257: HEART FAILURE: PATHOPHYSIOLOGY AND DIAGNOSIS o Post-admission mortality: 30 days 8–14%; 1 year 26–37%;
5 years up to 75%
I. Clinical Definitions o Readmission rates: 20–25% at 60 days; ~50% at 6 months
• Heart Failure (HF) o Each subsequent admission increases mortality risk
o Complex clinical syndrome from structural or functional o Black patients have higher case–fatality than Whites
impairment of ventricular filling or ejection o Prognosis improving with risk-factor management and
o Cardinal manifestations: dyspnea, fatigue, fluid retention guideline-directed therapies
o Terminology: • Economic Costs
▪ HF preferred over “congestive HF” (some patients o U.S. direct HF care: $30.7 billion (2012); projected hospital
lack overt volume overload) costs $70 billion by 2030
▪ Cardiomyopathy / LV dysfunction: broader o Indirect costs (lost productivity) may equal or exceed direct
terms for myocardial structural/functional disorders costs
that may lead to HF o Global HF economic burden (2012): $108 billion (60% direct
o Pathophysiologic definition: costs)
▪ Elevated cardiac filling pressures and/or o Pediatric acute HF inpatient costs ≈$1 billion/year and rising
inadequate peripheral oxygen delivery (at rest or
stress) due to cardiac dysfunction III. Phenotypes & Underlying Causes
A. By Ejection Fraction
• Chronic vs. Acute HF
o Chronic HF: symptoms/signs over months–years; managed • HF with Reduced EF (HFrEF)
with medical/device therapy o LVEF ≤40%
o Acute HF (formerly acute decompensated HF): rapid onset o Predominantly systolic dysfunction
or worsening of HF symptoms • HF with Preserved EF (HFpEF)
▪ ≈80% represent decompensation of chronic HF o LVEF ≥50%
▪ ≈20% are new-onset (e.g., ACS, acute valvular o Primarily diastolic dysfunction, but many have mixed
dysfunction, hypertensive urgency, abnormalities
postcardiotomy) o Requires exclusion of noncardiac causes of dyspnea/volume
o Acute pulmonary edema: rapid pulmonary congestion from overload
severely elevated left-heart filling pressures • HF with Mildly Reduced EF (HFmrEF)
o LVEF 41–49%
II. Epidemiology o Intermediate phenotype: mild systolic dysfunction + diastolic
• Global Burden features
o ≈6.2 million American adults treated for HF; >600,000 new o May represent improved HFrEF or declining HFpEF
U.S. cases/year o ESC recognizes HFmrEF as distinct to drive research
o 26 million people worldwide affected • HF with Recovered EF (HFrecEF)
• Age-Related Prevalence o Initial HFrEF with EF improvement to normal on therapy
o 1–2% prevalence in ages 40–59 o Predictors: younger age, shorter HF duration, nonischemic
o Up to 12% in adults >80 etiology, smaller ventricles, absence of fibrosis
o Lifetime HF risk at age 55: 33% (men), 28% (women) o Examples: fulminant myocarditis, stress cardiomyopathy,
peripartum, tachycardia-induced, toxin-induced
• Temporal Trends
(chemotherapy, alcohol)
o U.S. HF hospitalizations rose to ~1 million/year (1980–2000)
o Residual diastolic/exercise-induced pulmonary HTN may
o Decline from 1,020,000 (2006) to 809,000 (2016)
persist
o Projections: U.S. HF prevalence ↑46% from 2012→2030
o Therapy withdrawal can trigger recurrence
o Incidence improvement attributed to better CVD
B. By Etiology
prevention/treatment; may reverse with rising obesity
• Acquired Cardiovascular Disorders
• Racial/Ethnic Disparities
o Coronary artery disease: ≈2/3 of HF cases in developed
o Highest HF risk: Black > Hispanic > White > Chinese
countries
Americans
o Hypertension: contributes to HF in ≈75%
o Contributing factors: obesity, hypertension, diabetes,
o Diabetes mellitus: present in 10–40%
socioeconomic status, healthcare access
o HF hospitalization rates: Black men > Black women > White • Congenital Heart Disease (CHD)
men > White women o 1.4 million U.S. adults with CHD
o HF in CHD:
• Morbidity & Mortality
o 5-year survival post-HF diagnosis ≈50% ▪ Uncorrected defects presenting late
o Severe HF: 1-year mortality up to 40% ▪ Repaired/palliated defects with late valve or
o HF on death certificate in 1 of 8 U.S. deaths (predominantly ventricular failure
progressive HF or sudden cardiac death) ▪ Failing single‐ventricle physiology
o Hospitalization frequency after HF diagnosis: • Inherited Cardiomyopathies
▪ 83% ≥1 admission; 67% ≥2; 54% ≥3; 43% ≥4 o Hypertrophic, arrhythmogenic, lamin- and titin-related,
muscular dystrophies, mitochondrial diseases
o Mostly autosomal dominant
, o Importance of family history and genetic testing o Neprilysin degrades ANP/BNP/bradykinin → ARNI therapy
• Systemic & Infiltrative Diseases augments beneficial peptides
o Amyloidosis, sarcoidosis o BNP levels useful for diagnosis and risk stratification
o Autoimmune (SLE, RA), infectious (Chagas, HIV) o Endothelin, Cytokines & Oxidative Stress
o Drug/toxin-induced (chemotherapy, illicit agents) o Endothelin: potent vasoconstrictor, promotes myocyte
• Global Variants hypertrophy and fibrosis; key in pulmonary hypertension but
o Rheumatic heart disease in Africa/Asia (especially youth) endothelin antagonists not beneficial in HF
• High-Output HF (rare without structural disease)
o Inflammatory cytokines: TNF-α, IL-1β may contribute to
remodeling; anti-cytokine therapies unproven
o Anemia, thyrotoxicosis, cirrhosis, arteriovenous fistula,
Paget’s, beriberi • Reactive oxygen species: superoxide and related oxidants promote
o Must consider in differential for dyspnea/edema cellular injury
• Progressive Nature of HFrEF • Novel Biologic Targets
o Initiating “index” events: o SGLT-2 inhibitors: reduce glucose/Na⁺ reabsorption →
o Sudden (e.g., acute myocardial infarction) diuresis, improved endothelial function, altered myocardial
o Gradual (e.g., chronic pressure or volume overload) metabolism; proven mortality benefit in HFrEF and HFpEF
o Genetic (inherited cardiomyopathies) o Soluble guanylate cyclase stimulators: augment cGMP
o Congenital defects signaling → vasodilation and potential myocardial benefit
o Asymptomatic or mild symptoms initially due to compensatory • Dyssynchrony & Electrical Instability
mechanisms o QRS prolongation / LBBB: mechanical discoordination →
o Months–years of structural and functional remodeling worsened contractility, MR, remodeling
perpetuate decline o Cardiac resynchronization therapy (CRT): improves
• Ventricular Remodeling function, reverses remodeling, reduces morbidity/mortality in
symptomatic HFrEF with LBBB
• Patterns of hypertrophy
o Concentric hypertrophy: ↑ wall thickness > chamber volume o Arrhythmias: AF with rapid rate, frequent PVCs →
tachy-remodeling, ↑ wall stress, neurohormonal activation,
(pressure overload, e.g., HTN, aortic stenosis)
inflammation
o Eccentric hypertrophy: ↑ chamber size/volume (volume
overload, e.g., MR, AR)
o Secondary (Functional) Mitral Regurgitation
o LV dilation and altered geometry → incomplete leaflet
• Cellular and molecular changes coaptation, annular dilation, papillary muscle displacement
o Myocyte hypertrophy and interstitial fibrosis o MR severity drives volume overload and further remodeling
o Altered calcium handling and cytoskeletal proteins o Transcatheter mitral repair after optimized medical therapy
o Re-expression of fetal gene program can interrupt this vicious cycle
o Myocyte loss via necrosis and apoptosis
• Feedback loop CARDIORENAL & ABDOMINAL INTERACTIONS
o Remodeling ↑ wall stress → afterload mismatch → further Cardiorenal syndrome:
remodeling → clinical HF o Traditionally: ↓ cardiac output → renal hypoperfusion →
• HFpEF Remodeling (Emergent Concepts) RAAS/SNS activation → Na⁺/H₂O retention
o Beyond diastolic dysfunction: o Now: venous congestion and elevated intra-abdominal
o Vascular stiffness pressure also impair renal function
o Renal dysfunction and sodium retention • Splanchnic venous system: reservoir function; congestion →
o Metabolic inflammation (regional adiposity) hepatorenal and splenorenal reflexes → renal vasoconstriction
o Oxidative/nitrosative stress from impaired nitric oxide • Decongestive therapies (diuretics, ultrafiltration): reduce preload
signaling and abdominal pressure → improved renal function
COMPENSATORY MECHANISMS DRIVING PROGRESSION • Gut Congestion, Microbiome & Inflammation
o Congestion ↑ intestinal permeability → translocation of LPS
• Neurohormonal Activation → systemic macrophage activation → ↑ TNF-α, IL-1, IL-6 →
• SNS & RAAS upregulation → ↑ HR, BP, contractility; ↑ Na⁺/H₂O worsening cardiac dysfunction and cachexia
retention o Microbiome-derived metabolites (e.g., TMAO) correlate with
o Chronic activation → excessive vasoconstriction, electrolyte adverse outcomes in HF
disturbances, renal dysfunction, baroreceptor blunting, direct o Uremic toxins (e.g., indoxyl sulfate) from gut–kidney axis may
myocardial toxicity, arrhythmogenesis exacerbate HF
o Promotes remodeling of heart, vessels (atherosclerosis), • High-Output States
kidneys, other organs o Characterized by elevated CO with low SVR; rarely sole
o Therapeutic blockade (ACEi/ARBs, MRAs, β-blockers) cause of HF but precipitates decompensation when structural
reverses remodeling and improves outcomes heart disease present
• Vasodilatory Counter-regulators o Causes include:
o Natriuretic peptides (ANP, BNP): released in response to o Severe anemia (Hb ≤ 8 g/dL)
stretch → vasodilation, natriuresis, RAAS/SNS inhibition o Arteriovenous fistulae (e.g., ESRD dialysis access)
o Prostaglandins (PGE₁, PGI₂), bradykinin, o Obesity, liver disease, AV shunts, lung disease,
adrenomedullin, NO → vasodilation, renoprotection myeloproliferative disorders
,• Management focuses on treating underlying cause and optimizing o HF-related disease states: arrhythmias, ischemia,
cardiac function uncontrolled hypertension, infection
EVALUATION OF HEART FAILURE o Other causes: anemia, thyroid dysfunction, renal failure,
noncardiac medications (NSAIDs)
I. History
• Symptoms of Congestion II. Physical Examination
o Pulmonary (Left HF) • General Appearance
▪ Exertional dyspnea → orthopnea → PND → o Mild–moderate HF: well-nourished, comfortable at rest;
dyspnea at rest dyspnea with minimal exertion
▪ Exertional: with activity o Severe HF: orthopneic posture, anxiety, diaphoresis, pallor or
▪ Orthopnea: within 1–2 min recumbent; duskiness, cool extremities, peripheral cyanosis
relieved by head-elevation o Cardiac cachexia: >5% unintentional weight loss over
▪ Paroxysmal nocturnal dyspnea (PND): 12 months, bitemporal/upper-body muscle wasting
abrupt awakening after prolonged o Rare: scleral icterus/jaundice in severe right HF
recumbency; may take ≥30 min upright • Vital Signs
to improve; often with cough/wheezing o New HF: ↑ HR, ↑ BP (SNS activation)
(“cardiac asthma”) o Chronic HF on therapy: target HR <70–75 bpm; BP
▪ Acute pulmonary edema: severe low-normal
dyspnea, pink frothy sputum o Arrhythmias: irregular rhythm from AF/flutter or ectopy
▪ Mechanisms of dyspnea o Severe HF: hypotension, narrow pulse pressure, thready
▪ Pulmonary venous congestion → pulse
interstitial/alveolar fluid → ↓ lung o Pulsus alternans: alternating strong/weak pulse → severe
compliance, ↑ airway resistance, V/Q LV dysfunction
mismatch, hypoxemia o RR: may ↑ with recumbency or minimal exertion; periodic
▪ Juxtacapillary J-receptor stimulation → breathing/Cheyne–Stokes in advanced HF
↑ ventilatory drive, lactic acidosis o SpO₂: usually normal unless acute pulmonary edema, shunt,
PAH, or lung disease
▪ Sleep-disordered breathing (Cheyne–
Stokes, central sleep apnea) may
o Low-grade fever possible from cytokine release
precipitate PND • Neck Veins
o Systemic (Right HF) o JVP measured at 45°: normal ≤8 cmH₂O above sternal angle
▪ Peripheral edema & visceral congestion + 5 cm
▪ Weight gain, bilateral lower-extremity o Hepatojugular (abdominojugular) reflux: sustained rise in
pitting edema JVP with RUQ or mid-abdominal pressure → elevated filling
pressures
▪ Gastrointestinal: abdominal bloating,
anorexia, early satiety,
o Kussmaul’s sign (JVP ↑ on inspiration) → severe
biventricular HF
right-upper-quadrant pain (hepatic
capsule stretch) with nausea/vomiting • Lung Exam
▪ Hepatic congestion → abnormal LFTs o Basal rales/crackles from alveolar fluid; may extend
(mild AST/ALT/alk-phos ↑, possible throughout fields in acute edema
jaundice) o Wheezes/rhonchi (“cardiac asthma”)
▪ Anasarca: massive generalized edema, o Chronic HF: may lack rales due to lymphatic compensation
recurrent ascites/pleural effusions o Biventricular/right HF: bilateral pleural effusions (dullness, ↓
breath sounds)
• Symptoms of Reduced Perfusion (“Low-Output” Syndrome)
o Fatigue, weakness (especially legs) at rest or exertion • Cardiac Exam
▪ Mechanisms: ↓ muscle perfusion, endothelial o Displaced, diffuse, or sustained apical impulse
dysfunction, ↑ SVR, skeletal muscle metabolic
o RV heave/parasternal lift in biventricular or RV-dominant HF
changes
o Gallops:
o Cognitive: mental dullness, confusion in elderly with ▪ S3: volume overload, tachycardia, poor prognosis
cerebrovascular disease ▪ S4: non-specific; seen in HFpEF (hypertension)
o Contributing factors: volume depletion, hyponatremia, iron o Holosystolic MR/TR murmurs (functional regurgitation)
deficiency, medications (β-blockers) o Loud P₂ in secondary pulmonary hypertension
• Other Symptoms • Abdomen & Extremities
o Mood disturbances, poor sleep (nocturnal dyspnea, sleep o Hepatomegaly, RUQ tenderness (capsular stretch), pulsatile
apnea, nocturia) liver edge (TR)
o Oliguria in advanced HF o Chronic congestion → cardiac cirrhosis, congestive
splenomegaly, mild–moderate ascites
• Precipitating Factors for Decompensation
o Patient-related: nonadherence to diet/meds, excessive o Symmetric, pitting lower-extremity edema → chronic
changes (induration, cellulitis)
fluid/salt intake
o Provider-related: inadequate diuretic dosing, omission of o Anasarca: massive generalized edema
guideline-directed therapies
o Unilateral edema: consider DVT or post-surgical changes
o Non-pitting edema refractory to diuretics: lymphedema
, o SGLT-2 inhibitors reduce HF hospitalizations and mortality;
III. Diagnosis other GDMT indicated
• Clinical Suspicion in at-risk patients (age, CVD, HTN, DM, CKD) • Sleep Apnea
• Routine Labs o Obstructive & central types common; ↑ afterload, intermittent
o CMP, CBC, coagulation, urinalysis hypoxia, SNS activation
o BUN/Cr often ↑ (renal hypoperfusion/congestion) o CPAP benefits in OSA + HFrEF; no proven central sleep
o LFTs: mild AST/ALT/alk-phos ↑ in chronic congestion; apnea therapy beyond HF treatment
marked elevation → cardiogenic shock • Obesity
o Electrolytes: o Risk factor & prevalent, especially in HFpEF
▪ Hyponatremia (diuretics, vasopressin) → poor o “Obesity paradox”: better prognosis in overweight HF
prognosis o Weight loss improves symptoms and exercise capacity;
▪ Hypo/hyperkalemia (diuretics, RAAS inhibitors) → survival impact unclear
arrhythmia risk • Depression
▪ Hypophosphatemia/hypomagnesemia (alcohol o Independent risk factor for poor outcomes, particularly in
use) older women
o Anemia/iron deficiency: exacerbates HF; IV iron improves o Screen routinely; SSRIs safe but do not alter HF trajectory
symptoms o Effects of CBT, collaborative care, and novel therapies under
o Targeted tests (ANA, SPEP, ferritin, etc.) per clinical context study
• Chest X-Ray
o Cardiomegaly (CTR >0.5) V. Differential Diagnosis
o Pulmonary venous redistribution, interstitial septal lines, • Pulmonary vs. Cardiac Dyspnea
alveolar edema o COPD, pneumonia, asthma vs. HF (orthopnea relieved only
o Pleural effusions (often bilateral) by upright posture; cough vs. expectoration)
o Rule out noncardiac causes (pneumonia, COPD) o Coexistence common; PFTs or CPET post-diuresis may
• Electrocardiogram clarify
o LVH, LAE → HFpEF o BNP/NT-proBNP very low → HF less likely in non-obese
o Q waves (ischemia) vs. pseudo-infarct pattern (infiltrative) • Noncardiac Causes of Edema/Fluid Retention
o Conduction disease → consider sarcoid, Chagas o Renal failure, hepatic cirrhosis, nephrotic syndrome
o AF/flutter, PVCs, NSVT → risk markers o ARDS or high-permeability pulmonary edema
o QRS width/LBBB → CRT candidacy • Noncardiac Causes of Lower-Extremity Edema
• Noninvasive Imaging o Venous insufficiency, lymphedema, medication side effects
o Echocardiography: 2D + Doppler → chamber size, LVEF, (e.g., CCBs)
valve pathology, diastolic function, strain imaging
o CMR: gold standard for volumes/mass, tissue
characterization, CHD anatomy
o CT: pericardial disease, LV thrombus when CMR
contraindicated
o PET: ischemia, viability, inflammation (e.g., sarcoid)
• Cardiopulmonary Exercise Testing
o Symptom-limited ramp protocol
o Peak VO₂, VE/VCO₂ slope → prognostic in transplant/MCS
evaluation
o BP/HR response, exercise arrhythmias
• Biomarkers
o BNP & NT-proBNP: ↑ with wall stress; help diagnosis, risk
stratification, and therapy guidance
o Affected by age, sex, CKD, obesity, AF, PAH, PE
o Galectin-3, sST2: prognostic, less widely used
• Invasive Hemodynamics
o Pulmonary artery catheter: differentiate cardiogenic vs.
non-cardiogenic edema; guide vasoactive/diuretic therapy
o Cardiac cath: coronary angiography to identify reversible
ischemia; combined right/left pressures to distinguish
constriction vs. restriction
o Endomyocardial biopsy: reserved for myocarditis,
amyloidosis, allograft rejection
IV. Comorbidities
• Diabetes Mellitus (Type 2)
o Prevalence 10–40% in HF; worsens outcomes
5 years up to 75%
I. Clinical Definitions o Readmission rates: 20–25% at 60 days; ~50% at 6 months
• Heart Failure (HF) o Each subsequent admission increases mortality risk
o Complex clinical syndrome from structural or functional o Black patients have higher case–fatality than Whites
impairment of ventricular filling or ejection o Prognosis improving with risk-factor management and
o Cardinal manifestations: dyspnea, fatigue, fluid retention guideline-directed therapies
o Terminology: • Economic Costs
▪ HF preferred over “congestive HF” (some patients o U.S. direct HF care: $30.7 billion (2012); projected hospital
lack overt volume overload) costs $70 billion by 2030
▪ Cardiomyopathy / LV dysfunction: broader o Indirect costs (lost productivity) may equal or exceed direct
terms for myocardial structural/functional disorders costs
that may lead to HF o Global HF economic burden (2012): $108 billion (60% direct
o Pathophysiologic definition: costs)
▪ Elevated cardiac filling pressures and/or o Pediatric acute HF inpatient costs ≈$1 billion/year and rising
inadequate peripheral oxygen delivery (at rest or
stress) due to cardiac dysfunction III. Phenotypes & Underlying Causes
A. By Ejection Fraction
• Chronic vs. Acute HF
o Chronic HF: symptoms/signs over months–years; managed • HF with Reduced EF (HFrEF)
with medical/device therapy o LVEF ≤40%
o Acute HF (formerly acute decompensated HF): rapid onset o Predominantly systolic dysfunction
or worsening of HF symptoms • HF with Preserved EF (HFpEF)
▪ ≈80% represent decompensation of chronic HF o LVEF ≥50%
▪ ≈20% are new-onset (e.g., ACS, acute valvular o Primarily diastolic dysfunction, but many have mixed
dysfunction, hypertensive urgency, abnormalities
postcardiotomy) o Requires exclusion of noncardiac causes of dyspnea/volume
o Acute pulmonary edema: rapid pulmonary congestion from overload
severely elevated left-heart filling pressures • HF with Mildly Reduced EF (HFmrEF)
o LVEF 41–49%
II. Epidemiology o Intermediate phenotype: mild systolic dysfunction + diastolic
• Global Burden features
o ≈6.2 million American adults treated for HF; >600,000 new o May represent improved HFrEF or declining HFpEF
U.S. cases/year o ESC recognizes HFmrEF as distinct to drive research
o 26 million people worldwide affected • HF with Recovered EF (HFrecEF)
• Age-Related Prevalence o Initial HFrEF with EF improvement to normal on therapy
o 1–2% prevalence in ages 40–59 o Predictors: younger age, shorter HF duration, nonischemic
o Up to 12% in adults >80 etiology, smaller ventricles, absence of fibrosis
o Lifetime HF risk at age 55: 33% (men), 28% (women) o Examples: fulminant myocarditis, stress cardiomyopathy,
peripartum, tachycardia-induced, toxin-induced
• Temporal Trends
(chemotherapy, alcohol)
o U.S. HF hospitalizations rose to ~1 million/year (1980–2000)
o Residual diastolic/exercise-induced pulmonary HTN may
o Decline from 1,020,000 (2006) to 809,000 (2016)
persist
o Projections: U.S. HF prevalence ↑46% from 2012→2030
o Therapy withdrawal can trigger recurrence
o Incidence improvement attributed to better CVD
B. By Etiology
prevention/treatment; may reverse with rising obesity
• Acquired Cardiovascular Disorders
• Racial/Ethnic Disparities
o Coronary artery disease: ≈2/3 of HF cases in developed
o Highest HF risk: Black > Hispanic > White > Chinese
countries
Americans
o Hypertension: contributes to HF in ≈75%
o Contributing factors: obesity, hypertension, diabetes,
o Diabetes mellitus: present in 10–40%
socioeconomic status, healthcare access
o HF hospitalization rates: Black men > Black women > White • Congenital Heart Disease (CHD)
men > White women o 1.4 million U.S. adults with CHD
o HF in CHD:
• Morbidity & Mortality
o 5-year survival post-HF diagnosis ≈50% ▪ Uncorrected defects presenting late
o Severe HF: 1-year mortality up to 40% ▪ Repaired/palliated defects with late valve or
o HF on death certificate in 1 of 8 U.S. deaths (predominantly ventricular failure
progressive HF or sudden cardiac death) ▪ Failing single‐ventricle physiology
o Hospitalization frequency after HF diagnosis: • Inherited Cardiomyopathies
▪ 83% ≥1 admission; 67% ≥2; 54% ≥3; 43% ≥4 o Hypertrophic, arrhythmogenic, lamin- and titin-related,
muscular dystrophies, mitochondrial diseases
o Mostly autosomal dominant
, o Importance of family history and genetic testing o Neprilysin degrades ANP/BNP/bradykinin → ARNI therapy
• Systemic & Infiltrative Diseases augments beneficial peptides
o Amyloidosis, sarcoidosis o BNP levels useful for diagnosis and risk stratification
o Autoimmune (SLE, RA), infectious (Chagas, HIV) o Endothelin, Cytokines & Oxidative Stress
o Drug/toxin-induced (chemotherapy, illicit agents) o Endothelin: potent vasoconstrictor, promotes myocyte
• Global Variants hypertrophy and fibrosis; key in pulmonary hypertension but
o Rheumatic heart disease in Africa/Asia (especially youth) endothelin antagonists not beneficial in HF
• High-Output HF (rare without structural disease)
o Inflammatory cytokines: TNF-α, IL-1β may contribute to
remodeling; anti-cytokine therapies unproven
o Anemia, thyrotoxicosis, cirrhosis, arteriovenous fistula,
Paget’s, beriberi • Reactive oxygen species: superoxide and related oxidants promote
o Must consider in differential for dyspnea/edema cellular injury
• Progressive Nature of HFrEF • Novel Biologic Targets
o Initiating “index” events: o SGLT-2 inhibitors: reduce glucose/Na⁺ reabsorption →
o Sudden (e.g., acute myocardial infarction) diuresis, improved endothelial function, altered myocardial
o Gradual (e.g., chronic pressure or volume overload) metabolism; proven mortality benefit in HFrEF and HFpEF
o Genetic (inherited cardiomyopathies) o Soluble guanylate cyclase stimulators: augment cGMP
o Congenital defects signaling → vasodilation and potential myocardial benefit
o Asymptomatic or mild symptoms initially due to compensatory • Dyssynchrony & Electrical Instability
mechanisms o QRS prolongation / LBBB: mechanical discoordination →
o Months–years of structural and functional remodeling worsened contractility, MR, remodeling
perpetuate decline o Cardiac resynchronization therapy (CRT): improves
• Ventricular Remodeling function, reverses remodeling, reduces morbidity/mortality in
symptomatic HFrEF with LBBB
• Patterns of hypertrophy
o Concentric hypertrophy: ↑ wall thickness > chamber volume o Arrhythmias: AF with rapid rate, frequent PVCs →
tachy-remodeling, ↑ wall stress, neurohormonal activation,
(pressure overload, e.g., HTN, aortic stenosis)
inflammation
o Eccentric hypertrophy: ↑ chamber size/volume (volume
overload, e.g., MR, AR)
o Secondary (Functional) Mitral Regurgitation
o LV dilation and altered geometry → incomplete leaflet
• Cellular and molecular changes coaptation, annular dilation, papillary muscle displacement
o Myocyte hypertrophy and interstitial fibrosis o MR severity drives volume overload and further remodeling
o Altered calcium handling and cytoskeletal proteins o Transcatheter mitral repair after optimized medical therapy
o Re-expression of fetal gene program can interrupt this vicious cycle
o Myocyte loss via necrosis and apoptosis
• Feedback loop CARDIORENAL & ABDOMINAL INTERACTIONS
o Remodeling ↑ wall stress → afterload mismatch → further Cardiorenal syndrome:
remodeling → clinical HF o Traditionally: ↓ cardiac output → renal hypoperfusion →
• HFpEF Remodeling (Emergent Concepts) RAAS/SNS activation → Na⁺/H₂O retention
o Beyond diastolic dysfunction: o Now: venous congestion and elevated intra-abdominal
o Vascular stiffness pressure also impair renal function
o Renal dysfunction and sodium retention • Splanchnic venous system: reservoir function; congestion →
o Metabolic inflammation (regional adiposity) hepatorenal and splenorenal reflexes → renal vasoconstriction
o Oxidative/nitrosative stress from impaired nitric oxide • Decongestive therapies (diuretics, ultrafiltration): reduce preload
signaling and abdominal pressure → improved renal function
COMPENSATORY MECHANISMS DRIVING PROGRESSION • Gut Congestion, Microbiome & Inflammation
o Congestion ↑ intestinal permeability → translocation of LPS
• Neurohormonal Activation → systemic macrophage activation → ↑ TNF-α, IL-1, IL-6 →
• SNS & RAAS upregulation → ↑ HR, BP, contractility; ↑ Na⁺/H₂O worsening cardiac dysfunction and cachexia
retention o Microbiome-derived metabolites (e.g., TMAO) correlate with
o Chronic activation → excessive vasoconstriction, electrolyte adverse outcomes in HF
disturbances, renal dysfunction, baroreceptor blunting, direct o Uremic toxins (e.g., indoxyl sulfate) from gut–kidney axis may
myocardial toxicity, arrhythmogenesis exacerbate HF
o Promotes remodeling of heart, vessels (atherosclerosis), • High-Output States
kidneys, other organs o Characterized by elevated CO with low SVR; rarely sole
o Therapeutic blockade (ACEi/ARBs, MRAs, β-blockers) cause of HF but precipitates decompensation when structural
reverses remodeling and improves outcomes heart disease present
• Vasodilatory Counter-regulators o Causes include:
o Natriuretic peptides (ANP, BNP): released in response to o Severe anemia (Hb ≤ 8 g/dL)
stretch → vasodilation, natriuresis, RAAS/SNS inhibition o Arteriovenous fistulae (e.g., ESRD dialysis access)
o Prostaglandins (PGE₁, PGI₂), bradykinin, o Obesity, liver disease, AV shunts, lung disease,
adrenomedullin, NO → vasodilation, renoprotection myeloproliferative disorders
,• Management focuses on treating underlying cause and optimizing o HF-related disease states: arrhythmias, ischemia,
cardiac function uncontrolled hypertension, infection
EVALUATION OF HEART FAILURE o Other causes: anemia, thyroid dysfunction, renal failure,
noncardiac medications (NSAIDs)
I. History
• Symptoms of Congestion II. Physical Examination
o Pulmonary (Left HF) • General Appearance
▪ Exertional dyspnea → orthopnea → PND → o Mild–moderate HF: well-nourished, comfortable at rest;
dyspnea at rest dyspnea with minimal exertion
▪ Exertional: with activity o Severe HF: orthopneic posture, anxiety, diaphoresis, pallor or
▪ Orthopnea: within 1–2 min recumbent; duskiness, cool extremities, peripheral cyanosis
relieved by head-elevation o Cardiac cachexia: >5% unintentional weight loss over
▪ Paroxysmal nocturnal dyspnea (PND): 12 months, bitemporal/upper-body muscle wasting
abrupt awakening after prolonged o Rare: scleral icterus/jaundice in severe right HF
recumbency; may take ≥30 min upright • Vital Signs
to improve; often with cough/wheezing o New HF: ↑ HR, ↑ BP (SNS activation)
(“cardiac asthma”) o Chronic HF on therapy: target HR <70–75 bpm; BP
▪ Acute pulmonary edema: severe low-normal
dyspnea, pink frothy sputum o Arrhythmias: irregular rhythm from AF/flutter or ectopy
▪ Mechanisms of dyspnea o Severe HF: hypotension, narrow pulse pressure, thready
▪ Pulmonary venous congestion → pulse
interstitial/alveolar fluid → ↓ lung o Pulsus alternans: alternating strong/weak pulse → severe
compliance, ↑ airway resistance, V/Q LV dysfunction
mismatch, hypoxemia o RR: may ↑ with recumbency or minimal exertion; periodic
▪ Juxtacapillary J-receptor stimulation → breathing/Cheyne–Stokes in advanced HF
↑ ventilatory drive, lactic acidosis o SpO₂: usually normal unless acute pulmonary edema, shunt,
PAH, or lung disease
▪ Sleep-disordered breathing (Cheyne–
Stokes, central sleep apnea) may
o Low-grade fever possible from cytokine release
precipitate PND • Neck Veins
o Systemic (Right HF) o JVP measured at 45°: normal ≤8 cmH₂O above sternal angle
▪ Peripheral edema & visceral congestion + 5 cm
▪ Weight gain, bilateral lower-extremity o Hepatojugular (abdominojugular) reflux: sustained rise in
pitting edema JVP with RUQ or mid-abdominal pressure → elevated filling
pressures
▪ Gastrointestinal: abdominal bloating,
anorexia, early satiety,
o Kussmaul’s sign (JVP ↑ on inspiration) → severe
biventricular HF
right-upper-quadrant pain (hepatic
capsule stretch) with nausea/vomiting • Lung Exam
▪ Hepatic congestion → abnormal LFTs o Basal rales/crackles from alveolar fluid; may extend
(mild AST/ALT/alk-phos ↑, possible throughout fields in acute edema
jaundice) o Wheezes/rhonchi (“cardiac asthma”)
▪ Anasarca: massive generalized edema, o Chronic HF: may lack rales due to lymphatic compensation
recurrent ascites/pleural effusions o Biventricular/right HF: bilateral pleural effusions (dullness, ↓
breath sounds)
• Symptoms of Reduced Perfusion (“Low-Output” Syndrome)
o Fatigue, weakness (especially legs) at rest or exertion • Cardiac Exam
▪ Mechanisms: ↓ muscle perfusion, endothelial o Displaced, diffuse, or sustained apical impulse
dysfunction, ↑ SVR, skeletal muscle metabolic
o RV heave/parasternal lift in biventricular or RV-dominant HF
changes
o Gallops:
o Cognitive: mental dullness, confusion in elderly with ▪ S3: volume overload, tachycardia, poor prognosis
cerebrovascular disease ▪ S4: non-specific; seen in HFpEF (hypertension)
o Contributing factors: volume depletion, hyponatremia, iron o Holosystolic MR/TR murmurs (functional regurgitation)
deficiency, medications (β-blockers) o Loud P₂ in secondary pulmonary hypertension
• Other Symptoms • Abdomen & Extremities
o Mood disturbances, poor sleep (nocturnal dyspnea, sleep o Hepatomegaly, RUQ tenderness (capsular stretch), pulsatile
apnea, nocturia) liver edge (TR)
o Oliguria in advanced HF o Chronic congestion → cardiac cirrhosis, congestive
splenomegaly, mild–moderate ascites
• Precipitating Factors for Decompensation
o Patient-related: nonadherence to diet/meds, excessive o Symmetric, pitting lower-extremity edema → chronic
changes (induration, cellulitis)
fluid/salt intake
o Provider-related: inadequate diuretic dosing, omission of o Anasarca: massive generalized edema
guideline-directed therapies
o Unilateral edema: consider DVT or post-surgical changes
o Non-pitting edema refractory to diuretics: lymphedema
, o SGLT-2 inhibitors reduce HF hospitalizations and mortality;
III. Diagnosis other GDMT indicated
• Clinical Suspicion in at-risk patients (age, CVD, HTN, DM, CKD) • Sleep Apnea
• Routine Labs o Obstructive & central types common; ↑ afterload, intermittent
o CMP, CBC, coagulation, urinalysis hypoxia, SNS activation
o BUN/Cr often ↑ (renal hypoperfusion/congestion) o CPAP benefits in OSA + HFrEF; no proven central sleep
o LFTs: mild AST/ALT/alk-phos ↑ in chronic congestion; apnea therapy beyond HF treatment
marked elevation → cardiogenic shock • Obesity
o Electrolytes: o Risk factor & prevalent, especially in HFpEF
▪ Hyponatremia (diuretics, vasopressin) → poor o “Obesity paradox”: better prognosis in overweight HF
prognosis o Weight loss improves symptoms and exercise capacity;
▪ Hypo/hyperkalemia (diuretics, RAAS inhibitors) → survival impact unclear
arrhythmia risk • Depression
▪ Hypophosphatemia/hypomagnesemia (alcohol o Independent risk factor for poor outcomes, particularly in
use) older women
o Anemia/iron deficiency: exacerbates HF; IV iron improves o Screen routinely; SSRIs safe but do not alter HF trajectory
symptoms o Effects of CBT, collaborative care, and novel therapies under
o Targeted tests (ANA, SPEP, ferritin, etc.) per clinical context study
• Chest X-Ray
o Cardiomegaly (CTR >0.5) V. Differential Diagnosis
o Pulmonary venous redistribution, interstitial septal lines, • Pulmonary vs. Cardiac Dyspnea
alveolar edema o COPD, pneumonia, asthma vs. HF (orthopnea relieved only
o Pleural effusions (often bilateral) by upright posture; cough vs. expectoration)
o Rule out noncardiac causes (pneumonia, COPD) o Coexistence common; PFTs or CPET post-diuresis may
• Electrocardiogram clarify
o LVH, LAE → HFpEF o BNP/NT-proBNP very low → HF less likely in non-obese
o Q waves (ischemia) vs. pseudo-infarct pattern (infiltrative) • Noncardiac Causes of Edema/Fluid Retention
o Conduction disease → consider sarcoid, Chagas o Renal failure, hepatic cirrhosis, nephrotic syndrome
o AF/flutter, PVCs, NSVT → risk markers o ARDS or high-permeability pulmonary edema
o QRS width/LBBB → CRT candidacy • Noncardiac Causes of Lower-Extremity Edema
• Noninvasive Imaging o Venous insufficiency, lymphedema, medication side effects
o Echocardiography: 2D + Doppler → chamber size, LVEF, (e.g., CCBs)
valve pathology, diastolic function, strain imaging
o CMR: gold standard for volumes/mass, tissue
characterization, CHD anatomy
o CT: pericardial disease, LV thrombus when CMR
contraindicated
o PET: ischemia, viability, inflammation (e.g., sarcoid)
• Cardiopulmonary Exercise Testing
o Symptom-limited ramp protocol
o Peak VO₂, VE/VCO₂ slope → prognostic in transplant/MCS
evaluation
o BP/HR response, exercise arrhythmias
• Biomarkers
o BNP & NT-proBNP: ↑ with wall stress; help diagnosis, risk
stratification, and therapy guidance
o Affected by age, sex, CKD, obesity, AF, PAH, PE
o Galectin-3, sST2: prognostic, less widely used
• Invasive Hemodynamics
o Pulmonary artery catheter: differentiate cardiogenic vs.
non-cardiogenic edema; guide vasoactive/diuretic therapy
o Cardiac cath: coronary angiography to identify reversible
ischemia; combined right/left pressures to distinguish
constriction vs. restriction
o Endomyocardial biopsy: reserved for myocarditis,
amyloidosis, allograft rejection
IV. Comorbidities
• Diabetes Mellitus (Type 2)
o Prevalence 10–40% in HF; worsens outcomes
