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HEART FAILURE: Pathophysiology, Diagnosis & Management

Harrison's Principles of Internal Medicine, 22E - Chapters 264 & 265

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CHAPTER 264: HEART FAILURE - PATHOPHYSIOLOGY AND DIAGNOSIS

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I. CLINICAL DEFINITIONS, EPIDEMIOLOGY, AND PHENOTYPES

DEFINITIONS

• Elevated natriuretic peptide levels
• Objective evidence of cardiogenic pulmonary or systemic congestion

• Chronic HF = Longstanding (months-years) symptoms, on medical/device therapy; episodes of worsening = "decompensation"; resolution = "remission" (NOT stable, as risk persists)
• Acute HF (previously ADHF) = Rapid onset or worsening of symptoms; 80% = worsening chronic HF, ~20% = new-onset (ACS, acute valvular dysfunction, hypertensive urgency, postcardiotomy)
• Acute pulmonary edema = Rapidly worsening signs/symptoms of pulmonary congestion due to severe elevation of left heart filling pressures
• Prefer "heart failure" over "congestive heart failure"; "cardiomyopathy/LV dysfunction" are broader terms

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EPIDEMIOLOGY

• US: ~6.7 million adults treated for HF; >600,000 new cases/year
• Global: ~56.2 million people affected worldwide
• Lifetime risk: ~20% for adults >45 years
• Prognosis: ~50% 5-year mortality despite advances; significant morbidity and healthcare costs
• HF is the leading cause of hospitalization in adults >65 years in the US
• PAR by race/ethnicity (HFpEF): Hypertension predominates in all groups; obesity and diabetes are increasing contributors especially in Hispanic/African American populations

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TABLE 264-1: INDEPENDENT PREDICTORS OF ADVERSE OUTCOMES IN HEART FAILURE

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PHENOTYPES: HFrEF vs. HFpEF vs. HFmrEF vs. HFrecEF

• LVEF ≤40%
• Systolic dysfunction is predominant
• Evidence-based therapy most established
• Causes: ischemic (most common), dilated, myocarditis, toxic

• LVEF ≥50%
• Normal or near-normal systolic function; diastolic dysfunction predominant
• Multiple pathophysiologic mechanisms: vascular stiffness, renal dysfunction, inflammation, oxidative stress, insulin resistance
• Comorbidities (HTN, obesity, DM, CKD, AF, sleep apnea) play major role
• ~50% of all HF; prognosis comparable to HFrEF
• Limited evidence-based therapy (SGLT-2i now proven beneficial)

• LVEF 41-49%
• Intermediate zone; heterogeneous population
• Some may recover EF (overlap with HFrecEF)
• SGLT-2i, ARNi show benefit in clinical trials

• Previously HFrEF, now LVEF >40% (often ≥50%)
• Following treatment (e.g., tachycardiomyopathy, peripartum CMP, toxic CMP)
• Despite recovery, continued GDMT is recommended - discontinuation risks relapse
• Better prognosis but NOT benign; residual risk persists

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TABLE 264-2: SELECTED CAUSES OF HEART FAILURE

ACQUIRED CAUSES

FAMILIAL/GENETIC CAUSES

CONGENITAL AND OTHER DISORDERS

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II. PATHOPHYSIOLOGY

PROGRESSIVE DISEASE

• Sudden (acute MI)
• Gradual (chronic pressure/volume overload)
• Inherited (genetic CMP)
• Congenital

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VENTRICULAR REMODELING

• Myocyte hypertrophy and interstitial fibrosis
• Alterations in calcium-handling proteins and cytoskeletal proteins
• Molecular: re-expression of fetal genes
• Cell loss: necrosis, apoptosis (programmed cell death)
• Afterload mismatch from systemic vasoconstriction + loss of neurohormonal adaptation
• Feeds back on remodeling stimuli - vicious cycle

• Vascular stiffness, renal dysfunction, sodium avidity
• Inflammation related to regional adiposity
• Oxidative stress, impaired nitric oxide signaling (nitrosative stress)
• Insulin resistance
• Autophagy dysfunction (autophagosomes - normally cytoprotective but unchecked = maladaptive)

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FIGURE 264-6: REMODELING STIMULI IN HEART FAILURE

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MECHANISMS OF DISEASE PROGRESSION

Neurohormonal Activation

• Increased HR, BP, contractility
• Sodium/water retention to augment preload
• Maintains CO at rest and during exercise

• Excessive vasoconstriction and volume retention
• Electrolyte/renal abnormalities
• Baroreceptor dysfunction
• Direct myocardial toxicity (norepinephrine, angiotensin II)
• Cardiac arrhythmias
• Ventricular remodeling (heart + blood vessels)

Vasodilatory/Counter-Regulatory Hormones

• Natriuretic peptides (ANP, BNP): Vasodilation, natriuresis, anti-fibrotic, anti-hypertrophic; levels rise with wall stress - used as biomarkers
• Nitric oxide (NO): Vasodilation, anti-remodeling; impaired in HF (reduced NOS activity, increased ROS consumption)
• Prostaglandins: Vasodilatory, renoprotective

Endothelin

• ET-1 is a potent vasoconstrictor (>10x more potent than NE)
• Stimulates myocyte hypertrophy, fibrosis, and pulmonary vasoconstriction
• Elevated in proportion to HF severity
• Endothelin antagonists tested but NOT effective in HF (actually worsened outcomes in some trials)

Inflammatory Cytokines and Oxidative Stress

• TNF-α, IL-1β, IL-6: Directly depress myocardial function; induce myocyte apoptosis; contribute to cardiac cachexia
• Reactive oxygen species (ROS): Generated by xanthine oxidase, mitochondria, NADPH oxidase; cause protein oxidation, lipid peroxidation, DNA damage; impair myocyte function
• MMP (matrix metalloproteinases): Degrade ECM; contribute to LV dilatation
• Anti-cytokine therapy (e.g., etanercept, infliximab): NOT effective in HF trials

Novel Biological Targets

• ST2 (IL-1 receptor family): Decoy receptor for IL-33; elevated ST2 predicts adverse outcomes
• Galectin-3: Macrophage-derived; promotes fibrosis; elevated = poor prognosis
• GDF-15: Stress-responsive cytokine; marker of metabolic stress
• MicroRNAs: Gene regulatory molecules; potential therapeutic targets
• SGLT-2 pathway: Beyond glycemic control - reduces preload/afterload, improves cardiac metabolism, reduces oxidative stress, has direct cardiac effects

Dyssynchrony and Electrical Instability

• Dyssynchrony: Abnormal activation sequence (esp. with LBBB, QRS >150ms) leads to:
  • Paradoxical septal motion
  • Reduced mechanical efficiency
  • Secondary MR worsening
  • Further adverse remodeling
  • CRT reverses dyssynchrony and improves outcomes
• Electrical Instability:
  • Remodeled heart has heterogeneous refractoriness → substrate for re-entry
  • HFrEF: 40-50% of deaths are sudden (VF/VT); risk highest in early disease
  • ICD therapy reduces SCD

Secondary Mitral Regurgitation

• In dilated CMP: LV dilatation displaces papillary muscles laterally + tethers leaflets → incomplete coaptation
• Annular dilatation from LV dilatation further worsens MR
• Creates a vicious cycle: MR → more volume overload → more dilatation → worse MR
• Functional/secondary MR carries poor prognosis
• Guideline-directed therapy (GDMT) can reduce secondary MR; surgical repair in selected cases (MITRA-FR vs. COAPT trial controversy)

Cardiorenal and Abdominal Interactions

• Cardiorenal syndrome (CRS):
  • Low forward CO → reduced renal perfusion → prerenal azotemia
  • High venous pressure → elevated renal venous pressure → reduced filtration gradient → worsening renal function
  • Neurohormonal activation (RAAS, SNS) → renal vasoconstriction
  • Type 1 CRS: Acute worsening of HF causes acute kidney injury
  • Type 2 CRS: Chronic HF causes progressive CKD
• Abdominal congestion: Elevated venous pressure → gut wall edema → impaired absorption → malnutrition

Gut Congestion, Microbiome, and Inflammation

• Gut congestion → increased intestinal permeability → translocation of bacterial products (lipopolysaccharide = LPS/endotoxin)
• Endotoxemia → systemic inflammation → worsening HF (cytokine storm)
• Gut microbiome alterations in HF:
  • Reduced microbial diversity
  • Overgrowth of pathogenic species
  • Altered bile acid metabolism
  • Trimethylamine N-oxide (TMAO): gut microbiome-derived metabolite; elevated in HF → platelet aggregation, atherosclerosis, worsening cardiorenal function
• Active area of investigation for microbiome-targeted therapies

High-Output States

• Characterized by elevated CO (>8 L/min) with reduced SVR despite normal or increased contractility
• The heart fails to keep up with elevated metabolic demand
• Causes:
  • Severe anemia (Hgb <5 g/dL)
  • AV fistulae (acquired or dialysis access)
  • Thyrotoxicosis
  • Paget's disease of bone (extensive)
  • Wet beriberi (thiamine deficiency)
  • Pregnancy/cirrhosis/obesity
• Characteristics: Wide pulse pressure, bounding pulses, warm extremities, normal or elevated EF
• Treatment: directed at underlying cause

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III. EVALUATION

HISTORY

Symptoms of Congestion: Pulmonary vs. Systemic

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TABLE 264-4: NYHA FUNCTIONAL CLASSIFICATION (NYHAFC)

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Symptoms of Reduced Perfusion (Low Output)

• Fatigue and exercise intolerance (most common)
• Mental confusion, difficulty concentrating
• Cold, clammy extremities
• Oliguria or nocturia (as renal perfusion shifts nocturnally when supine)
• Anorexia and early satiety
• Pre-syncope or syncope (advanced HF)
• Hemodynamic profile: "Cold and wet" (elevated filling pressures + low output) = worst prognosis

Other Symptoms

• Palpitations (arrhythmias: AF, PVCs, VT)
• Chest pain (may represent underlying CAD, or from RV stretch in acute decompensation)
• Depression and anxiety (common, underdiagnosed)
• Sleep disturbances: Cheyne-Stokes breathing, central sleep apnea, OSA
• Weight loss/cardiac cachexia (advanced HF - TNF-α-mediated)

Precipitating Factors

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TABLE 264-5: PRECIPITATING FACTORS IN HEART FAILURE

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PHYSICAL EXAMINATION

General Appearance

• May appear comfortable at rest (compensated HF) or in obvious respiratory distress
• Cardiac cachexia: temporal wasting, temporal muscle loss (advanced HF, poor prognosis)
• Pallor, jaundice (hepatic congestion)
• Cyanosis: peripheral (reduced perfusion) or central (intracardiac shunt, severe pulmonary disease)

Vital Signs

• Heart Rate: On GDMT, resting HR ideally <70-75 bpm; tachycardia (>90 bpm) = poor prognosis
• Blood Pressure: May have hypotension with narrow pulse pressure in severe HF; hypertension suggests HFpEF or acute HF trigger
• Pulsus alternans: Alternating strong-weak pulse; incomplete LV recovery every alternate beat; indicates severe LV dysfunction
• Respiratory Rate: May increase with exertion or lying down; Cheyne-Stokes breathing in advanced HF
• O₂ saturation: Usually normal at rest; reduced with acute pulmonary edema, intracardiac shunting, pulmonary HTN, or concomitant lung disease
• Low-grade fever: May occur with severe HF (cytokine activation)

Jugular Venous Pulse (JVP)

• Method: 45° angle; JVP = height above sternal angle in cm + 5 cm H₂O
• Normal: ≤8 cm H₂O
• Hepatojugular reflux (HJR): Firm pressure over liver 15-30s + normal breathing → sustained JVP rise = elevated right-sided pressures
• Abdominojugular test: Rise in RA pressure during mid-abdominal compression + abrupt drop on release → elevated left-sided filling pressure
• Prominent V waves + Y descents = significant tricuspid regurgitation
• Kussmaul's sign: JVP rises with inspiration (instead of falling) - seen in severe biventricular HF, constrictive pericarditis, restrictive CMP; marker of poor outcome

Lung Examination

• Rales (crackles): Transudation into alveoli; bilateral basal; diffuse in severe HF/acute pulmonary edema
• Wheeze/Rhonchi: Bronchial mucosal congestion ("cardiac asthma") - may mimic COPD/asthma
• Absent rales: Despite elevated PCWP in chronic HF due to increased lymphatic drainage
• Pleural effusions: Dullness to percussion + decreased breath sounds at bases; usually bilateral (right > left when unilateral)

Cardiac Examination

• Apical impulse: Displaced laterally and inferiorly (dilated CMP); sustained/heaving (pressure overload)
• RV heave/parasternal lift: Biventricular or right HF
• S3 gallop: Volume overload + tachycardia; most commonly in HFrEF; hemodynamic compromise; negative prognostic significance
• S4 gallop: Reduced LV compliance (HFpEF, HTN); not specific to HF
• Murmurs: Holosystolic murmur of MR or TR (secondary to annular dilatation in HF); soft murmurs may indicate low-output state
• P2 loud: Pulmonary hypertension

Abdomen and Extremities

• Hepatomegaly: Tender, pulsatile (TR); painful with acute congestion
• Ascites: Advanced right/biventricular HF
• Splenomegaly: Chronic passive congestion
• Peripheral edema: Bilateral pitting; distribution follows gravity (ankles in ambulatory, sacrum in bedridden)
• Jaundice: Chronic hepatic congestion → cardiac cirrhosis (late)

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IV. DIAGNOSIS

Routine Laboratories

• CBC: Anemia (high-output HF trigger; predicts poor prognosis); leukocytosis (infection trigger)
• Metabolic panel: Hyponatremia (poor prognosis - dilutional; RAAS/vasopressin activation); hyperkalemia or hypokalemia (RAAS therapy effects); BUN/creatinine (cardiorenal syndrome)
• LFTs: Transaminase/bilirubin elevation (passive hepatic congestion)
• TSH: Thyroid disease as cause or comorbidity
• Iron studies (Fe, TIBC, ferritin): Iron deficiency = major contributor to exercise intolerance; treatable comorbidity
• Uric acid: Elevated in HF; marker of poor prognosis
• Lipid panel: CAD evaluation

Chest X-Ray (CXR)

• Cardiomegaly: Cardiothoracic ratio >50% on PA film (not reliable in portable AP)
• Pulmonary venous hypertension: Upper zone vascular redistribution ("cephalization")
• Interstitial edema: Kerley B lines (horizontal lines in costophrenic angles = engorged lymphatics); peribronchial cuffing
• Alveolar edema: "Bat-wing" or "butterfly" pattern; perihilar haziness
• Pleural effusions: Blunting of costophrenic angles (right > left)
• Normal CXR does NOT exclude HF (especially HFpEF or early HF)

ECG

• LVH (pressure overload HTN/AS)
• LBBB (dyssynchrony, suggests dilated CMP, guides CRT)
• Q waves (ischemic CMP)
• AF/atrial arrhythmias
• Low voltage (amyloid, pericardial effusion)
• Prolonged QRS (CRT candidate)
• Low voltage with pseudoinfarct pattern = amyloidosis

Noninvasive Imaging

• Measures LVEF (classifies HFrEF/HFmrEF/HFpEF)
• LV dimensions, volumes, wall thickness, wall motion
• Diastolic function (tissue Doppler E/e' ratio, E/A, deceleration time)
• Valvular disease, pericardial effusion
• Estimated RVSP (pulmonary HTN)
• Strain imaging (GLS - global longitudinal strain) - detects subclinical dysfunction

• Gold standard for volumes/EF when echo is inadequate
• Tissue characterization: LGE identifies fibrosis/scar (ischemic vs. non-ischemic pattern)
• Edema detection (myocarditis)
• Amyloid, sarcoidosis, ARVC diagnosis

• Radionuclide ventriculography (MUGA): accurate EF measurement
• Myocardial perfusion imaging (MPI): ischemia/viability assessment

• Rule out CAD as etiology (when echo/clinical data inconclusive)

Cardiopulmonary Exercise Testing (CPET)

• Peak VO₂ (<14 mL/kg/min = poor prognosis; threshold for transplant listing)
• VE/VCO₂ slope (>35 = poor prognosis)
• Used for transplant/LVAD evaluation
• Distinguishes cardiac from pulmonary etiology of dyspnea

Biomarkers

• BNP/NTproBNP: Released with wall stress; elevated in HF; useful for diagnosis, monitoring, prognosis
  • BNP >100 pg/mL or NTproBNP >300 pg/mL supports HF diagnosis in dyspneic patients
  • Used to guide decongestion therapy
  • "BNP-guided therapy" trials (SIGNAL-HF, PRIMA, GUIDE-IT): inconclusive benefits in outpatient setting
• Troponin (cTnI/cTnT): Chronic low-level elevation in HF = ongoing myocyte injury; predicts poor prognosis
• ST2 (sST2): Elevated = cardiac fibrosis and remodeling; additive to BNP for risk stratification
• Galectin-3: Fibrosis marker; predicts adverse events

Invasive Studies

• Right heart catheterization (RHC):
  • Measures RA, RV, PA pressures; PCWP (estimates LVEDP); CO by thermodilution/Fick
  • Indicated when: diagnosis uncertain, pre-transplant/LVAD evaluation, pulmonary HTN workup, hemodynamic-guided management of refractory HF
  • Hemodynamic profiles:
    • "Warm and wet" (high PCWP, normal CO) = most common; diuresis
    • "Cold and wet" (high PCWP, low CO) = advanced HF; inotropes + diuresis
    • "Cold and dry" (normal PCWP, low CO) = volume depletion or advanced HF
• Left heart catheterization: Coronary angiography for ischemic workup; LV end-diastolic pressure
• Endomyocardial biopsy: Giant cell myocarditis, cardiac amyloidosis, drug toxicity - when specific diagnosis impacts management

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V. COMORBIDITIES

Diabetes Mellitus

• Present in ~40% of HF patients
• Both HFrEF and HFpEF are more common in diabetics
• SGLT-2 inhibitors: cornerstone of both DM management and HF management (proven benefit in HFrEF and HFpEF regardless of DM status)
• GLP-1 agonists: reduce obesity, improve QOL; semaglutide shown to improve symptoms in HFpEF-obesity
• Avoid TZDs (pioglitazone) - cause fluid retention and worsen HF

Sleep Apnea

• Obstructive sleep apnea (OSA): ~40% of HF; contributes to HTN, pulmonary HTN, right heart dysfunction; CPAP effective
• Central sleep apnea/Cheyne-Stokes respiration: Driven by high loop gain and chronic hyperventilation; present in ~40% of advanced HFrEF
• Adaptive servo-ventilation (ASV) - CONTRAINDICATED in HFrEF with EF ≤45% and central sleep apnea - increased mortality (SERVE-HF trial)

Obesity

• Major risk factor for HFpEF; "obese HFpEF" is a distinct phenotype
• Pericardial constraint, increased ventricular interaction, elevated filling pressures
• GLP-1 agonists (semaglutide): reduced symptoms and improved QOL in STEP-HFpEF trial
• Paradox of obesity in HFrEF: higher BMI associated with better short-term outcomes ("obesity paradox") - may reflect cardiac reserve

Depression

• Prevalence ~30-40% in HF; independently predicts worse outcomes
• SSRIs: Do NOT improve survival (SADHART-CHF); neutral on mortality but may improve QOL
• Escitalopram shown to be neutral to negative in one trial
• Psychosocial support and collaborative care important

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TABLE 264-8: DIFFERENTIAL DIAGNOSIS OF HEART FAILURE

Differential Diagnosis - Clinical Approach

1. Elevated BNP/NTproBNP + structural cardiac abnormality on echo
2. Elevated JVP + pulmonary rales + S3 gallop
3. Response to diuresis
4. Symptoms in concordance with echocardiographic findings

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CHAPTER 265: HEART FAILURE MANAGEMENT

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I. HFpEF AND HFmrEF MANAGEMENT

General Principles

• Treat underlying causes and precipitants
• Aggressive control of comorbidities (HTN, AF, DM, obesity, sleep apnea, ischemia)
• Decongestion with diuretics (symptom relief)
• Avoid excessive preload reduction (risk of underfilling → azotemia, hypotension, syncope)

Clinical Trials in HFpEF

Other Therapeutic Agents in HFpEF

• Diuretics: Symptom relief; no mortality benefit demonstrated
• ACEIs/ARBs: Not proven effective (except prevention); guideline-directed for HTN management
• Spironolactone/MRA: May be beneficial; used especially when EF 45-55%
• Sacubitril-valsartan: Approved across full EF spectrum; greatest benefit EF below normal
• Beta-blockers: Useful for rate control in AF; not proven beneficial in pure HFpEF sinus rhythm
• GLP-1 agonists (semaglutide): Improve QOL irrespective of DM status in obese HFpEF
• Avoid: ASV (increased mortality), TZDs (fluid retention), calcium channel blockers (limited role)

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FIGURE 265-1: HFpEF - Pathophysiology, Therapeutic Principles and Directed Therapy

1. Reduce the congestive state - Caution: don't reduce preload excessively; implantable hemodynamic monitors useful
2. Control blood pressure - Central aortic BP control may be more relevant
3. Maintain atrial contraction and prevent tachycardia - AF ablation may reduce morbidity/mortality
4. Treat and prevent myocardial ischemia - May mimic HF as angina equivalent
5. Detect and treat sleep apnea - Common comorbidity; ASV INEFFECTIVE/harmful
6. Lifestyle modification - Diet + exercise for weight reduction and functional capacity

• RAAS: ACEIs/ARBs ineffective (except prevention); aldosterone antagonists may be beneficial
• Digoxin: Ineffective (may reduce hospitalizations)
• Beta blockers/CCBs: Ineffective (useful for tachycardia prevention in AF)
• PDE-5 inhibitors: Sildenafil ineffective
• Novel: ARNi (may be effective); SGLT-2i (reduce HF hospitalization) - PROVEN
• Chronotropic insufficiency: Targeted pacing - likely ineffective
• Obesity: GLP-1 agonists (improve QOL irrespective of DM)

Clinical Guiding Principles (HFpEF)

• Precise diagnosis essential - HFpEF is a heterogeneous group; infiltrative, storage, pericardial, valvular disease may require entirely different management
• Aggressive BP control to guideline targets
• Diuretics for volume overload
• Evaluate for ischemia if coronary risk present
• AF: aggressive rate control, anticoagulation, early rhythm restoration
• Comorbidities (obesity, OSA, CKD, anemia/iron deficiency) = important treatment targets
• Avoid excessive preload reduction

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II. ACUTE DECOMPENSATED HEART FAILURE (ADHF)

General Principles

• ADHF is a heterogeneous clinical syndrome resulting from decreased cardiac performance + renal dysfunction + vascular compliance alterations
• Admission with ADHF = excessive morbidity/mortality; ~50% readmission within 6 months
• Primary goal: Rapid decongestion while maintaining organ perfusion
• Hemodynamic profiling essential:
  • "Warm and wet" = most common; diuresis
  • "Cold and wet" = inotropes + diuresis
  • "Cold and dry" = volume challenge or advanced HF/cardiogenic shock

Volume Management - IV Diuretics

• Mechanisms: Poor gut absorption (IV route needed), aldosterone breakthrough, neurohormonal activation, renal hypoperfusion
• Management: IV loop diuretics + metolazone (thiazide) combination (synergistic); ultrafiltration

Cardiorenal Syndrome in ADHF

• Worsening renal function (WRF) during ADHF hospitalization = common and complex
• May NOT worsen outcomes if decongestion is achieved (CARRESS-HF data)
• Permissive approach to creatinine rise (if decongestion is ongoing) is often appropriate
• Persistent WRF with inadequate decongestion = poor prognosis

Ultrafiltration

• Mechanical removal of isotonic plasma water using semipermeable membrane
• CARRESS-HF trial: Ultrafiltration was NOT superior to pharmacologic diuresis; associated with more adverse events including worsening renal function
• Reserved for: true diuretic resistance, intractable volume overload, hypervolemic hyponatremia

Vasoactive Therapy

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TABLE 265-1: VASOACTIVE THERAPY IN ADHF

• Oxygen: Maintain SpO₂ >94%; high-flow nasal cannula for moderate hypoxia
• Non-invasive ventilation (NIV) - CPAP/BiPAP: Beneficial for cardiogenic pulmonary edema (reduces intubation rate, improves dyspnea)
• Mechanical ventilation: For refractory respiratory failure
• Morphine: Historical use; recent ADHF data (OPIATES trial) showed increased ICU transfer, mechanical ventilation, mortality - CAUTION/avoid
• Mechanical circulatory support (IABP, Impella, ECMO): For cardiogenic shock

1. Rapidly identify and treat precipitating cause
2. Hemodynamic profiling to guide therapy
3. Decongestion is the primary goal
4. Transition to oral GDMT before discharge
5. Intensive early postdischarge follow-up (STRONG-HF: 2-week intensive titration → reduced 180-day readmissions)
6. Avoid morphine
7. Correct electrolyte abnormalities

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III. HFrEF MANAGEMENT

TABLE 265-2: GUIDELINE-DIRECTED PHARMACOLOGIC THERAPY (GDMT) AND TARGET DOSES IN HFrEF

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NEUROHORMONAL ANTAGONISM (HFrEF)

• ACEIs/ARBs: Class effect; any can be used; titrate to evidence-based doses
• Beta-blockers: NOT a class effect - only carvedilol, bisoprolol, and metoprolol succinate proven to improve survival; agents with ISA (xamoterol, bucindolol) ineffective or harmful
• CIBIS III trial: Order of initiation (ACEI vs. BB first) does not affect outcome; what matters is achieving optimal doses of both
• Dose and outcome are correlated: Aggressive titration to target doses improves outcomes

• Aldosterone levels may "escape" ACE inhibitor therapy over time (via non-ACE pathways: chymase, kallikrein)
• Rationale for adding MRA (spironolactone/eplerenone) on top of ACEI/ARB
• RAAS triple therapy (ACEI + ARB + MRA): AVOID - increased adverse events (hyperkalemia, renal impairment) without additional benefit (ONTARGET)
• ARNi (Sacubitril-Valsartan) has REPLACED ACEI/ARB as preferred neurohormonal agent:
  • PARADIGM-HF: Sacubitril-valsartan reduced CV death/HF hospitalization by 20% vs. enalapril
  • Requires wash-out period of 36 hours when switching from ACEI (angioedema risk)
  • Neprilysin inhibition → ↑ BNP (can no longer use BNP for monitoring; use NTproBNP instead)

Mineralocorticoid Receptor Antagonists (MRA)

• Spironolactone (RALES trial): NYHA III-IV on ACEI + furosemide; 30% reduction in mortality
• Eplerenone (EMPHASIS-HF): NYHA II, EF ≤35%; significant mortality reduction
• Key safety: Monitor K+ and renal function (risk of hyperkalemia); avoid if K+ >5.0 mEq/L or eGFR <30

Alternative Vasodilators

• Hydralazine + Isosorbide dinitrate (H-ISDN):
  • Alternative for patients who cannot tolerate ACEI/ARB (renal insufficiency, bilateral RAS, angioedema)
  • A-HeFT trial: Significant mortality benefit specifically in African Americans - BiDil (fixed-dose combination) approved for this indication
  • Mechanism: Hydralazine (arteriodilation) + ISDN (venodilation) + hydralazine antioxidant effect (prevents nitrate tolerance)

Novel Neurohormonal Antagonists

• Stimulates soluble guanylyl cyclase (sGC) → ↑ cGMP → vasodilation; independent of NO availability
• VICTORIA trial: Significant reduction in HF hospitalization and CV death in high-risk HFrEF (after worsening HF event); absolute benefit modest
• Dose: 2.5 mg → 10 mg once daily
• Added to GDMT for high-risk patients

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HEART RATE MODIFICATION

• Selective If channel blocker (funny current in SA node) → ↓ HR without negative inotropy
• SHIFT trial: EF ≤35%, sinus rhythm, HR ≥70 bpm, on maximally tolerated beta-blocker
• Significant reduction in HF hospitalization (not mortality)
• Indication: LVEF ≤35%, sinus rhythm, HR ≥70 bpm despite maximally tolerated beta-blocker

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SGLT-2 INHIBITION

• Originally developed for diabetes; demonstrated striking CV benefits independent of glycemic effects
• Mechanisms in HF:
  • Osmotic diuresis/natriuresis (reduce preload)
  • Reduced sympathetic tone
  • Improved cardiac metabolism (ketone utilization)
  • Reduced oxidative stress and inflammation
  • Direct cardiac effects (anti-hypertrophic, anti-fibrotic)
  • Erythropoietic effects (increase EPO)
• DAPA-HF (dapagliflozin): 26% reduction in CV death/worsening HF in HFrEF (with AND without DM)
• EMPEROR-Reduced (empagliflozin): 25% reduction in CV death/HF hospitalization in HFrEF
• EMPEROR-Preserved + DELIVER: Proven benefit in HFpEF/HFmrEF
• Dose: Fixed: Dapagliflozin 10 mg OD, Empagliflozin 10 mg OD

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SOLUBLE GUANYLYL CYCLASE (sGC) STIMULATION

• Mechanism: sGC stimulator → ↑ cGMP → vasodilation + cardiac effects
• Works independently of NO availability (advantage in HF where NO signaling is impaired)
• VICTORIA trial: modest but significant benefit in very high-risk HFrEF

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MYOSIN ACTIVATION (Novel Agent)

• Selective cardiac myosin activator → prolongs systolic ejection time → ↑ stroke volume without ↑ intracellular calcium
• GALACTIC-HF trial: Modest reduction in HF events (significant primary endpoint); no significant mortality reduction; largest benefit in those with lowest LVEF (≤28%)
• Not yet approved; represents a new class targeting contractile apparatus rather than neurohormonal system

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DIGOXIN

• Oldest cardiac drug; inhibits Na+/K+ ATPase → increases intracellular Ca → modest positive inotropy; also reduces sympathetic tone and slows AV conduction
• DIG trial: No mortality benefit; significant reduction in HF hospitalizations
• Current role:
  • Rate control in HFrEF + AF (adjunct to beta-blockers)
  • Selected symptomatic patients with HFrEF despite GDMT
  • NARROW THERAPEUTIC WINDOW: Target digoxin level 0.5-0.9 ng/mL (higher levels = increased mortality)
  • Caution: renal failure, hypokalemia, hypomagnesemia, drug interactions (amiodarone, clarithromycin, verapamil)
  • NOTE: Ineffective in HFpEF

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ORAL DIURETICS

• Furosemide: 20-160 mg OD-BID PO; variable bioavailability (10-100%); consider switching to torsemide
• Torsemide: Superior oral bioavailability; may reduce HF hospitalizations vs. furosemide (TRANSFORM-HF: similar overall, but torsemide better tolerated)
• Metolazone: Added for diuretic resistance; 2.5-5 mg before loop diuretic; monitor electrolytes carefully
• Spironolactone/Eplerenone: Dual function (MRA + diuretic); especially useful with electrolyte-sparing effect
• Goal: Euvolemia; daily weight monitoring; adjust dose based on renal function and electrolytes

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CALCIUM CHANNEL ANTAGONISTS

• Non-dihydropyridines (verapamil, diltiazem): CONTRAINDICATED in HFrEF - negative inotropy worsens outcomes
• Amlodipine/Felodipine: Safe in HFrEF; no mortality benefit but no harm (PRAISE-1/2); used for hypertension or angina in HFrEF
• In HFpEF: CCBs may be used for rate control in AF or HTN management

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ANTI-INFLAMMATORY THERAPY

• IL-1 blockade (Anakinra): Small RCTs show improvement in functional capacity and inflammatory markers; larger trials needed
• Colchicine: COPE trial (post-pericardiotomy); data in HF limited
• TNF-α antagonists: Infliximab, etanercept - TESTED AND FAILED in HF trials (ATTACH, RENEWAL); harm in higher doses - AVOID/CONTRAINDICATED in HFrEF
• Pentraxin: No proven benefit
• SGLT-2i indirectly anti-inflammatory: Partly explains benefits

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HMG-CoA REDUCTASE INHIBITORS (STATINS)

• Theoretically beneficial (anti-inflammatory, anti-fibrotic, pleiotropic effects)
• CORONA and GISSI-HF trials: Rosuvastatin vs. placebo in HFrEF → NO mortality benefit
• Current recommendation:
  • Initiate statins if underlying CAD or other CV indications (primary indication remains lipid lowering/cardiovascular event prevention)
  • Do NOT start statins solely for HF treatment
  • If already on statins, continue (do not discontinue)

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ANTICOAGULATION AND ANTIPLATELET THERAPY

• AF + HF: Oral anticoagulation (OAC) is indicated - NOACs preferred over warfarin (ARISTOTLE, ROCKET-AF data)
• HFrEF in sinus rhythm: NO routine anticoagulation; WARCEF trial: warfarin vs. aspirin - net effect neutral; ↑ bleeding, modest stroke reduction
• Low-dose rivaroxaban (COMMANDER-HF): No benefit in HFrEF sinus rhythm with CAD
• Aspirin: If concurrent CAD/prior MI; not routinely for HF alone
• Heparin (DVT prophylaxis): LMWH during hospitalization for immobile patients

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FISH OIL (N-3 PUFA)

• GISSI-HF trial: Omega-3 (1 g/day) in HFrEF → modest but significant reduction in mortality and HF hospitalizations (NNT ~56 over 4 years)
• Mechanism: Anti-arrhythmic, anti-inflammatory, membrane stabilizing
• Considered "potentially effective" (see Fig 265-3)
• Recommended: 1 g OD omega-3 PUFA in symptomatic HFrEF (Class IIb recommendation)

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MICRONUTRIENTS

• Iron deficiency (without anemia): Common in HF; impairs exercise tolerance and quality of life
  • IV iron (ferric carboxymaltose - AFFIRM-AHF, CONFIRM-HF): Reduces HF hospitalizations; improves symptoms and functional capacity; AFFIRM-AHF: IV FCM reduced HF hospitalization by 26% after ADHF
  • Oral iron: Poorly absorbed in HF; generally less effective
• Thiamine: Deficiency possible in elderly HF patients on furosemide; supplementation reasonable
• Magnesium: Deplete with diuresis; supplement to prevent arrhythmias
• Zinc: Deficiency in cardiac cachexia; supplementation not proven

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ENHANCED EXTERNAL COUNTERPULSATION (EECP)

• Pneumatic compression of lower limbs during diastole → augments diastolic pressure and coronary perfusion
• MUST study: limited benefit in HFrEF
• Current role: Adjunct for refractory angina in patients not candidates for revascularization; limited HF use

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EXERCISE

• HF-ACTION trial: Aerobic exercise training (supervised + home-based) → modest but significant improvement in all-cause mortality/hospitalization; improved QOL and functional capacity
• Recommendation: Moderate-intensity aerobic exercise (e.g., walking 30 min, 5 days/week) in stable HFrEF is safe and beneficial
• Cardiac rehabilitation programs recommended
• Resistance training: Safe in stable HFrEF; improves muscle strength and functional capacity

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MANAGEMENT OF SELECTED COMORBIDITIES

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IV. DEVICE THERAPY (NEUROMODULATION)

Cardiac Contractility Modulation (CCM)

• Delivers non-excitatory electrical signals during absolute refractory period → ↑ contractility without initiating AP
• FIX-HF-5 trial: Improved VO₂ and QOL in NYHA III, EF 25-45%, QRS <130 ms (i.e., NOT CRT candidate)
• Approved in US as adjunct to GDMT for HFrEF in non-CRT candidates

Cardiac Resynchronization Therapy (CRT)

• LVEF ≤35%
• LBBB with QRS ≥150 ms
• NYHA Class II-III-IV (ambulatory) on GDMT
• Sinus rhythm

• CRT-D preferred in most patients with reasonable survival expectancy and no significant comorbidities
• CRT-P in older patients, significant comorbidity, shorter expected benefit

Sudden Cardiac Death Prevention in HF

• LVEF ≤35% (strongest predictor)
• Prior VT/VF
• NYHA Class II-III (paradoxically higher risk than NYHA IV)
• NSVT on Holter

• Wait ≥3 months of GDMT before reassessing EF for ICD/CRT eligibility (EF may recover)
• Wait ≥40 days post-MI before ICD implant
• Wearable ICD (LifeVest): Bridge to ICD in newly diagnosed HFrEF awaiting GDMT response assessment

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V. SURGICAL THERAPY IN HF

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VI. CELLULAR AND GENE-BASED THERAPY

• Bone marrow/cardiac-derived stem cells: Multiple trials; inconsistent results; not currently clinically established
• c-kit+ cells: Small pilot trials showed LV function improvement; not confirmed in larger studies
• Mesenchymal stem cells (DREAM-HF): Randomized trial - NEGATIVE primary and secondary endpoints
• SERCA2a gene therapy (CUPID trial): Initially promising; confirmatory trial failed primary endpoint
• Current status: Investigational; no approved cellular or gene therapy for HF as of 2025
• LVAD recovery strategy: Efforts to use MSCs for weaning from LVAD have been disappointing

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VII. DISEASE MANAGEMENT AND SUPPORTIVE CARE

• Despite excellent pharmacotherapy, ~50% readmitted within 6 months of discharge
• Recurrent HF = only half of readmissions; non-cardiac comorbidities drive the rest
• STRONG-HF trial: Intensive titration of GDMT within 2 weeks + frequent ambulatory follow-up through 2 months → significant reduction in all-cause mortality and HF readmission at 180 days
• Telemonitoring of weight/vital signs: NOT shown to decrease hospitalizations in RCTs
• Intrathoracic impedance monitoring (OptiVol): Not proven; high false-positive rate → may paradoxically increase hospitalizations
• CardioMEMS (implantable PA pressure sensor - CHAMPION trial): PA pressure-guided management → significant reduction in HF hospitalization; approved in US for NYHA III HF with prior HF hospitalization

• Comprehensive discharge planning + patient/caregiver education
• Appropriate visiting nurse involvement
• Optimized oral GDMT before discharge
• Follow-up within 7-14 days of discharge (STRONG-HF protocol)
• Daily weight monitoring; action plan for weight gain >2 kg

• Advance directives and goals-of-care discussions in advanced HF
• Symptom management: opioids for dyspnea (low-dose), diuretics
• Multidisciplinary HF team (cardiologist, HF nurse, pharmacist, social work, palliative care)
• Hospice referral for NYHA IV refractory to all therapy

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QUICK-REFERENCE FLOWCHARTS

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FLOWCHART 1: HF DIAGNOSIS

Symptoms (dyspnea, edema, fatigue) + Signs (elevated JVP, rales, S3)
                           ↓
              Measure BNP/NTproBNP
         ┌────────────────────────────────────┐
    BNP <100 pg/mL                    BNP ≥100 pg/mL
    (HF unlikely)                     (HF possible)
                                              ↓
                                    Echocardiography
                         ┌──────────────────────────────────┐
                    Structural cardiac abnormality?
                         YES                            NO
                          ↓                              ↓
              Classify EF:                   Consider alternative dx
        EF ≤40% → HFrEF                     (pulmonary, renal, etc.)
        EF 41-49% → HFmrEF
        EF ≥50% → HFpEF
                          ↓
                Search for cause (Table 264-2)
                Identify precipitants (Table 264-5)
                Assess severity (NYHA class - Table 264-4)

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FLOWCHART 2: ADHF MANAGEMENT

ADHF Presentation
       ↓
Hemodynamic Profiling
   ┌──────────────────────────────────────┐
"Warm & Wet"        "Cold & Wet"         "Cold & Dry"
(Most Common)       (Low output + HF)    (Advanced/Volume depleted)
   ↓                      ↓                     ↓
IV Diuretics          Inotropes +           Careful volume 
(loop diuretic)       IV Diuretics          challenge or
+ Vasodilators        (Dobutamine/          MCS/evaluation
(if BP ≥90)           Milrinone)            for advanced HF
       ↓
Assess response at 6-12 hours:
- Urine output >100 mL/h? ✓
- Dyspnea improving? ✓
- Weight decreasing? ✓
       ↓
If inadequate: Add metolazone or consider ultrafiltration
       ↓
Euvolemia achieved → Transition to oral GDMT
       ↓
Before Discharge:
- Start/optimize ARNi/ACEI + BB + MRA + SGLT-2i
- Patient education
- Follow-up within 7-14 days

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FLOWCHART 3: HFrEF GDMT INITIATION (THE "FANTASTIC FOUR")

New HFrEF Diagnosis (EF ≤40%)
              ↓
Start ALL FOUR simultaneously or sequentially:
    ┌─────────────────────────────────────────────────────┐
    │  1. ARNi (sacubitril-valsartan) - preferred over    │
    │     ACEI/ARB; if intolerant → ACEI or ARB or H-ISDN │
    │  2. Beta-blocker (carvedilol/metoprolol/bisoprolol)  │
    │  3. MRA (spironolactone/eplerenone)                  │
    │  4. SGLT-2i (dapagliflozin/empagliflozin)           │
    └─────────────────────────────────────────────────────┘
              ↓
          Reassess in 3 months:
    EF still ≤35% AND NYHA II-III AND HR ≥70?
              ↓ Yes
    Consider ivabradine (SHIFT trial)
              ↓
    EF still ≤35% on GDMT ≥3 months, LBBB QRS ≥150ms?
              ↓ Yes
    CRT-D implant
              ↓
    EF ≤35%, NYHA II-III, not CRT candidate?
              ↓ Yes
    ICD (primary prevention) or
    CCM (if QRS <130ms, EF 25-45%)
              ↓
    Refractory/NYHA IV despite GDMT + device therapy?
              ↓ Yes
    LVAD (bridge to transplant or destination therapy)
    → Cardiac transplantation if eligible

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FLOWCHART 4: SCD PREVENTION IN HFrEF

HFrEF (EF ≤35%)
       ↓
Optimize GDMT ≥3 months
       ↓
Reassess LVEF
    EF ≤35%?
       ↓ YES
NYHA II-III (ambulatory)?
       ↓ YES
Prior VT/VF? → ICD (Secondary prevention - Class I)
No prior VT/VF → ICD Primary prevention (SCD-HeFT/MADIT-II)
       ↓
LBBB + QRS ≥150ms? → CRT-D (preferred over ICD alone)
       ↓
Expected meaningful survival >1 year?
       ↓ YES
ICD or CRT-D implant

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KEY SUMMARY TABLE: 4 PILLARS OF HFrEF THERAPY

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Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapters 264 & 265 Authors: Michael M. Givertz, Mandeep R. Mehra