamponade (rapid effusion, hypotension, pulsus paradoxus)

— Constrictive pericarditis

— OSA and central sleep apnea both worsen HF; screen with STOP-BANG; treat with CPAP

— Adaptive servo-ventilation contraindicated in HFrEF (SERVE-HF showed harm)

Pulmonary disease mimicking HF:

Renal disease:

Hepatic disease:

Endocrine:

Hematologic:

Toxic/drug-induced:

Infiltrative:

Inflammatory:

Pericardial:

Sleep-disordered breathing:

Key distinction: BNP in cirrhosis vs HF — cirrhotic edema usually has normal/low BNP and JVP, with hypoalbuminemia and stigmata of liver disease; HF has elevated BNP and JVP. Coexistence (cardiac cirrhosis) blurs the picture.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— SGLT2 inhibitor (dapagliflozin or empagliflozin 10 mg daily)

— ACEi/ARB or ARNI at tolerated dose

— Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)

— MRA (spironolactone or eplerenone) if eGFR >30, K <5.0

— Loop diuretic at lowest effective dose for euvolemia

— Statin if ASCVD or indicated by risk

— Aspirin if CAD (otherwise not routinely indicated)

— Anticoagulation if AF, LV thrombus, mechanical valve

— Euvolemia documented (JVP, weight, exam)

— Transitioned from IV to PO diuretic ≥24 hours before discharge

— Renal function and K stable on regimen

— Patient knows daily weight monitoring, sodium <2–3 g/day, fluid <2 L if needed

— Follow-up scheduled within 7 days of discharge (associated with reduced readmission)

— Sodium restriction <2–3 g/day

— Fluid restriction 1.5–2 L if hyponatremic or refractory

— Daily weights — call for >2 lb overnight or >5 lb in a week

— Alcohol cessation (especially if alcohol-related CM)

— Smoking cessation

— Weight loss if BMI >30

— Influenza, pneumococcal, COVID-19, RSV (age-appropriate) vaccinations

— BP <130/80

— DM: HbA1c individualized; SGLT2i and GLP-1 RAs preferred

— Lipids: statin per ASCVD risk

— OSA: CPAP if confirmed

— Iron deficiency: IV iron

— Depression: PHQ-9 screening, SSRI if needed

— Class IIa recommendation; improves exercise capacity, quality of life, reduces hospitalizations

— Refer all stable HF patients

— Discuss prognosis, goals, code status, ICD deactivation in end-stage disease

Discharge medication bundle (HFmrEF):

Pre-discharge checklist:

Lifestyle and self-management:

Comorbidity optimization:

Cardiac rehabilitation:

Advance care planning:

Board pearl: 7-day post-discharge follow-up is the single most evidence-based intervention to reduce HF readmissions — make this the answer on any "what is the next best step at discharge" question.

Step 3 management: A patient discharged after first HF admission needs follow-up appointment scheduled before leaving the hospital, medication reconciliation, HF teaching with teach-back, scale at home, and a clear action plan for weight gain or worsening symptoms.

Follow-Up, Monitoring, and Rehab/Counseling

— 7 days post-discharge — clinical assessment, medication review, labs

— Every 2 weeks during GDMT titration

— Every 1–3 months once stable

— Echo at 3–6 months after GDMT optimization to reassess EF (defines HFimpEF if improves)

— BMP (Na, K, Cr) at every titration; every 3–6 months when stable

— BNP/NT-proBNP trending (controversial — GUIDE-IT was neutral, but useful as adjunct)

— Annual: CBC, LFTs, lipids, A1c, iron studies, TSH

— Digoxin level if used (target 0.5–0.9 ng/mL)

— Repeat TTE at 3–6 months after optimized GDMT

— Repeat TTE for clinical change, new murmur, suspected progression

— KCCQ (Kansas City Cardiomyopathy Questionnaire) for HRQoL

— 6-minute walk test for functional capacity

— Remote monitoring (CardioMEMS pulmonary artery pressure sensor) — Class IIb, reduces hospitalizations in selected NYHA III patients

— Structured supervised exercise + risk factor modification + education

— 36 sessions over 12 weeks typical

— Covered by Medicare for stable HFrEF (EF ≤35%) — HFmrEF coverage variable

— Recognize warning signs (worsening dyspnea, weight gain, edema, lightheadedness, palpitations)

— Medication adherence — pill organizer, family involvement

— Sodium label reading; restaurant/processed food awareness

— Vaccinations annually

— Avoid NSAIDs — ask about OTC products

— Influenza annually

— Pneumococcal: PCV20 or PCV15 + PPSV23

— COVID-19 boosters per CDC

— RSV vaccine if ≥60 with HF

— Tdap, zoster age-appropriate

— Safe in stable HF (NYHA I–II); avoid PDE5 inhibitors with nitrates

— After ICD shock for VT/VF: no driving for 6 months (private) or permanent restriction (commercial) per AHA

Follow-up cadence:

Routine labs:

Imaging:

Symptom monitoring tools:

Cardiac rehabilitation:

Patient education focus areas:

Vaccination schedule:

Sexual activity counseling:

Driving:

Step 3 management: At the 3-month follow-up, patient's EF improved from 45% to 55% — diagnosis updates to HFimpEF (not "cured" HFpEF). Continue all four pillars indefinitely; document trajectory in chart for future clinicians.

Board pearl: Cardiac rehab is one of the few non-pharmacologic interventions with mortality benefit in HF — refer at discharge.

Ethical, Legal, and Patient Safety Considerations

— Discuss prognosis honestly even when patient appears stable — HF is progressive

— Document health care proxy, advance directive, code status

— Revisit at each hospitalization, EF decline, or functional decline

— Patients with ICDs may receive painful shocks during dying process

— Ethically and legally permissible to deactivate the defibrillator function (preserving pacing) when consistent with patient's goals

— Requires informed consent or surrogate decision; does not constitute physician-assisted death

— Discuss proactively before transition to hospice

— LVAD/transplant evaluation requires extensive shared decision-making — discussion of stroke, infection, mechanical complications, lifestyle changes

— Patients with cognitive impairment need surrogate decision-maker engaged early

— Medication reconciliation is the highest-yield error prevention at discharge — confirm doses of diuretic, beta-blocker, RAAS inhibitor, anticoagulant

— Avoid "discharge med drift" — patients often arrive home on duplicated or omitted medications

— Teach-back method to confirm understanding

— Schedule follow-up before discharge, not "to be arranged"

— NSAID + ACEi + diuretic = "triple whammy" AKI

— Macrolides + QT-prolonging drugs in HF

— Warfarin INR monitoring when amiodarone added (potentiates anticoagulation)

— NYHA IV, optimal medical therapy, EF ≤20%, recurrent hospitalizations

— Hospice and HF care are not mutually exclusive; some GDMT continues for symptoms

— Sudden cardiac arrest in young athlete → consider HCM/ARVC; family screening

— Workplace concerns: pilots, commercial drivers with ICDs/HF — FAA/DOT restrictions

— Black patients historically underrepresented in HF trials; access to ARNI, SGLT2i, transplant disparities documented

— Cost barriers — assistance programs available for branded GDMT

Goals of care and advance directives:

ICD deactivation at end of life:

Informed consent edge cases:

Transition-of-care safety:

Polypharmacy and drug interactions:

Hospice eligibility for advanced HF:

Reporting and safety:

Equity considerations:

Step 3 management: A 78-year-old with HFmrEF, recurrent admissions, NYHA III despite optimized GDMT, expresses fatigue with hospital cycles. Best next step: initiate goals-of-care conversation, palliative care consult, and discuss ICD deactivation if present — alongside continued symptom-directed therapy. Hospice is not abandonment of care.

Board pearl: Deactivating an ICD at end of life is legal, ethical, and routinely appropriate when consistent with patient values — never the wrong answer when patient and family request comfort-focused care.

High-Yield Associations and Rapid-Fire Clinical Facts

• EF cutoffs (memorize cold): HFrEF ≤40	HFmrEF 41–49	HFpEF ≥50	HFimpEF previously ≤40, now >40
• SGLT2 inhibitor trials in HFmrEF/HFpEF:
— EMPEROR-Preserved (empagliflozin) — reduced HF hospitalization across EF ≥40%
— DELIVER (dapagliflozin) — reduced HF hospitalization across EF >40%
— Strongest evidence base in HFmrEF
• Sacubitril/valsartan in HFmrEF:
— PARAGON-HF — borderline overall, benefit in lower EF subgroup (45–57%)
— Class IIb recommendation in HFmrEF
• MRA in HFmrEF:
— TOPCAT — neutral overall, regional variability suggested benefit in HFmrEF subgroup
— Class IIb recommendation
• Beta-blockers in HF:
— Only three with mortality benefit: carvedilol, metoprolol succinate, bisoprolol
— Atenolol and metoprolol tartrate are NOT evidence-based for HF
• Iron deficiency in HF:
— Ferritin <100 OR (100–299 with TSAT <20%) → IV iron
— AFFIRM-AHF, IRONMAN trials
• Ivabradine:
— Sinus rhythm, HR ≥70 on max beta-blocker, EF ≤35%, NYHA II–III
— Not for HFmrEF or AF
• Vericiguat (soluble guanylate cyclase stimulator):
— Worsening HFrEF after hospitalization — VICTORIA trial
— Not first-line in HFmrEF
• Hydralazine + isosorbide dinitrate:
— Self-identified Black patients with HFrEF on optimal GDMT (A-HeFT)
— Also alternative when ACEi/ARB contraindicated
• CRT criteria: EF ≤35, LBBB, QRS ≥150 ms — sweet spot
• AF + HF anticoagulation: any CHA₂DS₂-VASc ≥1 in men, ≥2 in women warrants DOAC
• Avoid in HF:
— Non-DHP CCBs (verapamil, diltiazem) in HFrEF/HFmrEF
— NSAIDs, thiazolidinediones, saxagliptin, dronedarone (in advanced HF)
• Cardiac amyloid red flags: low ECG voltage + LVH on echo, carpal tunnel, bilateral biceps tendon rupture, autonomic dysfunction, age >70
• Key distinction: Metoprolol tartrate (immediate release) does NOT have HF mortality benefit — always metoprolol succinate (extended release) for HF. A common Step 3 trap is the patient discharged on tartrate "for HF" — switch it.
• Board pearl: The four pillars order of magnitude memorization — SGLT2i benefit ~25% HFH reduction in HFmrEF, ARNI/ACEi ~10–15%, BB ~30% in HFrEF (less clear HFmrEF), MRA ~15%.

Board Question Stem Patterns

— 68-year-old with HTN, prior MI, presents with progressive DOE, NYHA II symptoms. TTE shows EF 45%, mild LA dilation. NT-proBNP 850. Best initial medication?

— Answer: Dapagliflozin or empagliflozin (SGLT2 inhibitor — strongest evidence in HFmrEF)

— 55-year-old with prior EF 25%, now 45% after 18 months of GDMT. Asymptomatic. Patient asks if she can stop medications. Best response?

— Answer: Continue all GDMT indefinitely — TRED-HF showed 40% relapse with withdrawal

— Patient on lisinopril, carvedilol, spironolactone, furosemide with K 5.6, eGFR 35. Next step?

— Answer: Hold MRA, recheck K; consider patiromer to enable continued RAAS therapy long-term; do NOT abandon GDMT

— HFmrEF patient with EF 45% asks about ICD. Indicated?

— Answer: No primary prevention indication — needs EF ≤35% after 3 months optimal GDMT. Exception: secondary prevention (prior VT/VF/SCA)

— Known HFmrEF, presents with 8-lb weight gain, orthopnea, BP 150/90, HR 105, rales, JVP 12 cm. Best initial therapy?

— Answer: IV furosemide 2.5× home dose, supplemental O₂, IV nitroglycerin if hypertensive pulmonary edema, NIPPV if respiratory distress

— Hospitalized HF patient ready for discharge. Most important intervention to reduce readmission?

— Answer: Follow-up within 7 days post-discharge

— Patient on lisinopril, switching to sacubitril/valsartan. Required step?

— Answer: 36-hour washout to prevent angioedema

— HFmrEF, Hb 11.5, ferritin 80, TSAT 15%. Best therapy?

— Answer: IV ferric carboxymaltose (oral iron poorly absorbed/ineffective in HF)

— Patient on sacubitril/valsartan with BNP 600 (was 200 pre-treatment). Interpretation?

— Answer: BNP artifact from neprilysin inhibition — check NT-proBNP for true monitoring

— Newly pregnant woman with HFmrEF on lisinopril, carvedilol, spironolactone, empagliflozin. What to stop?

— Answer: Lisinopril, spironolactone, empagliflozin all teratogenic/contraindicated; continue beta-blocker (metoprolol or labetalol preferred over atenolol)

Stem 1 — Classic HFmrEF identification:

Stem 2 — HFimpEF trap:

Stem 3 — Hyperkalemia management:

Stem 4 — ICD eligibility:

Stem 5 — Acute decompensation:

Stem 6 — Discharge planning:

Stem 7 — Sacubitril switch:

Stem 8 — Iron deficiency:

Stem 9 — BNP interpretation on ARNI:

Stem 10 — Pregnancy:

Board pearl: When in doubt on a HFmrEF question, the SGLT2 inhibitor is usually the right answer for first-line drug therapy — no other class has Class IIa recommendation in this EF range.

One-Line Recap

Heart failure with mildly reduced ejection fraction (LVEF 41–49%) is now treated phenotypically as a "lite" HFrEF, with SGLT2 inhibitors as the strongest evidence-based pillar and the full four-drug regimen (SGLT2i, ARNI/ACEi/ARB, evidence-based beta-blocker, MRA) recommended for symptomatic patients alongside aggressive treatment of ischemia, hypertension, AF, and iron deficiency.

— Definition: LVEF 41–49% + symptoms/signs of HF + structural disease, elevated filling pressures, or elevated natriuretic peptides; distinct from HFimpEF (previously ≤40%, now improved) which retains full HFrEF GDMT indefinitely

— First-line therapy: Start SGLT2 inhibitor (dapagliflozin or empagliflozin) — Class IIa, strongest evidence in HFmrEF from DELIVER and EMPEROR-Preserved trials; add ARNI/ACEi/ARB, evidence-based beta-blocker (carvedilol, metoprolol succinate, bisoprolol), and MRA sequentially; use loop diuretics for congestion

— Devices and procedures: Primary prevention ICD/CRT require EF ≤35% after ≥3 months optimized GDMT, so most HFmrEF patients do not qualify; revascularize ischemic substrate, treat valvular disease, consider AF ablation; secondary prevention ICD regardless of EF if prior VT/VF

— Transitions and safety: 7-day post-discharge follow-up is the single highest-yield intervention to reduce 30-day readmission; reconcile medications carefully, screen and replete iron deficiency with IV iron, address OSA, vaccinate, refer to cardiac rehab, and revisit goals of care including ICD deactivation discussions as disease progresses

Rapid recap bullets:

Step 3 final pearl: When the EF lands between 41–49%, default to "treat like HFrEF, start with the SGLT2 inhibitor, and never stop GDMT just because the patient looks better" — that single mental model handles ~90% of HFmrEF questions on the exam.