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🫀 HEART FAILURE — COMPLETE STUDY NOTES

Harrison's Principles of Internal Medicine, 22nd Ed. | Chapters 264 & 265

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CHAPTER 264: HEART FAILURE — PATHOPHYSIOLOGY & DIAGNOSIS

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1. CLINICAL DEFINITIONS

Key point: "Heart failure" is preferred over "congestive heart failure" — not all patients have volume overload at presentation.

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2. EPIDEMIOLOGY

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TABLE 264-1: Independent Predictors of Adverse Outcomes in HF

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3. PHENOTYPES OF HEART FAILURE

The older terms "systolic HF" and "diastolic HF" have been abandoned — most patients have abnormalities in both systolic and diastolic function regardless of EF.

• Despite EF recovery → may remain symptomatic (diastolic dysfunction, exercise-induced PAH)
• Withdrawal of GDMT → recurrence in up to 50% within 6 months
• Prognosis: Better than both HFrEF and HFpEF

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TABLE 264-2: Selected Causes of Heart Failure

HFrEF

HFpEF

High-Output HF

Congenital Heart Disease

• ~13.3 million globally; ~467,000 U.S. adults
• Three groups: (1) uncorrected defects with late presentation; (2) repaired defects with late valve/ventricular failure; (3) failing single-ventricle physiology

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4. PATHOPHYSIOLOGY

A. Progressive Disease

INDEX EVENT
(MI / Pressure-Volume Overload / Genetic / Congenital)
         ↓
  Initial ↓ in cardiac performance
         ↓
  Compensatory mechanisms activated
  (asymptomatic or mildly symptomatic for months-years)
         ↓
  Compensatory mechanisms become MALADAPTIVE
         ↓
  Ventricular Remodeling → Clinical HF
         ↓
  Neurohormonal activation (SNS + RAAS)
         ↓
  Progressive myocardial dysfunction

B. Ventricular Remodeling

• Myocyte hypertrophy + interstitial fibrosis
• Altered calcium-handling proteins
• Re-expression of fetal gene programs (β-myosin heavy chain)
• β-adrenergic receptor desensitization
• Myocyte apoptosis (programmed cell death)

• Diastolic dysfunction (impaired SR calcium uptake)
• Vascular stiffness
• Renal dysfunction + sodium avidity
• Oxidative stress / nitrosative stress
• Insulin resistance
• Inflammation from regional adiposity
• Impaired nitric oxide signaling

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C. FIGURE 264-6: Remodeling Stimuli in Heart Failure

╔══════════════════════════════════════════════════════╗
║          CHRONIC HEMODYNAMIC STIMULI                 ║
║   (Pressure overload / Volume overload / Ischemia)   ║
╚══════════════╦═══════════════════════════════════════╝
               ↓
    ┌──────────┴────────────────────────────────┐
    ↓           ↓            ↓          ↓       ↓
Myocardial  Inflammatory  Signaling  Neuro-  Oxidative
wall stress  cytokines    peptides   endocrine  stress
    └──────────┬────────────────────────────────┘
               ↓
     ┌─────────┴───────────────────────┐
     ↓                                 ↓
ADAPTIVE changes              MALADAPTIVE changes
(initially compensatory)      
                                        ↓
                    Re-expression of FETAL contractile
                    + Ca²⁺-handling proteins
                    → impaired contraction & relaxation
                                        ↓
                    Myocytes unable to adapt
                    → APOPTOSIS
                                        ↓
                    ↓ pump function + ↑ wall stress
                    → AFTERLOAD MISMATCH
                                        ↓
                    ══════ VICIOUS CYCLE ══════
                    → Progressive myocardial dysfunction

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D. Neurohormonal Activation

↓ Cardiac Output
       ↓
"Unloading" of high-pressure baroreceptors
(LV, carotid sinus, aortic arch)
       ↓
↓ Parasympathetic tone
↑ Efferent sympathetic tone
       ↓
    ┌──┴────────────────────────────────────┐
    ↓                                       ↓
Nonosmotic AVP release              SNS activation of:
(pituitary)                         Heart / Kidney /
    ↓                               Vasculature / Muscle
Vasoconstriction                            ↓
Free water reabsorption               Renin release
                                            ↓
                                    ↑ Angiotensin II
                                    ↑ Aldosterone
                                            ↓
                           Salt/water retention
                           Peripheral vasoconstriction
                           Myocyte hypertrophy
                           Cell death + fibrosis

SHORT-TERM: Maintains BP and organ perfusion ✓
LONG-TERM: End-organ changes → MALADAPTIVE ✗

Clinical importance: RAAS inhibitors + beta-blockers + MRAs → attenuate/reverse remodeling → ↓ morbidity and mortality.

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E. Vasodilatory Hormones (Counterregulatory)

Neprilysin inactivates natriuretic peptides and bradykinin → explains benefit of ARNI (sacubitril-valsartan).

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F. Endothelin, Inflammatory Cytokines, and Oxidative Stress

• Potent vasoconstrictor + growth-promoting effects
• Causes myocyte hypertrophy + interstitial fibrosis
• Important in pulmonary HTN and RV failure
• Endothelin blockade does NOT slow progression of left ventricular HF (but IS beneficial in PAH)

• TNF-α, IL-1β - elevated in HF
• Sources: liver, gastrointestinal tract
• Role of anti-inflammatory therapies remains unproven in HF

• Reactive oxygen species: superoxide and peroxynitrite
• Role of antioxidant therapies remains unproven

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G. Novel Biological Targets

• Located in proximal tubule; reabsorbs ~90% of filtered glucose
• In HF contributes to: sodium/water retention, endothelial dysfunction, abnormal myocardial metabolism, impaired Ca²⁺ handling
• SGLT-2 inhibitors → beneficial effects on morbidity and mortality in HF (with or without diabetes)
• Mechanisms: diuretic, cardiac/vascular remodeling, anti-arrhythmic, renal, metabolic, anti-inflammatory, autophagy

• Downregulated in HF → contributes to endothelial dysfunction
• Oral soluble guanylate cyclase stimulants enhance cGMP → beneficial myocardial and vascular effects

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H. Dyssynchrony and Electrical Instability

• Up to 1/3 of HF patients have QRS prolongation
• LBBB → abnormal ventricular contraction (electrical dyssynchrony)
• CRT corrects dyssynchrony → improves contractile function, decreases MR, reverses remodeling
• Other forms of electrical instability: AF with inadequate rate control, frequent PVCs
• These arrhythmias → worsening HF via tachycardia, irregular rhythm, ↑ wall stress, neurohormonal activation, inflammation

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I. Secondary Mitral Regurgitation

• ↓ contractile force → ↓ leaflet coaptation
• Spherical ventricular shape → altered papillary muscle structure
• ↑ mitral annulus diameter (annulus cannot contract during systole)
• Dilation of posterior LA wall → distortion of posterior mitral leaflet

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J. Cardiorenal and Abdominal Interactions

• Splanchnic veins act as blood reservoir; regulate preload via transmural pressure + SNS
• Portal vein distension → hepatorenal + splenorenal reflex → renal vasoconstriction
• ↑ intraabdominal pressure (right HF) → correlates with renal dysfunction
• Decongestion → ↓ abdominal compartment pressure → may improve/stabilize renal function

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K. Gut Congestion, Microbiome, and Inflammation

• Elevated proinflammatory cytokines → HF disease progression
• Altered gut microbiome in HF:
  • ↓ microbial diversity → chronic inflammation + immune dysregulation
  • LPS (gram-negative bacterial product) → elevated in HF due to ↑ intestinal permeability → macrophage activation → TNF-α, IL-1, IL-6 → cardiac cachexia
  • TMAO (trimethylamine N-oxide) from dietary choline/carnitine → associated with poor outcomes
  • Uremic toxins (indoxyl sulfate) → role in HF with renal insufficiency

Bowel ischemia/congestion
        ↓
Morphologic + functional intestinal changes
        ↓
Bacterial endotoxemia
        ↓
Proinflammatory state
        ↓
Progressive cardiac dysfunction + cardiac cachexia

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L. High-Output States

• Most HF = low/normal CO + elevated SVR
• High-output states alone rarely cause HF without underlying cardiovascular disease
• Chronic anemia → high CO when Hgb ≤8 g/dL → vasodilatory metabolites, arteriolar dilation, ↓ blood viscosity
• ESRD patients: Particularly at risk when chronic anemia + AV fistula flow compound
• Most common causes: Pulmonary disease (19.8%), severe obesity (9.9%), sepsis (9.6%), cirrhosis (8.9%), hyperthyroidism (5.5%)

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5. EVALUATION — HISTORY

A. Symptoms of Congestion

LEFT HF — Pulmonary Venous Congestion

• Pulmonary venous congestion + fluid transudation → ↓ lung compliance, ↑ airway resistance, hypoxemia, V/Q mismatch
• Stimulation of juxtacapillary J receptors → ↑ ventilatory drive
• ↓ blood flow to respiratory muscles → lactic acidosis

Exertional dyspnea
      ↓
Bendopnea (dyspnea when bending forward, e.g., putting on socks)
      ↓
Orthopnea (dyspnea on lying flat; within 1-2 min; relieved by elevating head)
      ↓
Paroxysmal Nocturnal Dyspnea (PND: awakens from sleep;
requires ≥30 min upright; ± "cardiac asthma": wheeze/cough)
      ↓
Dyspnea at rest
      ↓
Acute pulmonary edema (pink, frothy sputum)

• Cheyne-Stokes / central sleep apnea (↑ respiratory center sensitivity to PCO₂ + prolonged circulatory time)
• Nocturnal cough

RIGHT HF — Systemic Venous Congestion

• Weight gain and lower extremity edema (initial manifestations)
• GI symptoms: abdominal bloating, anorexia, early satiety
• Right upper quadrant pain (hepatic capsule stretch) + nausea/vomiting
• Anasarca in refractory right HF; recurrent pleural effusions, ascites

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TABLE 264-4: NYHA Functional Classification

Note: NYHA class does NOT correlate well with objective measures (LV size, EF, peak VO₂).

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B. Symptoms of Reduced Perfusion

• Fatigue and weakness (especially lower extremities) — exertion or rest
  • Mechanisms: ↓ muscle blood flow, endothelial dysfunction, ↑ SVR, skeletal muscle changes
• Mental dullness, confusion — older patients; ↓ systemic perfusion
• Other causes of fatigue: volume depletion, hyponatremia, iron deficiency, beta-blocker effects

C. Other Symptoms

• Mood disturbances and poor sleep (dyspnea, sleep apnea)
• Nocturia (improved CO + renal perfusion supine + delayed diuresis)
• Oliguria (severe ↓ renal blood flow; advanced HF)

D. Precipitating Factors

Identifiable in 50-90% of admissions

TABLE 264-5: Precipitating Factors in HF

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6. PHYSICAL EXAMINATION

A. General Appearance

B. Vital Signs

C. Jugular Venous Pulse (JVP)

• Quantify: height of venous column above sternal angle + 5 cm = right atrial pressure
• Examine at 45° angle
• Normal JVP at rest (≤8 cm H₂O) in mild right HF → may increase with hepatic compression
• Hepatojugular reflux: Firm RUQ pressure for 15-30 sec → positive if JVP increases
• Kussmaul's sign (JVP rises with inspiration): Severe biventricular HF, constrictive pericarditis, restrictive CM → marker of poor outcome
• Significant TR → prominent V waves and Y descents

D. Lung Examination

E. Cardiac Examination

F. Abdomen and Extremities

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7. DIAGNOSIS

A. Routine Laboratories

B. Chest X-Ray

C. ECG

D. Noninvasive Imaging

• LV/RV size and function; valvular morphology/function
• Detection of intracavitary thrombi and pericardial effusions
• LVEF ≥50% = normal systolic function
• Myocardial strain rate (speckle tracking): incremental prognostic value
• Doppler: estimates CO, PA pressures, valve areas, LV diastolic filling

E. Cardiopulmonary Exercise Testing (CPET)

• Absolute and percent-predicted peak VO₂
• Ventilatory efficiency (VE/VCO₂ slope)

F. Biomarkers

G. Invasive Studies

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8. COMORBIDITIES

A. Diabetes Mellitus

• Prevalence in ambulatory HF: 10-40%; higher in hospitalized HF
• Mechanisms: altered myocardial substrate, mitochondrial dysfunction, oxidative stress, lipotoxicity, RAAS activation, advanced glycation end products (AGEs)
• SGLT-2 inhibitors → improved renal function, QOL, ↑ LVEF, ↓ HF hospitalization and death

B. Sleep Apnea

• Common in HF: both OSA and CSA
• ~1/3 of HF patients with sleep-disordered breathing have CSA → ↑ mortality
• OSA + HFrEF: CPAP → ↑ QOL, ↓ BP, ↓ arrhythmias, ↑ LVEF
• CSA: No proven therapy; treat the HF primarily

C. Obesity

• Particularly common in HFpEF; complicates volume assessment
• "Obesity paradox": Obese patients with HF have a more favorable prognosis than low/normal BMI
• Weight loss → ↑ QOL, ↑ exercise capacity, possible reverse remodeling
• Semaglutide (GLP-1) trials in obese HFpEF (STEP-HFpEF) → ↑ functional capacity + QOL

D. Depression

• Independent risk factor for adverse outcomes (especially older women)
• AHA recommends screening using validated questionnaires
• SSRIs: Safe but do NOT affect natural history of HF
• Cognitive behavioral therapy and collaborative care: effects on HF morbidity/mortality require further study

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TABLE 264-8: Differential Diagnosis of Heart Failure

• Orthopnea may occur in severe lung disease
• Cardiac asthma vs bronchial asthma: Cardiac → more diaphoresis + cyanosis
• PND from lung disease → relieved by coughing/expectoration (vs sitting upright in cardiac PND)
• Very low BNP/NT-proBNP → excludes HF as cause of dyspnea in nonobese patients

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CHAPTER 265: HEART FAILURE — MANAGEMENT

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1. HFpEF / HFmrEF MANAGEMENT

A. General Principles

• Clinical trials of RAAS antagonists, digoxin, beta-blockers, and neprilysin inhibitors → NOT conclusively proven to reduce mortality in HFpEF
• Variable benefits (↓ HF hospitalizations) with MRAs, ARBs, ARNIs — mainly in EF <60% (HFmrEF range)
• HFmrEF: Treat similar to HFrEF (same pharmacotherapy)
• True HFpEF management targets:
  • Relieve congestion (diuretics - carefully; avoid excessive preload reduction)
  • Control BP to guideline targets
  • Maintain sinus rhythm (AF ablation may ↓ morbidity/mortality)
  • Manage comorbidities: obesity, OSA, DM, anemia, iron deficiency, CKD
  • Treat myocardial ischemia
  • SGLT-2 inhibitors: Now foundational therapy regardless of EF (DELIVER, EMPEROR-PRESERVED)

B. Clinical Trials in HFpEF

C. FIGURE 265-1: HFpEF — Pathophysiologic Correlations

┌─────────────────────────┐     ┌──────────────────────┐
│      PATHOLOGY          │     │     RISK MARKERS      │
│ - Hypertrophy           │     │ - Hypertension        │
│ - Fibrosis/altered      │     │ - Aging               │
│   collagen              │     │ - Atherosclerosis     │
│ - Infarction/ischemia   │     │ - Diabetes            │
└─────────────┬───────────┘     │ - Obesity             │
              └────────┬────────┘
                       ↓
         GENERAL THERAPEUTIC PRINCIPLES
  ┌────────────────────────────────────────────┐
  │ 1. Reduce congestive state (diuretics)     │
  │    - Caution: avoid excessive ↓ preload   │
  │ 2. Control blood pressure                 │
  │ 3. Maintain AF sinus rhythm; prevent       │
  │    tachycardia                             │
  │ 4. Treat myocardial ischemia              │
  │ 5. Detect and treat sleep apnea           │
  │ 6. Lifestyle modification (diet, exercise) │
  └────────────────────────────────────────────┘
                       ↓
         SPECIFIC THERAPY OUTCOMES
  ┌──────────────────────┬───────────────────────┐
  │ INEFFECTIVE          │ EFFECTIVE/PROMISING   │
  ├──────────────────────┼───────────────────────┤
  │ ACEi/ARBs            │ SGLT-2 inhibitors     │
  │ Beta-blockers        │ ARNIs (selected pts)  │
  │ PDE-5 inhibitors     │ Aldosterone antag.    │
  │ Nitrates (NEAT-HFpEF)│ GLP-1 agonists (DM-) │
  │ Chronotropic pacing  │ Exercise training     │
  │ Digoxin              │ Bariatric surgery     │
  └──────────────────────┴───────────────────────┘

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2. ACUTE DECOMPENSATED HEART FAILURE (ADHF)

A. General Principles

• Heterogeneous syndrome: ↓ cardiac performance + renal dysfunction + vascular compliance alterations
• Nearly 50% readmitted within 6 months
• In-hospital mortality ~5%; 20% mortality at 1 year
• Combined CV deaths/HF hospitalization/MI/stroke/SCD: 50% at 12 months post-hospitalization

• Medication nonadherence; dietary salt indiscretion; NSAIDs/TZDs/TNF inhibitors; coronary ischemia; arrhythmias; valvular disease; systemic infection; PE

• BUN >43 mg/dL
• Systolic BP <115 mmHg
• Serum Cr >2.75 mg/dL
• Elevated natriuretic peptides + cardiac troponins

B. ADHF Phenotypes (Figure 265-2)

                    ADHF PRESENTATION
                           ↓
         ┌─────────────────┴──────────────────┐
         ↓                                     ↓
    CONGESTED                          NOT CONGESTED
         ↓                                     ↓
   ┌─────┴──────┐                    ↓ CO / Hypoperfusion
   ↓            ↓
NORMO/         HYPER-
TENSIVE        TENSIVE
   ↓            ↓
Diuretics  Vasodilators

PULMONARY EDEMA PHENOTYPE:           LOW OUTPUT PHENOTYPE:
Severe congestion + hypoxia          Hypoperfusion + end-organ
O₂ + NIV + Opiates                   dysfunction
Vasodilators + Diuretics             Vasodilators / Inotropes

CARDIOGENIC SHOCK PHENOTYPE:
Hypotension + low CO + end-organ failure
Inotropes (catecholamines) + MCS (IABP, VAD)

C. Volume Management — IV Diuretics

• IV loop diuretics essential when oral absorption is impaired
• Bolus vs continuous infusion: No clear superiority; continuous preferred for refractory cases
• Loop diuretic refractoriness: Add thiazide (metolazone or chlorothiazide) for sequential nephron blockade → ↑ natriuresis but ↑↑ risk of severe hypokalemia
• ADVOR trial: Acetazolamide + loop diuretics → ↑ decongestion but did NOT reduce HF readmissions/mortality
• Targets: ↓ JVP; resolution of rales; resolution of peripheral edema/hepatomegaly/ascites
• Predischarge BNP/NT-proBNP: correlates strongly with post-discharge mortality + readmission
• TRANSFORM-HF: No mortality/morbidity advantage of torsemide vs furosemide

D. Cardiorenal Syndrome

• ~30% of hospitalized ADHF patients have abnormal baseline renal function
• Most have preserved cardiac output (not low flow state)
• Mechanism: Complex neurohormonal interplay + "backward failure" from ↑ intraabdominal pressure
• Diuretics → ↓ GFR when right-sided filling pressures remain elevated
• Inotropes or MCS: preserve renal function short-term as bridge in profound low CO

E. Ultrafiltration (Aquapheresis)

• CARRESS-HF trial: Stepped pharmacologic care vs ultrafiltration in ADHF + worsening renal failure:
  • Similar weight loss (~5.5 kg) in both groups
  • UF group: ↑ serum creatinine, more adverse events (kidney failure, bleeding, catheter complications)
• Conclusion: UF NOT recommended as primary strategy; reserve for diuretic-refractory patients

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TABLE 265-1: Vasoactive Therapy in ADHF

F. Clinical Guiding Principles for ADHF

• Goal-directed: decongestion + trigger suppression + transition to longitudinal management
• Failing medical therapy → PAC for hemodynamic-guided vasoactive/inotropic titration
• Hemodynamic instability/cardiogenic shock → mechanical circulatory support
• PIONEER-HF: Predischarge initiation of sacubitril-valsartan → ↓ NT-proBNP + lower death/HF readmission at 8 weeks
• EMPULSE: Predischarge empagliflozin → ↓ hierarchical clinical composite at 90 days
• STRONG-HF: Intensive GDMT uptitration + frequent follow-up within 2 weeks of discharge → ↓ death/HF readmission at 180 days
• All patients: HF self-management education before discharge; early postdischarge follow-up

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3. HFrEF MANAGEMENT

Renocentric era (diuretics)
         ↓
Hemodynamic era (digoxin, inotropes)
         ↓
Neurohormonal antagonism era (ACEi/ARBs + beta-blockers + MRAs)
         ↓
Modern "Fantastic Four" era:
  ARNI + Beta-blocker + MRA + SGLT-2i

A. Neurohormonal Antagonism

• 23% reduction in mortality + 35% reduction in combined mortality/HF hospitalizations
• Recommended for ALL patients with HFrEF regardless of symptom burden

• Adding beta-blockers to ACEi → further 35% reduction in mortality
• NOT a class effect — only proven agents:
  • Carvedilol (nonselective β + α₁ blocker)
  • Bisoprolol (selective β₁)
  • Metoprolol succinate CR/XL (selective β₁)
  • Agents with intrinsic sympathomimetic activity and bucindolol: NO survival benefit
• CIBIS III: Sequence (beta-blocker first vs ACEi first) does NOT affect outcomes — what matters is achieving optimal titrated doses of BOTH

• Noninferior to ACEi → suitable alternative for ACEI intolerance (cough, angioedema)

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B. Mineralocorticoid Receptor Antagonists (MRAs)

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C. RAAS Therapy and Neurohormonal Escape

• Angiotensin II generated by non-ACE pathways → levels recover during long-term ACEi therapy
• Dual RAAS blockade (ACEi + ARB): ↓ HF hospitalizations but not clearly superior to maximizing single agent
• VALIANT: ACEi + ARB at evidence-based doses → ↑ adverse events, no added benefit
• Guidelines: Discourage ACEi + ARB + spironolactone triple combination → risk of hyperkalemia/renal dysfunction

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D. Alternative Vasodilators

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E. Novel Neurohormonal Antagonists

• Combined ARB + neprilysin inhibitor
• Blockade at angiotensin receptor → ACE pathway for bradykinin breakdown intact → ↓ angioedema risk (vs omapatrilat)
• PARADIGM-HF (8,399 HFrEF patients on GDMT):
  • 20% ↓ in CV death or HF hospitalization
  • 16% ↓ in all-cause mortality
  • ↑ QOL; ↓ hyperkalemia + worsening renal function vs enalapril
  • ↑ symptomatic hypotension
• Contraindicated in prior history of angioedema; must wait 36 hours after last ACEi dose before starting
• Guidelines: Switch to ARNI in symptomatic HFrEF who tolerate ACEi/ARB; up-front use in de novo HF also appropriate

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TABLE 265-2: Guidelines-Directed Pharmacologic Therapy and Target Doses for HFrEF

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F. Heart Rate Modification

• Ivabradine: Selective I_f current inhibitor in SA node → ↓ HR without affecting contractility
• SHIFT trial: NYHA II-III HFrEF, sinus rhythm, HR >70 bpm on GDMT:
  • ↓ combined CV death + HF hospitalization (proportional to degree of HR reduction)
• Indication: Symptomatic HFrEF, sinus rhythm, HR >70 bpm despite maximized beta-blocker + GDMT; also for beta-blocker intolerance

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G. SGLT-2 Inhibition

• DAPA-HF: 4,744 HFrEF on GDMT → Dapagliflozin 10 mg/day → 26% ↓ in worsening HF or CV death (consistent with and without DM)
• EMPEROR-Reduced: 3,730 HFrEF → Empagliflozin 10 mg/day → 25% ↓ in CV death or HF hospitalization
• Now considered foundational therapy for HF alongside ARNI, beta-blockers, and MRAs
• Benefits are independent of glucose-lowering effect

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H. Soluble Guanylyl Cyclase (sGC) Stimulation

• Vericiguat: Oral sGC stimulator → directly stimulates sGC AND sensitizes it to endogenous NO → enhances cGMP signaling
• VICTORIA trial: 5,050 HFrEF (NYHA II-IV, LVEF <45%, elevated NPs, worsening HF):
  • 10% relative risk reduction in CV death or HF hospitalization
  • Effect driven primarily by ↓ HF hospitalization
• Role as adjunct in high-risk HFrEF with recent congestive exacerbations

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I. Myosin Activation

• Omecamtiv mecarbil: Selective myosin activator
  • Prolongs ventricular systole + ↑ fractional shortening without altering force of contraction or ↑ myocardial O₂ demand
  • NOT a traditional inotrope → can be used chronically orally
• GALACTIC-HF trial: 8,256 symptomatic HFrEF (EF ≤35%):
  • 14% ↓ in CV death or first HF event
  • Greater benefit in more advanced HF (lower EF, higher NPs, worse symptoms)
  • No effect on CV death alone; additional study required before routine adoption

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J. Digoxin

• Mild inotrope; ↓ neurohormonal activation
• DIG trial: ↓ HF hospitalizations; NO reduction in mortality; higher mortality/hospitalizations in women
• Current role: Late-line therapy for profoundly symptomatic patients despite optimal GDMT + volume control
• Monitor drug levels; low doses sufficient; do NOT adjust for low levels

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K. Oral Diuretics

• Loop diuretics (furosemide, torsemide, bumetanide) for congestive symptoms
• Frequent dose adjustments needed (variable oral absorption, fluctuating renal function)
• Minimize doses as much as possible — loop diuretics enhance neurohormonal activation
• No trial data confirming survival benefit

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L. Calcium Channel Antagonists

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M-T. Additional Therapies Summary

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4. MANAGEMENT OF SELECTED COMORBIDITIES

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5. DEVICE THERAPY

A. Neuromodulation

B. Cardiac Contractility Modulation (CCM)

• Nonexcitatory electrical stimulation during absolute refractory period → augments myocardial contractile strength
• Best for: Symptomatic HFrEF, EF 25-45%, narrow QRS (not candidate for CRT)
• ↑ symptoms + QOL; NO confirmed effect on HF hospitalization or mortality
• NOT endorsed for routine use by U.S./European guidelines

C. Cardiac Resynchronization Therapy (CRT)

• Wide QRS → ↓ systolic function, ↓ mechanical efficiency, ↑ wall stress, ↑ functional MR

• Coronary sinus lead → lateral wall pacing → more synchronous ventricular contraction → reverse remodeling

• QRS >149 ms + LBBB pattern on ECG

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TABLE 265-3: ICD Implantation Principles for Primary SCD Prevention

• NYHA class II-III + LVEF <35% on optimal GDMT (irrespective of etiology)
• Post-MI + optimal therapy + LVEF ≤30% (even asymptomatic)
• Survivors of SCD (secondary prevention)
• Meets QRS criteria for CRT → combined CRT-D often employed

• Terminal illness (<6 months predicted survival)
• NYHA class IV refractory to medications + not transplant candidate → risk of multiple shocks

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6. SURGICAL THERAPY IN HF

A. Coronary Artery Bypass Grafting (CABG)

• Indicated for ischemic CM + multivessel CAD + ongoing angina + LV failure
• STICH trial (LVEF ≤35%):
  • Initial: No significant benefit vs medical therapy
  • 10-year follow-up: CABG → ↓ CV deaths + ↓ death/CV hospitalization
  • Viability testing did NOT predict which patients would benefit from revascularization
• REVIVED-BCIS2: PCI in ischemic LV dysfunction → No clinical benefit

B. Surgical Ventricular Restoration (SVR)

• 1,000-patient trial (CABG alone vs CABG + SVR) → No added disease-modifying effect of SVR
• LV aneurysm surgery: Still advocated for refractory HF, ventricular arrhythmias, or thromboembolic risk from akinetic segment

C. Mitral Valve Repair for Functional MR

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7. CELLULAR AND GENE-BASED THERAPY

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8. DISEASE MANAGEMENT AND SUPPORTIVE CARE

Discharge Planning

• ~50% of all patients readmitted within 6 months; only half readmissions for recurrent HF/CV conditions
• Begins at index hospitalization:
  • Comprehensive discharge planning
  • Patient + caregiver HF education (diet, fluid restrictions, daily weights, symptom recognition)
  • Visiting nurses; planned follow-up
• Early postdischarge follow-up within first 2 weeks → critical; most readmissions occur in this window

Telemonitoring

Advanced HF and End-of-Life Care

• Regular review of disease course and end-of-life preferences
• Integrate social work, pharmacists, community-based nursing
• Seasonal influenza + periodic pneumococcal vaccines
• Shift to outpatient/hospice palliation as appropriate
• Discuss continued ICD prophylaxis near end of life (may worsen QOL and prolong dying)
• Palliative care integration → ↑ QOL, ↓ anxiety/depression, goal-concordant care

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MASTER FLOWCHART: HF MANAGEMENT ALGORITHM

NEW PATIENT WITH HF SYMPTOMS
              ↓
CONFIRM DIAGNOSIS: Echo + BNP/NT-proBNP + CXR + ECG
              ↓
     DETERMINE PHENOTYPE
     ┌────────┬────────┐
     ↓        ↓        ↓
  HFrEF    HFmrEF   HFpEF
 (≤40%)   (41-49%) (≥50%)
              ↓
     ASSESS VOLUME STATUS
     ┌────────────────────────┐
     ↓                        ↓
VOLUME OVERLOADED (ADHF)   STABLE/EUVOLEMIC (CHRONIC HF)
     ↓                        ↓
ADMIT → IV DIURETICS       OUTPATIENT GDMT
Identify + treat triggers  Titrate every 2 weeks
Goal: decongestion         (target doses)
Early GDMT initiation

═══════════════════════════════════════════════════════
HFrEF PHARMACOTHERAPY ("FANTASTIC FOUR"):
═══════════════════════════════════════════════════════
STEP 1: Start ARNI (sacubitril-valsartan) OR ACEi/ARB
STEP 2: Add Beta-blocker (carvedilol / bisoprolol / metoprolol succinate)
STEP 3: Add MRA (spironolactone / eplerenone)
STEP 4: Add SGLT-2 inhibitor (dapagliflozin / empagliflozin)
              ↓
If LVEF <35% on optimal GDMT:
  → ICD (NYHA II-III)
  → CRT-D if QRS >149 ms + LBBB
              ↓
If sinus rhythm + HR >70 bpm despite GDMT:
  → Add Ivabradine
              ↓
If NYHA II-IV + recent worsening HF + elevated NPs:
  → Consider Vericiguat
              ↓
If LVEF ≤35% + advanced HF + poor functional capacity:
  → Consider Omecamtiv mecarbil (investigational)
              ↓
REFRACTORY HF (STAGE D):
  → Refer for heart transplant evaluation
  → Consider LVAD / MCS
  → Palliative care integration

═══════════════════════════════════════════════════════
HFpEF MANAGEMENT:
═══════════════════════════════════════════════════════
STEP 1: SGLT-2 inhibitor (foundational)
STEP 2: Diuretics for congestion (cautiously)
STEP 3: Aggressive BP control
STEP 4: AF → rhythm control (ablation preferred)
STEP 5: Treat comorbidities (obesity, DM, OSA, CKD)
STEP 6: Consider ARNI (if EF <60% / HFmrEF)
STEP 7: Exercise training / cardiac rehab

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QUICK REFERENCE: DRUG EFFICACY AT A GLANCE

HFrEF — PROVEN MORTALITY BENEFIT ✅:
  ✅ ACEi (lisinopril, enalapril, captopril, trandolapril)
  ✅ ARBs (as ACEi alternative — valsartan, candesartan, losartan)
  ✅ Beta-blockers (carvedilol, bisoprolol, metoprolol succinate ONLY)
  ✅ MRAs (spironolactone, eplerenone)
  ✅ ARNI (sacubitril-valsartan — PARADIGM-HF)
  ✅ SGLT-2 inhibitors (dapagliflozin, empagliflozin)
  ✅ H-ISDN (if RAAS intolerant — especially Black patients)
  ✅ ICD (LVEF <35%, NYHA II-III)
  ✅ CRT (LBBB + QRS >149 ms + symptomatic HFrEF)
  ✅ Catheter ablation for AF in HFrEF (CASTLE-AF)

HFrEF — SYMPTOM/HOSPITALIZATION BENEFIT ONLY ⚡:
  ⚡ Digoxin (DIG trial — ↓ HF hospitalizations, no mortality benefit)
  ⚡ Loop diuretics (symptom relief — no mortality data)
  ⚡ Ivabradine (HR reduction — SHIFT trial)
  ⚡ Vericiguat (↓ HF hospitalization — VICTORIA)
  ⚡ IV iron (↑ functional capacity — FAIR-HF, CONFIRM-HF)
  ⚡ Fish oil (modest benefit — GISSI-HF)

HARMFUL / AVOID IN HFrEF ❌:
  ❌ First-generation CCBs (verapamil, diltiazem) — negative inotropy
  ❌ NSAIDs — sodium retention
  ❌ Thiazolidinediones — worsen HF
  ❌ Dronedarone (ANDROMEDA — ↑ mortality)
  ❌ Oral inotropes (vesnarinone, flosequinan — ↑ mortality)
  ❌ Moxonidine — ↑ mortality
  ❌ TNF-α blockers (infliximab, etanercept) — worsen HF
  ❌ Adaptive servo-ventilation (SERVE-HF — ↑ CV mortality)
  ❌ Triple RAAS blockade (ACEi + ARB + MRA) — hyperkalemia/renal failure

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