Heart Failure

Heart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR) (HF) is a progressive syndrome where the heart cannotpumpPumpACES and RUSH: Resuscitation Ultrasound Protocols blood adequately to meet metabolic demands.

Key Pathophysiology:

• ↓Cardiac outputCardiac outputThe volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat).Cardiac Mechanics → Compensatory mechanisms activate
• SNS activation → ↑ HR, contractility, andvasoconstrictionVasoconstrictionThe physiological narrowing of blood vessels by contraction of the vascular smooth muscle.Vascular Resistance, Flow, and Mean Arterial Pressure
• RAASRAASA blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system.Adrenal Hormones activation → Na+/fluid retention and ventricular remodeling
• Neurohormonal cascade → Progressive deterioration

Classifications:

• Byejection fractionEjection fractionCardiac Cycle:Heart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR) with reducedejection fractionEjection fractionCardiac Cycle (HFrEF) ≤40% vsheart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR) with preservedejection fractionEjection fractionCardiac Cycle (HFpEF) ≥50% vsheart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR) with mid-rangeejection fractionEjection fractionCardiac Cycle (HFmrEF) between 41 and 49%
• New York Heart Association (NYHA) classification:
  • Class I: nolimitationsLimitationsConflict of Interest in physical activity, asymptomatic
  • Class II: comfortable at rest, but slight limitation during moderate/prolonged physical activity
  • Class III: comfortable only at rest. Daily activities, such as dressing up, result in markedlimitationsLimitationsConflict of Interest of physical activity.
  • Class IV: symptomatic even at rest

Clinical Presentation:

• Left-sided:
  • DyspneaDyspneaDyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary).Dyspnea
  • OrthopneaOrthopneaPulmonary Edema
  • Paroxysmal nocturnal dyspneaParoxysmal nocturnal dyspneaA disorder characterized by sudden attacks of respiratory distress in at rest patients with heart failure and pulmonary edema. It usually occurs at night after several hours of sleep in a reclining position. Patients awaken with a feeling of suffocation, coughing, a cold sweat, and tachycardia. When there is significant wheezing, it is called cardiac asthma.Pulmonary Edema (PND)
  • Pulmonary edemaPulmonary edemaPulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure.Pulmonary Edema
• Right-sided:
  • Jugular venous distention (JVDJVDCardiovascular Examination)
  • Peripheral edemaPeripheral edemaPeripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles.Edema
  • Hepatomegaly
  • AscitesAscitesAscites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection).Ascites

Pharmacologic Management of HF – The Big 4 + 1

1.ACE InhibitorsACE inhibitorsTruncus Arteriosus / ARBs /ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors

• Mechanism: BlockRAASRAASA blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system.Adrenal Hormones →
  • ↓preloadPreloadCardiac Mechanics/afterloadAfterloadAfterload is the resistance in the aorta that prevents blood from leaving the heart. Afterload represents the pressure the LV needs to overcome to eject blood into the aorta.Cardiac Mechanics
  • Prevent remodeling
• Side effects:
  • HyperkalemiaHyperkalemiaHyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs.Hyperkalemia
  • ↑ creatinine
  • HypotensionHypotensionHypotension is defined as low blood pressure, specifically< 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause.Hypotension
  • AngioedemaAngioedemaAngioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability.Angioedema (ACE)
  • Cough (ACE)
• ContraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation:
  • Bilateralrenal arteryRenal arteryA branch of the abdominal aorta which supplies the kidneys, adrenal glands and ureters.Glomerular FiltrationstenosisStenosisHypoplastic Left Heart Syndrome (HLHS)
  • PregnancyPregnancyThe status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth.Pregnancy: Diagnosis, Physiology, and Care
  • SeverehyperkalemiaHyperkalemiaHyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs.Hyperkalemia

2.Beta-BlockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers)

• Mechanism: Block SNS →
  • ↓ HR
  • ↓ oxygen demand
  • Prevent arrhythmias
• HF-specificbeta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers):
  • MetoprololMetoprololA selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias.Antiadrenergic Drugs succinate (XL formulation only)
  • CarvedilolCarvedilolA carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction.Class 2 Antiarrhythmic Drugs (Beta Blockers) (α + β blockade)
  • BisoprololBisoprololA cardioselective beta-1 adrenergic blocker. It is effective in the management of hypertension and angina pectoris.Class 2 Antiarrhythmic Drugs (Beta Blockers)
• Key Points:
  • Gradual increase in dosage, starting with a low dose and slowly increasing it over time, reduces risk of side effects (“start low, go slow”)
  • ReducesmortalityMortalityAll deaths reported in a given population.Measures of Health Status in HFrEF
• Side effects:
  • BradycardiaBradycardiaBradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea.Bradyarrhythmias
  • HypotensionHypotensionHypotension is defined as low blood pressure, specifically< 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause.Hypotension
  • FatigueFatigueThe state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.Fibromyalgia
  • BronchospasmBronchospasmAsthma Drugs
• ContraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation:
  • Decompensated HF
  • SeverebradycardiaBradycardiaBradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea.Bradyarrhythmias
  • SevereasthmaAsthmaAsthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea.Asthma

3.Mineralocorticoid Receptor AntagonistsMineralocorticoid receptor antagonistsDrugs that bind to and block the activation of mineralocorticoid receptors by mineralocorticoids such as aldosterone.Potassium-sparing Diuretics (MRAsMRAsDrugs that bind to and block the activation of mineralocorticoid receptors by mineralocorticoids such as aldosterone.Potassium-sparing Diuretics)

• Mechanism: BlockaldosteroneAldosteroneA hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium.Hyperkalemia →
  • ↓ K+ loss
  • ↓fibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans
  • ↓ remodeling
• Side effects:
  • HyperkalemiaHyperkalemiaHyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs.Hyperkalemia (monitor!)
  • GynecomastiaGynecomastiaGynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men.Gynecomastia (spironolactoneSpironolactoneA potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects.Potassium-sparing Diuretics)
• Monitor:
  • K+ (baseline, 1 week, monthly initially)
  • Creatinine (baseline, 1 week, monthly initially)

4.SGLT2 InhibitorsSGLT2 inhibitorsNon-insulinotropic Diabetes Drugs

• Mechanism: BlockglucoseGlucoseA primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement.Lactose Intolerance/Na+ reabsorption →
  • Diuresis
  • ↓preloadPreloadCardiac Mechanics
  • Cardioprotective
• First class to show outcome benefit in HFpEF (mainly ↓hospitalizationHospitalizationThe confinement of a patient in a hospital.Delirium, modestmortalityMortalityAll deaths reported in a given population.Measures of Health Status reduction)
• HF-approvedSGLT2 inhibitorsSGLT2 inhibitorsNon-insulinotropic Diabetes Drugs:
  • DapagliflozinDapagliflozinNon-insulinotropic Diabetes Drugs: HFrEF and HFpEF
  • EmpagliflozinEmpagliflozinNon-insulinotropic Diabetes Drugs: HFrEF and HFpEF
• Side effects:
  • UTIs
  • GenitalinfectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease
  • DKADKADiabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency.Hyperglycemic Crises (rare)
  • Fournier gangreneFournier gangreneAn acute necrotic infection of the scrotum; penis; or perineum. It is characterized by scrotum pain and redness with rapid progression to gangrene and sloughing of tissue. Fournier gangrene is usually secondary to perirectal or periurethral infections associated with local trauma, operative procedures, or urinary tract disease.Necrotizing Fasciitis (rare)

+1.Loop DiureticsLoop diureticsLoop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent.Loop Diuretics

• Mechanism: BlockNa-K-2Cl cotransporterNa-K-2Cl cotransporterRenal Potassium Regulation → diuresis
• Symptom relief only, does not reducemortalityMortalityAll deaths reported in a given population.Measures of Health Status
• Side effects:
  • HypokalemiaHypokalemiaHypokalemia is defined as plasma potassium (K+) concentration< 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake.Hypokalemia
  • HyponatremiaHyponatremiaHyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism.Hyponatremia
  • OtotoxicityOtotoxicityDamage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation.Glycopeptides
  • Kidney injury

Additional HF Therapies

Adjunctive Options

Emerging Therapies

Drugs to Avoid in HF

• CalciumCalciumA basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Electrolytes channel blockers (non-dihydropyridineNon-DihydropyridinePulmonary Hypertension Drugs):VerapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs,diltiazemDiltiazemA benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
• Antiarrhythmics: Class I (exceptamiodaroneAmiodaroneAn antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance.Pulmonary Fibrosis),dronedaroneDronedaroneA non-iodinated derivative of amiodarone that is used for the treatment of arrhythmia.Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
• NSAIDsNSAIDSPrimary vs Secondary Headaches: worsen kidney function and fluid retention
• ThiazolidinedionesThiazolidinedionesThiazoles with two keto oxygens. Members are insulin-sensitizing agents which overcome insulin resistance by activation of the peroxisome proliferator activated receptor gamma (ppar-gamma).Non-insulinotropic Diabetes Drugs: cause fluid retention

Device Therapy

• ICD (Implantable CardioverterDefibrillatorDefibrillatorCardiac electrical stimulators that apply brief high-voltage electroshocks to the heart. These stimulators are used to restore normal rhythm and contractile function in hearts of patients who are experiencing ventricular fibrillation or ventricular tachycardia that is not accompanied by a palpable pulse. Some defibrillators may also be used to correct certain noncritical dysrhythmias (called synchronized defibrillation or cardioversion), using relatively low-level discharges synchronized to the patient’s ECG waveform.Cardiac Arrest):
  • Indication:EFEFCardiac Cycle ≤35% + optimal medical therapy ≥3 months +life expectancyLife expectancyBased on known statistical data, the number of years which any person of a given age may reasonably expected to live.Population Pyramids >1 year
  • Primary prevention ofsudden cardiac deathSudden cardiac deathCardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity.Cardiac Arrest
• CRT (Cardiac Resynchronization Therapy):
  • Indication:EFEFCardiac Cycle ≤35% +LBBBLBBBBundle Branch and Fascicular Blocks + QRS ≥150ms + NYHA II-IV
  • BiV pacing improves synchrony
• CardioMEMS:
  • Indication: NYHA III + recenthospitalizationHospitalizationThe confinement of a patient in a hospital.Delirium
  • Emerging evidence for hemodynamic monitoring

Chronic Coronary Syndrome (CCS)

Chronic coronary syndrome (CCS), formerly known as “Stable Angina”, is a chronicischemic heart diseaseIschemic heart diseaseCoronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis.Coronary Heart Disease with predictable angina patterns.

• Pathophysiology:Fixed coronarystenosisStenosisHypoplastic Left Heart Syndrome (HLHS) → supply-demand mismatch

Antianginal Therapy

• First-line:
  • Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers): ↓ HR, ↓ oxygen demand
  • CalciumCalciumA basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Electrolytes channel blockers: coronaryvasodilationVasodilationThe physiological widening of blood vessels by relaxing the underlying vascular smooth muscle.Pulmonary Hypertension Drugs
    • DihydropyridinesDihydropyridinesPyridine moieties which are partially saturated by the addition of two hydrogen atoms in any position.Pulmonary Hypertension Drugs:amlodipineAmlodipineA long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension.Hypertension Drugs (peripheralvasodilationVasodilationThe physiological widening of blood vessels by relaxing the underlying vascular smooth muscle.Pulmonary Hypertension Drugs)
    • Non-dihydropyridines:diltiazemDiltiazemA benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers),verapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs (↓ HR +vasodilationVasodilationThe physiological widening of blood vessels by relaxing the underlying vascular smooth muscle.Pulmonary Hypertension Drugs)
• Second-line:
  • Long-actingnitratesNitratesNitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand.Nitrates:venodilationVenodilationVenous Function, ↓preloadPreloadCardiac Mechanics
  • Ranolazine: late Na+ channel blocker

Cardiovascular Protection

• Mandatory therapy:
  • AspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs): antiplatelet (75-100mg daily)
    • Routine use ofaspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs) is NOT recommended in stablecoronary arteryCoronary ArteryTruncus Arteriosus disease without prior atherosclerotic events.
  • High-intensity statin:plaquePlaquePrimary Skin Lesions stabilization
  • ACE inhibitor: if HTN,DMDMDiabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance.Diabetes Mellitus, or LV dysfunction
• Additional options:
  • ClopidogrelClopidogrelA ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation.Antiplatelet Drugs: ifaspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs) intolerant
  • Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers): post-MI or with HF

Combined Treatment of HF + CCS

Dual-Benefit “Win-Win” Medications

1.ACE InhibitorsACE inhibitorsTruncus Arteriosus/ARBs/ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors

• HF benefit:
  • ↓preloadPreloadCardiac Mechanics/afterloadAfterloadAfterload is the resistance in the aorta that prevents blood from leaving the heart. Afterload represents the pressure the LV needs to overcome to eject blood into the aorta.Cardiac Mechanics
  • Prevent remodeling
  • ReducesmortalityMortalityAll deaths reported in a given population.Measures of Health Status
• CCSCCSCentral cord syndrome (CCS) is a neurological syndrome caused by an injury to the center of the spinal cord, affecting the spinothalamic tracts ((STTs) sensory) and medial aspect of the corticospinal tracts ((CSTs) motor), most often due to trauma in patients with cervical spondylosis.Central Cord Syndrome benefit: provenmortalityMortalityAll deaths reported in a given population.Measures of Health Status benefit post-MI, especially with LV dysfunction
• Choice:ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors (sacubitril/valsartanValsartanA tetrazole derivative and angiotensin II type 1 receptor blocker that is used to treat hypertension.Hypertension Drugs) preferred if HFrEF

2.Beta-BlockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers)

• HF benefit:
  • ↓ SNS activation
  • Prevent arrhythmias
  • ReducesmortalityMortalityAll deaths reported in a given population.Measures of Health Status in HFrEF
• CCSCCSCentral cord syndrome (CCS) is a neurological syndrome caused by an injury to the center of the spinal cord, affecting the spinothalamic tracts ((STTs) sensory) and medial aspect of the corticospinal tracts ((CSTs) motor), most often due to trauma in patients with cervical spondylosis.Central Cord Syndrome benefit:
  • ↓ HR and oxygen demand
  • First-line antianginal therapy
• Choice:CarvedilolCarvedilolA carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction.Class 2 Antiarrhythmic Drugs (Beta Blockers) ormetoprololMetoprololA selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias.Antiadrenergic Drugs succinate (HF-proven formulations)

3.SGLT2 InhibitorsSGLT2 inhibitorsNon-insulinotropic Diabetes Drugs

• HF benefit: reducesmortalityMortalityAll deaths reported in a given population.Measures of Health Status in both HFrEF and HFpEF
• CCSCCSCentral cord syndrome (CCS) is a neurological syndrome caused by an injury to the center of the spinal cord, affecting the spinothalamic tracts ((STTs) sensory) and medial aspect of the corticospinal tracts ((CSTs) motor), most often due to trauma in patients with cervical spondylosis.Central Cord Syndrome benefit: cardiovascular protection, especially if diabetic
• Choice:DapagliflozinDapagliflozinNon-insulinotropic Diabetes Drugs orempagliflozinEmpagliflozinNon-insulinotropic Diabetes Drugs

Emerging Dual-Benefit Options:

• GLP-1GLP-1A peptide of 36 or 37 amino acids that is derived from proglucagon and mainly produced by the intestinal l cells. Glp-1(1-37 or 1-36) is further n-terminally truncated resulting in glp-1(7-37) or glp-1-(7-36) which can be amidated. These glp-1 peptides are known to enhance glucose-dependent insulin release, suppress glucagon release and gastric emptying, lower blood glucose, and reduce food intake.InsulinomasRAsRASRenal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH).Renal Artery Stenosis: emerging evidence for HFpEF +obesityObesityObesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors.Obesity (semaglutide, tirzepatide)

Complete Treatment Plan

• Core Triple Therapy (both conditions):
  • ACE/ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors: start low, uptitrate to maximum tolerated
  • Beta-blocker: target HR 60-70 bpm
  • SGLT2 inhibitor: standard dose
• HF-specific additions:
  • MRAMRAImaging of the Heart and Great Vessels: reducesmortalityMortalityAll deaths reported in a given population.Measures of Health Status in HFrEF
  • Loop diuretic: for volume management (symptom relief only)
• CCS-specific additions:
  • AspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs): 81mg daily (mandatory)
  • High-intensity statin: LDL goal <70 mg/dL
  • Additional antianginals if needed:
    • AmlodipineAmlodipineA long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension.Hypertension Drugs
    • Long-actingnitratesNitratesNitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand.Nitrates
    • Ranolazine

What to AVOID in Combined Disease

• Non-dihydropyridineNon-DihydropyridinePulmonary Hypertension DrugsCCBsCCBsCalcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) (verapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs,diltiazemDiltiazemA benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)): negativeinotropesInotropesHypoplastic Left Heart Syndrome (HLHS)
• NitratesNitratesNitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand.Nitrates + PDE5 inhibitors: severehypotensionHypotensionHypotension is defined as low blood pressure, specifically< 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause.Hypotension
• NSAIDsNSAIDSPrimary vs Secondary Headaches: worsen HF and increaseCVCVVasculitides risk

Key Drug Interactions & Contraindications

Major Interactions:

• ACE + ARB +MRAMRAImaging of the Heart and Great Vessels → SeverehyperkalemiaHyperkalemiaHyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs.Hyperkalemia
• NitratesNitratesNitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand.Nitrates + PDE5 inhibitors → SeverehypotensionHypotensionHypotension is defined as low blood pressure, specifically< 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause.Hypotension
• Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers) +verapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs/diltiazemDiltiazemA benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) → Heart block
• DigoxinDigoxinA cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small.Cardiac Glycosides levels ↑ withverapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs,amiodaroneAmiodaroneAn antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance.Pulmonary Fibrosis, andquinidineQuinidineAn optical isomer of quinine, extracted from the bark of the cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potentials, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)

Monitoring Parameters:

• ACE/ARB/MRAMRAImaging of the Heart and Great Vessels: K+, creatinine (1-2 weeks after initiation)
• DigoxinDigoxinA cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small.Cardiac Glycosides: Level 0.5-2.0 ng/mL, kidney function
• Loop diureticsLoop diureticsLoop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent.Loop Diuretics:ElectrolytesElectrolytesElectrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions.Electrolytes, kidney function
• SGLT2i: A1c if diabetic, genital/urinary symptoms (monitor eGFR)

High-Yield USMLE Pearls

Pharmacology Pearls

• ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors > ACE inhibitor for HFrEFmortalityMortalityAll deaths reported in a given population.Measures of Health Status benefit
• OnlySGLT2 inhibitorsSGLT2 inhibitorsNon-insulinotropic Diabetes Drugs help HFpEFmortalityMortalityAll deaths reported in a given population.Measures of Health Status
• SpironolactoneSpironolactoneA potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects.Potassium-sparing Diuretics causesgynecomastiaGynecomastiaGynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men.Gynecomastia;eplerenoneEplerenoneA spironolactone derivative and selective aldosterone receptor antagonist that is used in the management of hypertension and congestive heart failure, post-myocardial infarction.Potassium-sparing Diuretics doesn’t
• CarvedilolCarvedilolA carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for alpha 1 adrenergic receptors and, at higher doses, may function as a blocker of calcium channels; it also has antioxidant properties. Carvedilol is used in the treatment of hypertension; angina pectoris; and heart failure. It can also reduce the risk of death following myocardial infarction.Class 2 Antiarrhythmic Drugs (Beta Blockers) has additional α-blocking activity
• Loop diureticsLoop diureticsLoop diuretics are a group of diuretic medications primarily used to treat fluid overload in edematous conditions such as heart failure and cirrhosis. Loop diuretics also treat hypertension, but not as a 1st-line agent.Loop Diuretics don’t improvemortalityMortalityAll deaths reported in a given population.Measures of Health Status, just symptoms

Clinical Pearls

• Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers) contraindicated in decompensated HF (use after stabilization)
• Start ACE inhibitor before beta-blocker in HF
• Don’t combine ACE + ARB (no benefit, more side effects)
• Ivabradine only works if LVEF ≤35%, NYHA II–III, HR ≥70 bpm despite max beta-blocker, and insinus rhythmSinus rhythmA heart rate and rhythm driven by the regular firing of the SA node (60–100 beats per minute)Cardiac Physiology.
• Hydralazine/nitratesNitratesNitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand.Nitrates are especially beneficial in BlackpatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship

Side Effect Pearls

• ACE inhibitor cough → Switch to ARB
• HyperkalemiaHyperkalemiaHyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs.Hyperkalemia risk highest with ACE + ARB +MRAMRAImaging of the Heart and Great Vessels combination
• Loop diureticototoxicityOtotoxicityDamage to the ear or its function secondary to exposure to toxic substances such as drugs used in chemotherapy; immunotherapy; or radiation.Glycopeptides: dose-related, usually reversible
• SGLT2i can cause euglycemicDKADKADiabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency.Hyperglycemic Crises

Combined Disease Pearls

• 3 of 4 foundational HF drugs also benefit coronary disease
• Dual-benefit approach reduces pill burden and improves adherence
• AmlodipineAmlodipineA long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension.Hypertension Drugs is the only safe CCB in HFpatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship
• Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers) are first-line for both conditions

Memory Aids

Study Tip:

• Focus on mechanisms, major side effects, andcontraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation for Step 1.
• Emphasize clinical decision-making and drugselectionSelectionLymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen.B cells: Types and Functions for Step 2 CK.
• For patients with both HF and CCS, remember the “Triple Threat” approach using dual-benefit medications first.

HF Management – “SAGE” Approach

• SGLT2 inhibitor
• ACE inhibitor/ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors
• Get a beta-blocker going
• Eplerenone/spironolactoneSpironolactoneA potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects.Potassium-sparing Diuretics

Advanced HF Referral – “I NEED HELP”

• Inotrope dependence
• NYHA Class IV symptoms
• EF <20%
• Escalating diuretic needs
• Defibrillator shocks
• Hospitalizations frequent
• End-organ dysfunction
• Low blood pressure <90
• Prognostic medication intolerance

Combined HF + CCS – “Triple Threat”

Triple Threat = 3 medications that each provide dual benefits forpatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship with both HF and coronary disease, creating a synergistic treatment approach

• ACE/ARNIARNiRenin-Angiotensin-Aldosterone System Inhibitors (both conditions)
• Beta-blocker (both conditions)
• SGLT2 inhibitor (both conditions)
• Then add condition-specific therapies

References

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. https://doi.org/10.1161/CIR.0000000000001063
2. Virani SS, Newby LK, Arnold SV, et al. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. https://doi.org/10.1161/CIR.0000000000001168
3. McDonagh TA, Metra M, Bauersachs J. The 2023 ESC Guidelines for the management of heart failure. Eur Heart J. 2023;44(32):3028-3114. https://doi.org/10.1093/eurheartj/ehad195
4. Maddox TM, Januzzi JL Jr, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2021;77(6):772-810. https://doi.org/10.1016/j.jacc.2020.11.022
5. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2023;81(18):1835-1878. https://doi.org/10.1016/j.jacc.2023.03.393
6. Usman MS, Siddiqi TJ, Anker SD, Bakris GL, Bhatt DL, Filippatos G, Fonarow GC, Greene SJ, Januzzi JL, Khan MS, Kosiborod MN, McGuire DK, Pina IL, Rosenstock J, Vaduganathan M, Verma S, Zieroth S, Butler J. SGLT2 inhibition in heart failure: New mechanistic insights and expanded clinical indications. J Am Coll Cardiol. 2024;83(12):1432-1445. https://www.jacc.org/doi/10.1016/j.jacc.2023.04.034
7. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. https://www.nejm.org/doi/full/10.1056/NEJMoa1911303
8. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477. https://doi.org/10.1093/eurheartj/ehz425
9. Colucci WS, Borlaug BA. (2025). Heart failure: Clinical manifestations and diagnosis in adults. UpToDate. 2024. Retrieved August 2025, fromhttps://www.uptodate.com/contents/heart-failure-clinical-manifestations-and-diagnosis-in-adults
10. Colucci WS. (2024). Overview of the management of heart failure with reduced ejection fraction in adults. UpToDate. Retrieved August 2025, from https://www.uptodate.com/contents/overview-of-the-management-of-heart-failure-with-reduced-ejection-fraction-in-adults
11. Borlaug BA, Colucci WS. (2025). Treatment and prognosis of heart failure with preserved ejection fraction. UpToDate. Retrieved August 2025, from https://www.uptodate.com/contents/treatment-and-prognosis-of-heart-failure-with-preserved-ejection-fraction
12. Mahler SA. (2025). Approach to the patient with suspected angina pectoris. UpToDate. Retrieved August 2025, fromhttps://www.uptodate.com/contents/approach-to-the-patient-with-suspected-angina-pectoris