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Questions and Answers
What is the primary function of the sarco-endoplasmic reticulum calcium ATPase (SERCA) in cardiac cells?
What is the primary function of the sarco-endoplasmic reticulum calcium ATPase (SERCA) in cardiac cells?
- To facilitate troponin activation for muscle contraction
- To promote calcium release from the sarcoplasmic reticulum
- To sequester calcium back into the sarcoplasmic reticulum (correct)
- To increase calcium influx from extracellular space
How does sympathetic stimulation affect the L type calcium channels?
How does sympathetic stimulation affect the L type calcium channels?
- It inhibits their function, decreasing calcium influx
- It phosphorylates other proteins to decrease channel activity
- It phosphorylates them, increasing calcium current (correct)
- It has no effect on their activation
What role does Protein Kinase A (PKA) play in cardiac muscle contraction?
What role does Protein Kinase A (PKA) play in cardiac muscle contraction?
- It directly induces muscle contraction by activating Troponin C
- It promotes the opening of potassium channels
- It reduces intracellular cAMP levels
- It phosphorylates phospholamban, enhancing calcium reuptake (correct)
What effect does calcium-induced calcium release (CICR) have on muscle contraction?
What effect does calcium-induced calcium release (CICR) have on muscle contraction?
What is the effect of phosphorylation of Troponin I in cardiac muscle?
What is the effect of phosphorylation of Troponin I in cardiac muscle?
What influences the conduction velocity of action potentials in the heart?
What influences the conduction velocity of action potentials in the heart?
What physiological effect is primarily achieved through sympathetic stimulation in the heart?
What physiological effect is primarily achieved through sympathetic stimulation in the heart?
Which mechanism is responsible for the extruding calcium from the cardiac cell?
Which mechanism is responsible for the extruding calcium from the cardiac cell?
What effect does the phosphorylation of Troponin I have on myocyte relaxation?
What effect does the phosphorylation of Troponin I have on myocyte relaxation?
Which of the following β-adrenergic agonists is selective for the β1 subtype?
Which of the following β-adrenergic agonists is selective for the β1 subtype?
What is the primary function of phosphodiesterases (PDEs) in cardiac myocytes?
What is the primary function of phosphodiesterases (PDEs) in cardiac myocytes?
What is a negative effect of non-selective β-adrenergic blockers such as propranolol?
What is a negative effect of non-selective β-adrenergic blockers such as propranolol?
Which drug is used to inhibit PDE3 and enhance cardiac contractility?
Which drug is used to inhibit PDE3 and enhance cardiac contractility?
What is the primary effect of calcium channel blockers like Verapamil and Diltiazem on cardiac myocytes?
What is the primary effect of calcium channel blockers like Verapamil and Diltiazem on cardiac myocytes?
Which of the following statements about PDE3 is correct?
Which of the following statements about PDE3 is correct?
What is the mechanism by which adrenergic agonists affect heart function?
What is the mechanism by which adrenergic agonists affect heart function?
What is the primary reason Digoxin can lead to toxicity at low serum concentrations?
What is the primary reason Digoxin can lead to toxicity at low serum concentrations?
What effect does hypokalemia have on Digoxin's potency and toxicity?
What effect does hypokalemia have on Digoxin's potency and toxicity?
Which of the following best describes the role of NCX in the context of delayed afterdepolarizations?
Which of the following best describes the role of NCX in the context of delayed afterdepolarizations?
What limitation is commonly associated with drugs that mobilize intracellular calcium?
What limitation is commonly associated with drugs that mobilize intracellular calcium?
What mechanism does Pimovendan utilize to affect cardiac myofilaments?
What mechanism does Pimovendan utilize to affect cardiac myofilaments?
Why was the development of Pimovendan in the US discontinued?
Why was the development of Pimovendan in the US discontinued?
Which drug increases cardiac contractility by binding to troponin C?
Which drug increases cardiac contractility by binding to troponin C?
What is a common consequence of calcium release from the sarcoplasmic reticulum when Digoxin is present?
What is a common consequence of calcium release from the sarcoplasmic reticulum when Digoxin is present?
What is the primary aim of heart failure therapy in relation to pathological remodeling?
What is the primary aim of heart failure therapy in relation to pathological remodeling?
Which of the following drug classes is NOT indicated for the treatment of heart failure with reduced ejection fraction (HFrEF)?
Which of the following drug classes is NOT indicated for the treatment of heart failure with reduced ejection fraction (HFrEF)?
What mechanism is primarily targeted by Angiotensin Receptor Blockers (ARBs) in heart failure treatment?
What mechanism is primarily targeted by Angiotensin Receptor Blockers (ARBs) in heart failure treatment?
SGLT2 inhibitors have shown effectiveness in treating heart failure independent of what specific condition?
SGLT2 inhibitors have shown effectiveness in treating heart failure independent of what specific condition?
Which combination of treatments is highlighted for its potential effectiveness in heart failure therapy?
Which combination of treatments is highlighted for its potential effectiveness in heart failure therapy?
What role do Mineralocorticoid Receptor Antagonists (MRAs) play in heart failure management?
What role do Mineralocorticoid Receptor Antagonists (MRAs) play in heart failure management?
Which aspect of heart failure does ongoing activation of historical compensatory mechanisms lead to?
Which aspect of heart failure does ongoing activation of historical compensatory mechanisms lead to?
Which drug class is specifically recommended for the treatment of heart failure with preserved ejection fraction (HFpEF)?
Which drug class is specifically recommended for the treatment of heart failure with preserved ejection fraction (HFpEF)?
What role does calcium play beyond being a charge carrying ion in the heart?
What role does calcium play beyond being a charge carrying ion in the heart?
What is the primary mechanism by which sympathetic stimulation affects cardiac function?
What is the primary mechanism by which sympathetic stimulation affects cardiac function?
Which class of drugs is primarily used to block calcium channels in the heart?
Which class of drugs is primarily used to block calcium channels in the heart?
What is the significance of the T tubules in cardiac contractions?
What is the significance of the T tubules in cardiac contractions?
How do cardiac glycosides function in the regulation of heart function?
How do cardiac glycosides function in the regulation of heart function?
What is the primary mechanism through which calcium sensitizers affect cardiac contractility?
What is the primary mechanism through which calcium sensitizers affect cardiac contractility?
Which phase of the cardiac action potential is primarily responsible for calcium influx?
Which phase of the cardiac action potential is primarily responsible for calcium influx?
In the context of heart failure, what is a critical pharmacological goal?
In the context of heart failure, what is a critical pharmacological goal?
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Study Notes
Introduction
- Cardiac action potential and contractility are important for treating heart failure.
Excitation-Contraction Coupling in the Heart
- Calcium influx during phases 2 and 3 of the cardiac action potential is crucial.
- Calcium acts as a second messenger linking membrane depolarization to contraction.
- L-type calcium channels are activated by action potentials, triggering calcium release from the sarcoplasmic reticulum (SR).
- Calcium-induced calcium release (CICR) leads to a transient increase in intracellular calcium, activating troponin C and initiating muscle contraction.
- Calcium is returned to the SR by SERCA (sarco-endoplasmic reticulum calcium ATPase) and extruded from the cell by NCX (sodium-calcium exchange pump).
Sympathetic Regulation of Cardiac Calcium Channels
- Sympathetic stimulation increases heart contractility (inotropic effect) and heart rate (chronotropic effect).
- Sympathetic stimulation activates β-adrenergic receptors.
- β-adrenergic receptors act via Gs and adenylate cyclase to increase intracellular cAMP.
- cAMP activates Protein Kinase A (PKA) which phosphorylates L-type calcium channels leading to:
- Increased calcium current.
- Increased rate of rise of the action potential.
- Increased conduction velocity of the action potential.
- PKA also phosphorylates phospholamban and troponin I, increasing the rate of relaxation of the myocytes, further supporting the increased heart rate.
Pharmacological Regulation of Heart Function
- Adrenergic Mechanisms:
- Beta-adrenergic agonists (e.g., isoproterenol, dobutamine) increase both heart rate and contractility.
- Beta-adrenergic blockers (e.g., propranolol, atenolol, metoprolol) decrease both heart rate and contractility.
- PDE3 inhibitors (e.g., milrinone) potentiate downstream beta receptor stimulation, regulating heart rate and contractility.
Calcium Channel Blockers
- Calcium channel blockers target L-type calcium channels on the plasma membrane.
- Examples include: Verapamil, Diltiazem, and dihydropyridines (e.g. Nifedipine, Amlodipine)
- Effects:
- Reduce calcium influx, thus limiting the force of contraction.
- Reduce the duration of the action potential.
Cardiac Glycosides
- Cardiac glycosides (e.g., digoxin) inhibit the Na+/K+ ATPase.
- Digoxin binds to the potassium binding site, increasing its potency in cases of hypokalemia.
- Cardiac glycosides can cause delayed afterdepolarizations (DADs) and triggered arrhythmias by overfilling the SR with calcium and activating NCX.
Beyond Calcium
- Calcium sensitizers potentiate the effect of calcium on the contractile apparatus.
- Examples include:
- Pimobendan: inhibits PDE3 and sensitizes cardiac myofilaments to intracellular calcium, but is associated with increased mortality.
- Levosimendan: increases cardiac contractility by binding troponin C and activating KATP channels.
Treatment of Heart Failure
- Heart failure treatment primarily focuses on:
- Blocking pathological remodeling.
- Targeting the vasculature and kidneys.
- Major drug classes:
- ACE inhibitors
- ARBs
- ARNi (ARB + neprilysin inhibitor)
- Beta Blockers
- MRAs
- SGLT2 inhibitors
- SGLT2 inhibitors are effective for both HFrEF and HFpEF and are recommended in AHA guidelines.
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