Heart Failure and Ischemic Disease Quiz

Chronic Heart Failure (CHF)

• CHF is a progressive clinical syndrome resulting from any change in cardiac structure or function impairing ventricular filling or ejection of blood.

Outline

• Background: Physiology of heart function
• HF Pathophysiology:
  • HFrEF (systolic dysfunction) and HFpEF (diastolic dysfunction)
  • Hemodynamics (preload, afterload, and contractility)
  • Neurohormonal hypotheses (SNS/RAAS hypertrophy/fibrosis)
  • Compensatory responses
• Drugs to treat HF:
  • Beta-blockers
  • ACE inhibitors/ARBs
  • ARNI (Angiotensin Receptor-Neprilysin Inhibitor)
  • SGLT2 inhibitors
  • Vericiguat
  • MRA loop diuretics (e.g., spironolactone, eplerenone)
  • Hydralazine/Nitrates
  • Inotropes

Cardiac Function

• Cardiac output (CO) = Heart rate (HR) x Stroke volume (SV)
• Stroke volume (SV) is influenced by preload, afterload, and contractility.

Ejection Fraction (EF)

• EF = (Amount of blood pumped out/ Amount of blood in chamber) * 100
• Normal EF: 50-70%
• Borderline EF: 41-49%
• Reduced EF: <40%

Symptoms of HF

• Fatigue
• Dizziness
• Muscle weakness/exercise intolerance
• Shortness of breath
• Pulmonary edema (fluid in lungs)
• Peripheral edema (swelling)
• Ascites (fluid in abdominal cavity)

Types of HF

• HFrEF (systolic dysfunction): reduced ejection fraction
• HFpEF (diastolic dysfunction): preserved ejection fraction

HFrEF (Systolic Dysfunction)

• Reduced contractility results in reduced stroke volume (SV) and ejection fraction (EF).
• End-diastolic volume (EDV) is increased.

HFpEF (Diastolic Dysfunction)

• Lower stroke volume (SV) leading to lower cardiac output (CO).
• Ejection fraction (EF) is normal due to reduced end-diastolic volume (EDV).
• EF = SV/EDV

HFrEF and HFpEF Comparison

• Both have reduced cardiac output (CO).
• Differ in hemodynamics and cardiac remodeling

HFrEF and Frank-Starling Mechanism

• Impaired contractile function of the myocardium.
• Reduced cardiac output (CO) for given preload/pressure.

HFpEF and Increased Diastolic Pressure

• Stiff ventricles and/or impaired relaxation signaling function.
• Increased left ventricular end-diastolic pressure (LVEDP) for a given volume.
• Reduced left ventricular end-diastolic volume (LVEDV) and stroke volume (SV).

Pressure-Volume Loops

• Diagrams illustrating ventricular pressure and volume changes during the cardiac cycle.

PV loops in Heart Failure

• Diagrams illustrating differences between normal, HFrEF, and HFpEF in pressure-volume loops, impacting stroke volume and cardiac output.

Summary of Pressure-Volume Changes in HF

• Differences in pressure-volume loops for HFrEF and HFpEF (summarized table).

Vasodilation and HF

• Vasodilation reduces afterload.
• In HF, decreased stroke volume (SV) for a given afterload.
• decreasing afterload increased the amount able to be pumped out at a given force
• Increased cardiac output (CO).

Causes of HFrEF

• Structural abnormalities (previous MI, CAD)
• Diabetes
• Metabolic syndrome
• Lipids (dyslipidemia)
• Inflammation
• O2 disruption
• Hypertension
• Genetic cardiomyopathies
• Myocardial damage/toxicity

Causes of HFpEF

• Obesity
• Hypertension
• Coronary artery disease (CAD)
• Diabetes
• Metabolic syndrome
• Kidney disease
• Chronic obstructive pulmonary disease (COPD)
• Sleep apnea
• Anemia

Neurohormonal Hypothesis of CHF

• CHF is a progressive disease.
• Compensatory mechanisms to increase cardiac output, causing initial injury and structural/signaling alterations.
• Low CO elicits reflex response and increased SNS and RAAS activation.
• Results in remodeling and progressively declining function.

Progressive Injury in HF

• Chronic activation of hemodynamic and neurohormonal compensatory responses leads to cardiac hypertrophy, alterations in extracellular matrix, myocyte loss, and ventricular remodeling.

Different Stages of Heart Failure

• Stages of heart failure outlined (A-D), including symptoms and treatment strategies.

Two Major Classifications of CHF

• HFrEF - reduced EF and stroke volume
• HFpEF - preserved EF, lower SV and lower ventricular volume, high pressures

Myocardial Hypertrophy

• Abnormal growth of cardiomyocytes.
• Not proliferation, but cellular growth in response to stress or strain

Fibrosis and Cardiac Remodeling

• Fibrosis is a major component of cardiac remodeling, adding stiffness and reducing contractile function.
• Fibrotic molecules promote fibrosis.
• Fibrotic hearts are stiffer

Cardiac Fibroblasts

• Drive myocardial fibrosis

Hypertrophy and Fibrosis

• Mechanisms of hypertrophy and fibrosis (multi-stage process)

Complex Interplay Mediating Fibrosis

• Pro-fibrotic signals and mediators:
• TGF/CTGF
• Inflammatory cytokines
• Growth factors (ET-1, Ang II)

Pathological Hypertrophy and Fibrosis Signaling

• Various pathways and mediators involved in pathological hypertrophy and fibrosis in the heart caused by:
  • Angiotensin II
  • Adrenergic signals
  • Mechanical forces
• Natriuretic peptides as opposing forces

Angiotensin II

• Potent vasoconstrictor (increase renal pressures)
• Stimulates aldosterone release (fluid retention)
• Direct effects on cardiomyocytes and fibroblasts (leading to hypertrophy and fibrosis)
• Enhances SNS activity

ACEi/ATRB

• Block angiotensin converting enzyme (ACE)
• Block angiotensin receptor (AT1-receptor blocking)
• Have similar effects, except with bradykinin (dilator) formation

Summary: ACEi in HF

• Major benefits include:
  • Decreased vasoconstriction, limiting afterload, and improving CO
  • Limit cardiac hypertrophy and re-modeling
  • Stimulation of SNS activity
  • Limit cardiac fibroblast proliferation, and improved mechanical function
  • Lowering of blood volume and Na excretion
  • Lowering of aldosterone and SNS activity

Aldosterone and HF

• Part of the RAAS System.
• Even with ACEi, mechanisms remain to make aldosterone.
• Aldosterone enhances fibrosis (myocardial, renal, vascular).

Aldosterone and Fibrosis

• Aldosterone binds to Mineralocorticoid receptor (MR), which can be a transcriptional or non-transcriptional regulator.
• Non-transcriptional effects can increase ROS and fibrosis.

Summary: MRA

• Spironolactone and eplerenone are used for improved survival in HFrEF
• K+ sparing diuretic
• Reduced volume and decrease afterload
• Limit fibrosis and remodeling in cardiac cells

ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

• Entresto (sacubitril/valsartan)
• Newer drug that exerts many benefits through elevation of natriuretic peptides (ANP, BNP)
• Demonstrated improved survival over enalapril in HFrEF

Neprilysin

• Ectoenzyme that degrades numerous vasoactive peptides.
• Breaks down Natriuretic Peptides (ANP, BNP) and others

Natriuretic Peptides

• Released in response to stretch (expansion of the heart).
• Decrease blood volume and Na (natriuresis).
• Direct vasodilator
• Protect against cardiac remodeling through the NP receptor pathway

NP Receptors and Vessels

• NPRA, NPRB, and NPRC receptors.
• cGMP activates PKG signaling
• Promotes vasodilation and is anti-fibrotic and anti-hypertrophic

Major Anti-fibrotic Effects of ANP/BNP

• Increased cGMP.
• NP-R's activation of PGC in fibroblasts/myocytes to reduce fibrosis
• Also are vasodilatory through PGC and PKG.

Vericiguat (sGC)

• Soluble guanylate cyclase activator.
• Demonstrated to improve survival in patients with HFrEF through cGMP production

Beta-Blockers and HF

• Used in settings where the heart is lowered.
• Decrease in cardiac contractility and heart rate, resulting in reduced CO consumption
• Block of Beta-adrenergic receptors (BARs).
• Chronic increased HR and contractility due to SNS overactivation may lead to pathological remodeling of the heart.
• Beta blockers can limit fibrosis.

Beta-Blocker Inhibition and HF

• Β-blockers reduce ventricular cardiomyocyte contraction and slow HR through SA Node.
• Chronic increased HR and contractility due to SNS overactivation can lead to pathological remodeling and cell death.

B-AR and Additional Cascades in Promoting Hypertrophy/Fibrosis

• Other additional cascades promote hypertrophy and fibrosis.
• Some are regulated by PKA in the heart.

B-blockers and Heart Failure

• Different Beta-blockers have varied half-lives.
• Important considerations like selective vs. non-selective B-blockers (1 vs. 1 and 2 receptors)

B-blockers

• Should be initiated at low doses and gradually titrated.
• Acute inotropic effects (reduced CO) and hypotension are initial concerns.

SGLT2 Inhibitors

• Reduce hyperglycemia.
• Several beneficial non-SGLT2 effects to improve function, like reduction blood volume leading to preload/afterload decrease.

Loop Diuretics

• Inhibit the Na+, K+, 2Cl− symporter in ascending loop of Henle.
• Increase K+ excretion leading to hypokalemia.
• Decrease preload and volume retention.

Nitrates/Hydralazine

• Pure vasodilators.
• ISDN and hydralazine combination to decrease preload, increase efficacy, and reduce tolerance.
• Nitrates are often used with hydralazine as a dual-therapy

Inotropes and HF

• Not commonly used routinely, only in specific settings where compromised CO is an concern.
• Digoxin inhibits Na+/K+ ATPase to increase intra-cellular Ca++.
• Elevated intra-cellular Ca++ via NCX

Additional Inotropes (Omecamtiv mecarbil)

• Novel myosin activator
• Tested and being used to improve cardiac contractions without modulating cellular Ca++.
• Promotes interaction between myosin and actin for greater force generation.
• Goal: contraction without other negative signaling consequences

Summary: Therapeutic Effects of B-Blockers

• Reverse or halt LV remodeling
• Decrease hypertrophy/improve LV shape (sphericity) and mass
• Reduce myocyte apoptosis/necrosis
• Increase EF
• Limit renin release - reduce volume retention
• Lower BP and afterload (especially carvedilol)

SGLT2 Summary

• Multiple effects on cardiomyocytes:
  • Decrease fibrosis
  • Normalize cardiomyocyte Ca++ handling
  • Improve cardiac mitochondrial function
  • improved BP and vasodilation

Loop Diuretic Summary

• Decrease volume retention.
• Decrease preload/afterload and improve overall CO.
• Often utilized with K+ sparing diuretics.
• Concern for hypokalemia (since it removes Na+, K+, and Ca++).

Summary - ATTR - Cardiac Amyloidopathy

• Similar presentation to HFpEF, with misfolded proteins (TTR) in myocardium.
• TTR is normally a circulating tetramer, but misfolding leads to deposition and dysfunction
• Tafamadis (stabilizes TTR and reduces amyloid deposition) can be a treatment

Practice Questions and Answers

• Included questions regarding various topics (SIHD, CHF) and their answers

Overview of mechanisms of Chronic Heart Failure and Treatments

• Diagram showing the major impacts of Chronic Heart Failure and treatments to counter the negative effects on cardiac output, pressure, and vascular function