Heart Failure and Ischemic Disease Quiz

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Questions and Answers

Which of the following signaling pathways is NOT directly involved in reducing heart rate in patients with stable ischemic heart disease (SIHD)?

cAMP/PKA

NO/cGMP/PKG

MLCK and MYPT (correct)

All of the above are involved

What is the primary mechanism by which decreasing heart rate benefits patients with SIHD?

It reduces myocardial oxygen demand, thus decreasing the risk of ischemia (correct)

It prevents arrhythmias by increasing the time interval between heart beats

It directly improves coronary blood flow by increasing diastolic filling time

It promotes the formation of new blood vessels, improving blood flow to the heart

Which of the following accurately describes the difference between verapamil and nifedipine in the management of SIHD?

Nifedipine has a greater effect on reducing heart rate compared to verapamil

Verapamil has a greater effect on reducing heart rate compared to nifedipine

Nifedipine primarily targets vascular smooth muscle, while verapamil acts on both vascular smooth muscle and the heart (correct)

Nifedipine preferentially dilates veins, while verapamil preferentially dilates arteries

Which of the following is a key mechanism by which diuretics benefit patients with congestive heart failure (CHF)?

Decreasing preload by reducing blood volume, which helps to reduce the workload on the heart (B) Signup and view all the answers

Which of the following accurately describes the role of aldosterone in heart failure?

Aldosterone promotes sodium retention in the kidneys, leading to fluid retention and increased blood volume, which worsens heart failure (B) Signup and view all the answers

Why are beta-agonists not suitable for long-term treatment of heart failure?

Long-term beta-agonist use leads to desensitization of beta receptors, rendering them less effective over time (B) Signup and view all the answers

Which of the following describes a key mechanism by which natriuretic peptides (ANP, BNP) exert their beneficial effects in heart failure?

Natriuretic peptides activate cGMP signaling, which counteracts the detrimental effects of vasoconstriction and fibrosis (A) Signup and view all the answers

Which signaling pathway is directly involved in mediating the beneficial effects of natriuretic peptides in heart failure?

NO/cGMP/PKG (D) Signup and view all the answers

Which of the following drug classes directly reduces preload in patients with heart failure?

Loop diuretics (D) Signup and view all the answers

Which of the following medications acts primarily by inhibiting the breakdown of natriuretic peptides?

Vericiguat (B) Signup and view all the answers

The mechanism by which beta-blockers improve symptoms in patients with heart failure is primarily attributed to:

Inhibition of renin-angiotensin-aldosterone system (RAAS), reducing myocardial remodeling. (C) Signup and view all the answers

Which of the following drug classes is most likely to improve diastolic function in patients with heart failure with preserved ejection fraction (HFpEF)?

Calcium channel blockers (B) Signup and view all the answers

Which of the following b-blockers has a half-life that is significantly longer than the others, making it suitable for once-daily dosing?

Bisoprolol (A) Signup and view all the answers

Which of the following drug classes is commonly used to treat heart failure with reduced ejection fraction (HFrEF) and works by increasing cGMP levels, resulting in vasodilation?

Hydralazine/nitrates (C) Signup and view all the answers

What is the primary mechanism by which b-blockers improve heart failure?

Blocking the effects of the sympathetic nervous system to reduce remodeling (A) Signup and view all the answers

Which of the following medications would be considered a positive inotrope, increasing myocardial contractility?

Digoxin (D) Signup and view all the answers

Which of the following is NOT a common therapeutic effect of b-blockers in heart failure?

Increasing heart rate to improve cardiac output (B) Signup and view all the answers

Which of the following drug classes directly inhibits the enzyme neprilysin?

ARNIs (B) Signup and view all the answers

Which of the following drug classes primarily targets the sodium-glucose cotransporter 2 (SGLT2), resulting in glucose excretion and reduced blood volume?

SGLT2 inhibitors (A) Signup and view all the answers

Which of the following b-blockers has a unique mechanism of action that involves nitric oxide (NO) release, potentially providing additional benefits beyond b-blockade?

Nebivolol (A) Signup and view all the answers

Which of the following statements about the use of b-blockers in heart failure is TRUE?

b-blockers should be initiated at low doses and gradually increased to avoid adverse effects (C) Signup and view all the answers

Which of the following is a potential mechanistic explanation for the beneficial effects of SGLT2 inhibitors in heart failure?

Improving renal function and reducing preload/afterload (C) Signup and view all the answers

What is the primary mechanism of action of SGLT2 inhibitors?

Inhibiting the reuptake of glucose in the kidneys (B) Signup and view all the answers

Which of the following is a common adverse effect associated with the use of b-blockers in patients with heart failure?

Hypotension (A) Signup and view all the answers

Study Notes

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

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Description

Test your knowledge on signaling pathways involved in heart rate regulation, mechanisms benefiting patients with stable ischemic heart disease (SIHD) and congestive heart failure (CHF). This quiz covers pharmacological differences, the role of hormones, and beneficial effects of peptides in heart failure management.