Heart Failure Updates: From SHF to HFpEF and the New Pharmacopeia

A Comprehensive Review for Critical Care Fellows

Dr Neeraj Manikath , claude.ai

Abstract

Heart failure remains a leading cause of morbidity and mortality worldwide, with paradigm-shifting advances in classification, diagnosis, and treatment emerging over the past decade. This review synthesizes contemporary evidence on the spectrum of heart failure phenotypes, from systolic heart failure (SHF) to heart failure with preserved ejection fraction (HFpEF), emphasizing the revolutionary impact of guideline-directed medical therapy (GDMT) and novel pharmacologic agents. We provide practical guidance for the critical care physician managing both acute decompensated heart failure and chronic optimization, with emphasis on actionable pearls and evidence-based strategies.

The Shifting Paradigm: Redefining the Types of Heart Failure

Evolution of Heart Failure Classification

The traditional dichotomy of "systolic versus diastolic" heart failure has been replaced by a more nuanced classification based on left ventricular ejection fraction (LVEF). The current taxonomy recognizes three distinct phenotypes:

Heart Failure with Reduced Ejection Fraction (HFrEF): LVEF ≤40%
Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF): LVEF 41-49%
Heart Failure with Preserved Ejection Fraction (HFpEF): LVEF ≥50%

This classification system, endorsed by both the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association (ACC/AHA), reflects accumulating evidence that the "middle zone" of HFmrEF represents a distinct entity with unique pathophysiology and therapeutic responses.[1,2]

The Forgotten Category: HFmrEF

Pearl: HFmrEF patients demonstrate intermediate characteristics between HFrEF and HFpEF, with mounting evidence suggesting they derive benefit from HFrEF therapies. The CHARM-Preserved trial post-hoc analysis demonstrated that patients with EF 40-50% benefited from angiotensin receptor blockade, while those with EF >50% did not.[3]

Hack: When managing HFmrEF patients in the ICU, treat them as HFrEF until proven otherwise—initiate the four pillars of GDMT and observe for improvement. Many will demonstrate EF recovery with appropriate therapy.

HFpEF: The Growing Epidemic

HFpEF now accounts for approximately 50% of all heart failure cases, with prevalence increasing due to aging populations and rising rates of obesity, diabetes, and hypertension.[4] Unlike HFrEF, which primarily involves impaired systolic function, HFpEF is characterized by:

Diastolic dysfunction with elevated filling pressures
Left ventricular stiffness
Impaired ventricular-arterial coupling
Systemic inflammation
Metabolic derangements

Oyster: HFpEF is not a single disease but rather a clinical syndrome with multiple phenotypes. Recognizing these phenotypes—such as the obese-metabolic phenotype, the atrial fibrillation phenotype, or the right ventricular dysfunction phenotype—allows for more targeted therapy.[5]

The Concept of HF with Improved Ejection Fraction (HFimpEF)

Recent guidelines acknowledge a fourth category: patients with previously reduced EF who demonstrate improvement to >40%. These patients require continued GDMT, as discontinuation often leads to recurrent decline.[6]

Critical Care Consideration: When managing recovered cardiomyopathy patients with acute non-cardiac illness, maintain their heart failure regimen unless hemodynamically contraindicated. Abrupt withdrawal can precipitate acute decompensation.

GDMT Demystified: The Four Pillars of Therapy for Systolic HF

The Foundation: Understanding GDMT

Guideline-directed medical therapy for HFrEF has undergone revolutionary transformation. The 2022 ACC/AHA/HFSA Guidelines established the "Fantastic Four" pillars that should be initiated in virtually all HFrEF patients barring contraindications:[7]

Angiotensin Receptor-Neprilysin Inhibitors (ARNI) or ACE Inhibitors/ARBs
Beta-blockers
Mineralocorticoid Receptor Antagonists (MRAs)
Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2i)

Pillar 1: ARNI—The Preferred First-Line Agent

Sacubitril/Valsartan (Entresto) combines neprilysin inhibition with angiotensin receptor blockade, providing superior outcomes compared to enalapril in the landmark PARADIGM-HF trial.[8] The study demonstrated:

20% reduction in cardiovascular death
21% reduction in heart failure hospitalizations
Number needed to treat (NNT) of 32 to prevent one death over 27 months

Initiation Protocol:

Starting dose: 24/26 mg or 49/51 mg twice daily
Target dose: 97/103 mg twice daily
Prerequisite: 36-hour washout from ACE inhibitors
Monitor: Blood pressure, renal function, potassium

Pearl: In the ICU setting, don't wait for "perfect" stability to initiate ARNI. The PIONEER-HF trial demonstrated that in-hospital initiation during acute decompensation was safe and associated with greater natriuretic peptide reduction compared to enalapril.[9]

Hack: Use the "Rule of Threes" for uptitration—increase dose every 3 weeks if tolerated, checking labs at weeks 1-2 after each increase. Target dosing within 3 months of initiation.

Pillar 2: Beta-Blockers—Mortality Benefit Maintained

Three beta-blockers have proven mortality benefit in HFrEF:

Carvedilol: 3.125-50 mg twice daily
Metoprolol succinate: 12.5-200 mg daily
Bisoprolol: 1.25-10 mg daily

Oyster: The conventional wisdom of "start low, go slow" needs revision. The CIBIS-III trial suggested early beta-blocker initiation may be as effective as initial ACE inhibitor therapy, and recent data support simultaneous initiation of ARNI and beta-blockers for faster optimization.[10]

Critical Care Consideration: In acute decompensation without cardiogenic shock, continue beta-blockers at reduced doses rather than complete cessation. The OPTIMIZE-HF registry showed that continuation was associated with improved outcomes.[11]

Hack for the Bradycardic Patient: If heart rate is 50-60 bpm but patient is symptomatic or on submaximal doses, consider extended-release metoprolol succinate once daily at bedtime—the nadir effect during sleep hours may allow higher dosing.

Pillar 3: Mineralocorticoid Receptor Antagonists

Spironolactone (12.5-50 mg daily) or eplerenone (25-50 mg daily) reduce mortality by 30% in NYHA Class II-IV heart failure patients.[12,13]

Initiation Thresholds:

Serum potassium <5.0 mEq/L
eGFR >30 mL/min/1.73m² (use with caution if 30-49)
Close monitoring in patients on ARNI due to additive hyperkalemia risk

Pearl: The new non-steroidal MRA finerenone offers reduced hyperkalemia risk compared to spironolactone. The FINEARTS-HF trial demonstrated benefit across the ejection fraction spectrum, including HFmrEF and HFpEF.[14]

Hack for Hyperkalemia Management: Before abandoning MRA therapy for potassium 5.5-6.0 mEq/L:

Switch to low-potassium diet
Add patiromer or sodium zirconium cyclosilicate (potassium binders)
Optimize diuretic dosing to enhance potassium excretion
Consider finerenone as alternative

Pillar 4: SGLT2 Inhibitors—The Game Changer (Detailed Below)

The Uptitration Challenge: Rapid Optimization Protocols

Oyster: Traditional uptitration over 6-12 months is obsolete. Contemporary protocols target complete optimization within 6-8 weeks using simultaneous initiation strategies.

The Stanford Rapid Optimization Protocol:

Week 0: Initiate all four pillars at low doses simultaneously
Week 2: Labs and titrate based on tolerance
Week 4: Labs and further titration
Week 6-8: Target dose achievement

This approach, validated in multiple real-world implementations, achieves >70% full optimization compared to 20-30% with sequential traditional approaches.[15]

The SGLT2 Inhibitor Revolution: From Diabetes to Heart Failure Cornerstone

Mechanism of Action: Beyond Glucose

Originally developed for type 2 diabetes, SGLT2 inhibitors have emerged as foundational heart failure therapy through multiple mechanisms:[16]

Natriuresis and osmotic diuresis without neurohormonal activation
Metabolic shift toward ketone body utilization (more efficient fuel)
Reduced ventricular preload and afterload
Anti-inflammatory and anti-fibrotic effects
Improved mitochondrial function
Reduced sympathetic activation

Pearl: The benefits appear independent of diabetes status—HFrEF patients without diabetes derive equal benefit.[17]

The Evidence: Three Landmark Trials

DAPA-HF (Dapagliflozin)

Population: 4,744 HFrEF patients (LVEF ≤40%)
Results: 26% reduction in cardiovascular death or worsening HF (NNT=21 over 18 months)[18]
Dose: 10 mg once daily

EMPEROR-Reduced (Empagliflozin)

Population: 3,730 HFrEF patients (LVEF ≤40%)
Results: 25% reduction in cardiovascular death or HF hospitalization[19]
Dose: 10 mg once daily

DELIVER and EMPEROR-Preserved (HFpEF)

These trials extended SGLT2i benefits to HFpEF patients:

EMPEROR-Preserved: 21% reduction in CV death or HF hospitalization in HFpEF (EF >40%)[20]
DELIVER: Similar benefits with dapagliflozin in HFpEF population[21]

Pooled meta-analysis of >20,000 patients demonstrates consistent benefit across the entire ejection fraction spectrum, including HFmrEF and HFpEF.[22]

Practical Implementation in Critical Care

Initiation Guidelines:

No dose titration required—start at target dose (10 mg daily)
Safe to initiate during acute decompensation once euvolemic
Continue in hospital unless cardiogenic shock present
No specific eGFR cutoff for heart failure indication (unlike diabetes)

Pearl: SGLT2i reduce heart failure hospitalizations by ~30% regardless of baseline natriuretic peptide levels, comorbidities, or other GDMT use—making them perhaps the single most impactful agent we can prescribe.[23]

Hack for Early Discharge: Initiating SGLT2i before discharge reduces 30-day readmissions. The EMPULSE trial showed empagliflozin initiated during acute HF hospitalization improved clinical outcomes.[24]

Adverse Effects and Monitoring

Common concerns:

Genital mycotic infections (3-5% incidence)
Volume depletion (rarely significant)
Euglycemic diabetic ketoacidosis (rare, primarily with type 1 diabetes)

Oyster: Despite theoretical concerns about volume depletion, SGLT2i are remarkably well-tolerated during acute HF. The osmotic diuresis is mild and transient, unlike loop diuretics.

Critical Care Monitoring:

Check baseline eGFR (though no strict cutoff)
Monitor for transient creatinine elevation (0.1-0.3 mg/dL increase is expected and benign)
Counsel on genital hygiene
Hold during prolonged fasting or surgery

Cost Considerations and Alternatives

Hack: If cost is prohibitive, generic canagliflozin is FDA-approved for cardiovascular risk reduction and costs significantly less than branded dapagliflozin or empagliflozin. While specific HF trials used dapa/empagliflozin, class effects suggest benefit.

Diagnosing HFpEF: The HFA-PEFF Score and Role of Advanced Imaging

The Diagnostic Challenge

HFpEF diagnosis remains challenging because:

Echocardiography may appear relatively normal
No single diagnostic test confirms HFpEF
Multiple HF mimics exist (obesity, deconditioning, pulmonary disease)
Diastolic dysfunction alone doesn't equal HFpEF

The HFA-PEFF Diagnostic Algorithm

The Heart Failure Association (HFA) proposed a stepwise diagnostic algorithm combining clinical, laboratory, and imaging variables:[25]

Step 1: Pre-test Assessment (P)

Major Criteria (each scores 2 points):

Atrial fibrillation
Use of ≥2 diuretics

Minor Criteria (each scores 1 point):

Age >60 years
Obesity (BMI >30)
Hypertension on ≥2 antihypertensives

Scoring:

0-1 points: HFpEF unlikely, consider alternate diagnoses
2-4 points: Proceed to echocardiography (Step 2)
≥5 points: HFpEF likely, initiate therapy

Step 2: Echocardiographic Assessment (E)

Major Criteria (2 points each):

Septal e' velocity <7 cm/s or lateral e' <10 cm/s
Average E/e' ratio >15
Left atrial volume index >34 mL/m²
Peak TR velocity >2.8 m/s

Minor Criteria (1 point each):

Septal e' 7-9 cm/s or lateral e' 10-12 cm/s
Average E/e' ratio 9-15
LA volume index 29-34 mL/m²
Peak TR velocity 2.5-2.8 m/s
Global longitudinal strain <16%

Scoring of Step 2:

0-1 points: HFpEF unlikely
2-4 points: Proceed to functional testing or natriuretic peptides
≥5 points: HFpEF confirmed

Step 3: Functional Testing (F) or Invasive Measurements (F)

When Steps 1+2 are inconclusive:

Exercise echocardiography: Assess for E/e' >15 with exercise
Cardiopulmonary exercise testing: Reduced peak VO₂ with elevated VE/VCO₂ slope
Invasive hemodynamics: PCWP ≥15 mmHg at rest or ≥25 mmHg with exercise

Pearl: Natriuretic peptides add diagnostic value:

NT-proBNP >125 pg/mL (or BNP >35 pg/mL) supports HFpEF diagnosis
However, normal values don't exclude HFpEF in obese patients
In AF, use higher thresholds (NT-proBNP >365 pg/mL)

Hack: For borderline cases in the ICU, perform passive leg raise with simultaneous POCUS assessment of E/e' ratio. An increase in E/e' >15 with PLR strongly suggests elevated filling pressures.[26]

Advanced Imaging: Beyond Standard Echocardiography

Speckle-Tracking Echocardiography

Global Longitudinal Strain (GLS): GLS >-16% indicates subclinical systolic dysfunction
GLS impairment predicts outcomes even with preserved EF
Useful for identifying early cardiomyopathy in HFpEF

Cardiac MRI

Gold standard for:

Accurate EF measurement
Myocardial fibrosis detection (late gadolinium enhancement)
Infiltrative disease identification (amyloidosis, sarcoidosis)
Ischemic scar burden quantification

Oyster: In unexplained HFpEF, particularly with LVH, always consider cardiac amyloidosis. Red flags include:

Biventricular wall thickness ≥12 mm
Low voltage ECG with increased wall thickness
Apical sparing pattern on strain imaging
Elevated troponin out of proportion to EF

Hack: Use the technetium pyrophosphate (PYP) scan as a non-invasive screen for transthyretin cardiac amyloidosis (ATTR-CA) before proceeding to endomyocardial biopsy.[27]

Phenotyping HFpEF for Targeted Therapy

Recent data suggest HFpEF comprises distinct phenotypes requiring tailored approaches:[5]

Cardiometabolic phenotype: Obesity, diabetes, insulin resistance → SGLT2i
Atrial fibrillation phenotype: AF as primary driver → Rate/rhythm control
RV dysfunction phenotype: Elevated PA pressures → Pulmonary vasodilators
Elderly-frail phenotype: Advanced age, sarcopenia → Supportive care
Inflammatory phenotype: Systemic inflammation → Immunomodulation (investigational)

Acute Decompensated HF: Management Strategies for the Inpatient

Initial Assessment: The 2x2 Classification

Rapidly categorize patients using the Forrester-Stevenson hemodynamic classification:[28]

	Warm (Well perfused)	Cold (Poorly perfused)
Dry (Euvolemic)	Profile A: Compensated	Profile L: Low output
Wet (Congested)	Profile B: Volume overload	Profile C: Cardiogenic shock

Pearl: Clinical signs guide classification:

Congestion: Orthopnea, edema, JVD, hepatomegaly, pulmonary rales
Hypoperfusion: Cool extremities, altered mentation, narrow pulse pressure, oliguria

Hack: Use the "2-sign rule"—patients with ≥2 signs of congestion or ≥2 signs of hypoperfusion reliably fall into their respective categories, guiding initial therapy.[29]

Profile B (Wet-Warm): The Most Common Presentation

Represents ~70% of acute HF admissions. Primary problem is volume overload without hypoperfusion.

Diuretic Strategy: The DOSE Trial Insights

The DOSE trial compared continuous versus bolus furosemide and low versus high doses:[30]

Key Findings:

High-dose strategy (2.5× home dose) improved dyspnea and fluid loss without worsening renal function
Continuous infusion showed trend toward better outcomes
Target: Net negative 3-5 L over first 24-48 hours

Practical Protocol:

Step 1: Assess home diuretic dose
Step 2: Bolus 2-2.5× home dose IV (minimum 40 mg furosemide equivalent)
Step 3: If inadequate response (net negative <1 L in 6 hours):
   - Add continuous infusion (5-10 mg/hour)
   - Add thiazide diuretic (metolazone 2.5-5 mg daily or chlorothiazide 500 mg IV)
Step 4: Monitor: I/Os, daily weights, electrolytes q12-24h

Pearl: Diuretic resistance is common. Mechanisms include:

Reduced renal perfusion
Distal tubule hypertrophy (compensatory reabsorption)
Reduced loop diuretic secretion into tubular lumen

Overcoming Resistance—The Sequential Nephron Blockade:

Maximize loop diuretic: Continuous infusion + double dose
Add thiazide: Blocks distal convoluted tubule
Add acetazolamide: Blocks proximal tubule carbonic anhydrase
Consider aquaresis: Vasopressin antagonist (tolvaptan) for hyponatremia

The ADVOR Trial recently demonstrated that adding acetazolamide 500 mg IV to loop diuretics improved decongestion without worsening renal function.[31]

Hack: When adding metolazone, give it 30-60 minutes before the loop diuretic dose to maximize sequential blockade. Monitor potassium and magnesium closely—expect significant losses.

Profile L (Dry-Cold): Low Cardiac Output Syndrome

Less common but higher mortality. Problem is inadequate perfusion, not volume overload.

Management Priorities:

Rule out cardiogenic shock (SBP <90 mmHg, evidence of end-organ hypoperfusion)
Identify reversible causes: ACS, acute valvular disease, arrhythmia, PE
Gentle fluid challenge if truly hypovolemic (250 mL bolus with reassessment)
Avoid aggressive diuresis—may worsen perfusion

Advanced therapy considerations:

Inotropic support if persistent hypoperfusion despite optimization
Mechanical circulatory support evaluation (Impella, IABP, VA-ECMO)
Urgent cardiology consultation for possible catheterization or surgical intervention

Profile C (Wet-Cold): Cardiogenic Shock

Highest mortality profile (~40-50%). Requires ICU-level care.

Hemodynamic Optimization Strategy

Step 1: Establish monitoring

Arterial line
Central venous access
Consider PA catheter for refractory cases

Step 2: Inotrope selection

Dobutamine (2-20 mcg/kg/min): β₁-agonist, increases contractility
- Advantage: Peripheral vasodilation may reduce afterload
- Disadvantage: Tachycardia, arrhythmias, increased myocardial O₂ demand
Milrinone (0.125-0.75 mcg/kg/min): Phosphodiesterase-3 inhibitor
- Advantage: Inodilation (inotrope + vasodilator), no increased O₂ demand
- Disadvantage: Hypotension, long half-life (problematic if arrhythmias develop)

Pearl: In "cold-wet" shock with elevated SVR and hypertension, milrinone is often superior—it simultaneously improves contractility while reducing afterload.[32]

Step 3: Vasopressor support if needed

Add norepinephrine if SBP <80 mmHg despite inotropes
Target MAP ≥65 mmHg
Minimize vasopressor use—excessive afterload worsens HF

Step 4: Gentle decongestion

Start diuresis only after perfusion restored (SBP >90, improved UOP/mentation)
Lower diuretic doses than Profile B
Consider ultrafiltration if refractory

Hack: Use the "Shock Index" (HR/SBP) to rapidly assess severity:

<0.7: Normal
0.7-1.0: Compensated shock
1.0: Decompensated shock, mortality risk >30%

The Role of Vasodilators

Nitrates (nitroglycerin) reduce preload through venodilation:

Indications: Hypertensive acute HF, flash pulmonary edema, preserved BP
Dosing: Start 10-20 mcg/min, titrate to effect
Caution: Right ventricular infarction (preload-dependent), severe AS

Nitroprusside provides combined afterload and preload reduction:

Reserved for severe afterload excess (HTN emergency + pulmonary edema)
Requires ICU monitoring due to rapid BP changes
Risk of cyanide toxicity with prolonged use

Pearl: The GALACTIC trial showed that early vasodilator therapy (within 3 hours) in normotensive acute HF improved dyspnea without increasing adverse events.[33]

Ultrafiltration: When Diuretics Fail

Indications:

Diuretic resistance despite combination therapy
Worsening renal function with diuretics
Severe volume overload with electrolyte derangements

The CARRESS-HF trial showed no benefit of ultrafiltration over stepped pharmacologic therapy for worsening renal function, so reserve for true diuretic resistance.[34]

Hack: Before proceeding to ultrafiltration, ensure you've truly maximized medical therapy:

✓ Continuous loop diuretic infusion
✓ Sequential nephron blockade (thiazide + acetazolamide)
✓ Optimized perfusion pressure
✓ Corrected electrolyte abnormalities

Managing Congestion: Underrecognized Pearls

Oyster: Discharge patients at their true "dry weight," not when symptoms resolve. Residual congestion at discharge is the single strongest predictor of 30-day readmission.[35]

How to assess euvolemia:

Resolution of orthopnea (patient flat without dyspnea)
Jugular venous pressure <8 cm H₂O
No lower extremity edema
Stable weight for 24-48 hours
NT-proBNP decline >30% from admission

Hack: Use daily standing NT-proBNP to guide decongestion. Failure to decrease suggests inadequate diuresis despite symptomatic improvement.

Inpatient GDMT Initiation: The Window of Opportunity

Critical pearl: Hospitalization for acute HF is the highest-yield opportunity to initiate and optimize GDMT. Post-discharge initiation rates are dismal (20-40%).[36]

Safe Initiation Protocol:

Continue beta-blockers unless cardiogenic shock
Hold ARNI/ACE-I/ARB initially if SBP <100 or creatinine rising
Restart/initiate ARNI once net negative 3-5 L and SBP stable >100
Start SGLT2i once euvolemic (safe even if GFR <30 for HF indication)
Add/continue MRA if K <5.0 and eGFR >30

STRONG-HF trial demonstrated that intensive uptitration before discharge (starting all GDMT at low doses with close follow-up) reduced 180-day HF readmissions by 34%.[37]

Discharge Checklist: □ All four GDMT pillars initiated or optimized □ Patient at dry weight (euvolemic) □ SBP >100 mmHg on standing □ Stable creatinine for 24-48 hours □ Follow-up arranged within 7 days □ Clear diuretic adjustment plan provided

Pearls Summary: Top 10 Takeaways for Critical Care

HFmrEF is HFrEF: Treat patients with EF 41-49% with full GDMT as if they have HFrEF.
Simultaneous GDMT initiation achieves optimization in 6-8 weeks versus 6-12 months with sequential therapy.
SGLT2 inhibitors are the single most impactful medication—30% reduction in HF hospitalizations regardless of diabetes status, EF, or other medications.
Inpatient GDMT initiation during acute decompensation is safe (even with ARNI/SGLT2i) and dramatically improves post-discharge optimization rates.
High-dose loop diuretics (2.5× home dose) with early sequential nephron blockade overcome diuretic resistance without worsening renal function.
Acetazolamide addition to loop diuretics enhances decongestion—consider it early in diuretic resistance.
Profile classification (wet/dry + warm/cold) guides initial therapy: most patients are "wet-warm" requiring aggressive diuresis.
Residual congestion at discharge is the #1 predictor of 30-day readmission—ensure true euvolemia before discharge.
HFpEF diagnosis requires integrating clinical, echocardiographic, and biomarker data using the HFA-PEFF algorithm.
Finerenone extends MRA benefits to HFmrEF/HFpEF with lower hyperkalemia risk—emerging as the preferred MRA across the EF spectrum.

References

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Additional Clinical Scenarios and Problem-Solving

Scenario 1: The Obese HFpEF Patient with Refractory Dyspnea

Clinical Problem: 68-year-old woman with BMI 42, EF 58%, severe dyspnea, and minimal response to diuretics.

Oyster: Obesity-related HFpEF is driven by metabolic inflammation, epicardial adiposity, and insulin resistance—not just fluid overload. Traditional diuretic-focused strategies often fail.

Multimodal Approach:

SGLT2 inhibitor: Addresses metabolic dysfunction (dapagliflozin 10 mg daily)
Finerenone: Anti-inflammatory and anti-fibrotic effects (10-20 mg daily)
GLP-1 agonist: Weight loss and cardiovascular benefits (semaglutide if diabetic or overweight)
Structured exercise: Supervised cardiac rehabilitation improves functional capacity independent of weight loss
Sleep apnea screening: >80% prevalence in obese HFpEF—treat with CPAP

Pearl: The SELECT trial demonstrated that semaglutide reduced cardiovascular events in obese patients, with particular benefit in those with baseline HFpEF features.[38]

Scenario 2: Atrial Fibrillation and HFpEF—Chicken or Egg?

Clinical Problem: 75-year-old with persistent AF and HFpEF—should you pursue rhythm control?

Evidence Update: The EAST-AFNET 4 trial showed early rhythm control reduced cardiovascular outcomes in AF patients, with greatest benefit in those with heart failure.[39]

Strategy:

First-line rhythm control if symptoms attributable to AF
Catheter ablation superior to antiarrhythmic drugs in HF patients (CASTLE-AF trial)[40]
Rate control acceptable if asymptomatic, but optimize to <100 bpm at rest, <110 with activity

Hack: Use AV node ablation + cardiac resynchronization therapy (CRT) as last resort for refractory rapid AF with HFrEF—"ablate and pace" strategy improves EF and symptoms.[41]

Scenario 3: Cardiorenal Syndrome—Breaking the Vicious Cycle

Clinical Problem: Worsening heart failure with rising creatinine during diuresis.

Classification:

Type 1: Acute HF causing acute kidney injury
Type 2: Chronic HF causing chronic kidney disease
Type 3: Acute kidney injury causing acute HF
Type 4: CKD causing chronic HF
Type 5: Systemic disease causing both

Management Principles:

Distinguish true renal injury from pseudo-worsening: Small creatinine increases (0.3-0.5 mg/dL) with effective decongestion are acceptable and often reversible
Optimize renal perfusion: Ensure adequate cardiac output (MAP >65 mmHg)
Continue decongestion: Congestion causes more renal damage than diuretics
SGLT2 inhibitors: Renoprotective despite transient GFR reduction

Oyster: The "usual suspects" causing creatinine elevation:

✓ Overdiuresis (check orthostatic vitals)
✓ Excessive RAAS blockade (hold ACE-I/ARB temporarily)
✓ NSAIDs or other nephrotoxins
✓ Contrast exposure
✓ Hypotension

When to stop diuresis:

Orthostatic hypotension with symptoms
Creatinine >3.0 mg/dL or doubling from baseline
Oliguria despite adequate perfusion
Electrolyte abnormalities refractory to replacement

Scenario 4: Right Ventricular Failure—The Forgotten Ventricle

Clinical Problem: Persistent low cardiac output and elevated CVP despite LV-directed therapy.

Recognition:

Elevated JVP with clear lungs
Hepatomegaly, ascites, peripheral edema
Severe TR on echo
RV dilation and dysfunction

Etiologies:

Left heart disease (most common—backward transmission)
Pulmonary hypertension (PAH, CTEPH, Group 3 PH)
RV infarction
PE
Congenital heart disease

Management:

Maintain RV preload: Unlike LV failure, RV needs adequate filling pressure (CVP 8-12 mmHg)
Reduce RV afterload:
- Treat hypoxemia aggressively (target SpO₂ >90%)
- Inhaled pulmonary vasodilators (inhaled epoprostenol, nitric oxide)
- Avoid systemic vasodilators (can worsen RV perfusion)
Optimize contractility: Low-dose inotropes if hypoperfusion
Maintain sinus rhythm: RV is highly dependent on atrial kick
Avoid excessive PEEP: Increases RV afterload

Pearl: In isolated RV failure, milrinone is superior to dobutamine due to pulmonary vasodilation effects.[42]

Hack: Use the TAPSE/PASP ratio on echo as a surrogate for RV-PA coupling. Ratio <0.31 mm/mmHg predicts poor outcomes and need for advanced therapy.[43]

Emerging Therapies and Future Directions

Vericiguat: The Soluble Guanylate Cyclase Stimulator

Mechanism: Enhances nitric oxide-cGMP pathway, improving vasodilation and reducing fibrosis.

VICTORIA Trial: In high-risk HFrEF patients (recent hospitalization), vericiguat reduced cardiovascular death or HF hospitalization by 10% (NNT=24).[44]

Role in Practice: Reserved for patients with recent decompensation despite optimal GDMT—a "fifth pillar" for refractory cases.

Dosing: Start 2.5 mg daily, titrate to 10 mg daily over 4-8 weeks.

Omecamtiv Mecarbil: The Cardiac Myosin Activator

Mechanism: Increases cardiac contractility by prolonging systolic ejection time without increasing oxygen consumption.

GALACTIC-HF Trial: Modest reduction in HF events in HFrEF, primarily in those with EF <28%.[45]

Status: FDA-approved but limited adoption due to marginal benefit compared to established GDMT.

Iron Repletion: The Overlooked Intervention

Prevalence: Iron deficiency affects 30-50% of HF patients, independent of anemia.

AFFIRM-AHF Trial: IV ferric carboxymaltose in iron-deficient acute HF patients reduced HF hospitalizations by 26%.[46]

Definition of Iron Deficiency in HF:

Ferritin <100 ng/mL, OR
Ferritin 100-300 ng/mL with transferrin saturation <20%

Dosing: Ferric carboxymaltose 500-1000 mg IV (weight-based), repeat dose at 6 weeks if needed.

Pearl: Check iron studies on all HF admissions—iron repletion improves functional capacity and QOL even without anemia.

Novel Targets on the Horizon

Cardiac Myosin Inhibitors (mavacamten, aficamten): FDA-approved for HCM, under investigation for HFpEF
NLRP3 Inflammasome Inhibitors: Targeting inflammatory pathways in HFpEF
AT2 Receptor Agonists: Counterbalancing AT1 receptor blockade
Gene Therapy: Early trials for genetic cardiomyopathies
RNA Therapeutics: Silencing pathologic gene expression (e.g., patisiran for ATTR amyloidosis)

Special Populations

Heart Failure in Advanced Chronic Kidney Disease (CKD Stage 4-5)

Challenges:

Volume overload despite massive diuretic doses
Hyperkalemia limiting RAAS blockade
Uremia contributing to cardiac dysfunction

Management Adaptations:

Higher loop diuretic doses: Bumetanide preferred (better oral bioavailability)
SGLT2 inhibitors: Safe and effective even with eGFR <20 for HF indication
Patiromer or ZS-9: Enable MRA continuation despite hyperkalemia
Early nephrology referral: Consider ultrafiltration or dialysis initiation

Hack: Use bumetanide 3-4 mg instead of furosemide 40 mg in CKD—40:1 potency ratio means better absorption and effect.

Peripartum Cardiomyopathy (PPCM)

Definition: HF developing in last month of pregnancy or within 5 months postpartum without identifiable cause.

Unique Features:

EF often severely reduced (20-35%)
High recovery rate (50-70% normalize EF)
Risk of recurrence in subsequent pregnancies

Management:

Standard HFrEF therapy EXCEPT avoid RAAS inhibitors during pregnancy (teratogenic)
Bromocriptine: May improve outcomes by blocking pathologic prolactin fragments (2.5 mg daily × 2 weeks, then 2.5 mg twice daily × 6 weeks)[47]
Anticoagulation if EF <30% (high thromboembolism risk)

Pearl: Counsel against future pregnancies if EF fails to recover—maternal mortality risk >10% in subsequent pregnancies.

Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD)

High-risk agents:

Anthracyclines (doxorubicin): Dose-dependent cardiomyopathy
HER2 inhibitors (trastuzumab): Usually reversible
Tyrosine kinase inhibitors: Hypertension and HF
Immune checkpoint inhibitors: Myocarditis

Prevention and Management:

Baseline echo before cardiotoxic chemotherapy
Consider prophylactic beta-blockers and ACE-I in high-risk patients
Early detection with GLS monitoring (>15% reduction warrants intervention)
Cardio-oncology co-management

Hack: Use dexrazoxane as cardioprotectant when cumulative doxorubicin dose >300 mg/m²—reduces CTRCD risk by 80%.[48]

System-Level Interventions: Reducing Heart Failure Readmissions

The 30-Day Readmission Crisis

HF readmission rates remain 20-25% despite advances in therapy. Multifactorial causes include:

Inadequate decongestion at discharge
Suboptimal GDMT
Medication non-adherence
Lack of follow-up
Social determinants of health

Evidence-Based Strategies

STRONG-HF Rapid Uptitration Protocol (discussed earlier): 34% reduction in 180-day readmissions.[37]

Telemonitoring Programs: Mixed results, but intensive interventions with daily weight monitoring and algorithm-driven diuretic adjustment show promise.

Transitional Care Models:

Discharge with 7-day follow-up appointment (preferably within 3 days)
Home health nursing visit within 48 hours
Pharmacist medication reconciliation
"Teach-back" method for patient education

Pearl: The single most effective intervention is ensuring patients leave at euvolemic weight with clear instructions on daily weights and self-adjustment of diuretics.

The "HF Dashboard" for ICU Discharge Planning

Before transferring out of ICU or discharging:

□ Volume status: At dry weight (orthopnea resolved, no edema, stable weight ×48h)
□ GDMT: All four pillars initiated at maximally tolerated doses
□ Blood pressure: SBP >100 mmHg on standing (tolerating GDMT)
□ Renal function: Creatinine stable or improving ×48h
□ Electrolytes: K 3.5-5.0, Mg >2.0
□ Education: Teach-back on daily weights, low-sodium diet, medication purpose
□ Follow-up: Appointment scheduled within 7 days
□ Contact: Patient has phone number to call with questions or weight gain >2-3 lbs

Conclusion: Paradigm Shifts and the Path Forward

The landscape of heart failure management has undergone revolutionary transformation in the past decade. Key paradigm shifts include:

From sequential to simultaneous: Rapid optimization protocols achieve GDMT targets in weeks rather than months, dramatically improving outcomes.
From HFrEF-only to pan-HF therapy: SGLT2 inhibitors and finerenone provide benefit across the ejection fraction spectrum, finally offering evidence-based therapies for HFpEF.
From outpatient optimization to inpatient initiation: Hospitalization represents the highest-yield opportunity for GDMT implementation.
From symptom-driven to congestion-driven decongestion: Achieving true euvolemia before discharge prevents readmissions more effectively than symptom relief alone.
From one-size-fits-all to phenotype-directed therapy: Recognizing HFpEF subtypes enables targeted interventions.

As critical care physicians, we are uniquely positioned to impact the heart failure epidemic. Mastering acute decompensation management while simultaneously optimizing chronic GDMT during hospitalization represents the dual mandate of modern HF care. The tools now exist to dramatically improve outcomes—our challenge is implementing them consistently and completely for every patient under our care.

The future promises even more innovation: gene therapies, RNA-based treatments, anti-inflammatory strategies, and artificial intelligence-guided personalized medicine. But the present already offers powerful, life-extending therapies. Our responsibility is ensuring every patient receives them.

Key Abbreviations

ACC/AHA: American College of Cardiology/American Heart Association
ARNI: Angiotensin Receptor-Neprilysin Inhibitor
ATTR-CA: Transthyretin Cardiac Amyloidosis
CRT: Cardiac Resynchronization Therapy
CTRCD: Cancer Therapeutics-Related Cardiac Dysfunction
ESC: European Society of Cardiology
GDMT: Guideline-Directed Medical Therapy
GLS: Global Longitudinal Strain
HFA: Heart Failure Association
HFimpEF: Heart Failure with Improved Ejection Fraction
HFmrEF: Heart Failure with Mildly Reduced Ejection Fraction
HFpEF: Heart Failure with Preserved Ejection Fraction
HFrEF: Heart Failure with Reduced Ejection Fraction
LVEF: Left Ventricular Ejection Fraction
MRA: Mineralocorticoid Receptor Antagonist
NT-proBNP: N-Terminal Pro-B-Type Natriuretic Peptide
PCWP: Pulmonary Capillary Wedge Pressure
PPCM: Peripartum Cardiomyopathy
SGLT2i: Sodium-Glucose Cotransporter-2 Inhibitor

Additional References (38-48)

Lincoff AM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232.
Kirchhof P, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316.
Marrouche NF, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378(5):417-427.
Khan MN, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med. 2008;359(17):1778-1785.
Kerbaul F, et al. Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure. Crit Care Med. 2007;35(8):1948-1954.
Guazzi M, et al. Tricuspid annular plane systolic excursion and pulmonary arterial systolic pressure relationship in heart failure: an index of right ventricular contractile function and prognosis. Am J Physiol Heart Circ Physiol. 2013;305(9):H1373-1381.
Armstrong PW, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-1893.
Teerlink JR, et al. Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure. N Engl J Med. 2021;384(2):105-116.
Ponikowski P, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895-1904.
Sliwa K, et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation. 2010;121(13):1465-1473.
van Dalen EC, et al. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2011;(6):CD003917.

Disclosure: The author has no relevant financial disclosures.

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Wednesday, October 1, 2025