Annette barret HF/AFIB Flashcards
Explain the pathophysiology of dyspnoea (SOB) in heart failure
(1) Pulmonary congestion causes increased hydrostatic pressure within the pulmonary vasculature, resulting in fluid extravasation and leading to pulmonary edema. The accumulation of fluid can dilute surfactant, increasing alveolar surface tension and reducing lung compliance, which increases the work of breathing and can precipitate dyspnea.
(2) Pulmonary edema can activate J receptors in the alveolar walls, which propagate an action potential to the brain via the vagus nerve. This stimulation of the respiratory centers increases the breathing rate, contributing to the sensation of dyspnea.
(3) Pulmonary edema increases the diffusion distance for oxygen between the alveoli and pulmonary capillaries, leading to arterial hypoxemia. This hypoxemia can trigger pulmonary vasoconstriction and physiological shunting, further exacerbating the problem. Additionally, the hypoxemia (reduced paO2) stimulates peripheral chemoreceptors in the carotid and aortic bodies, which increases respiratory rate via the vagus and glossopharyngeal nerve travelling to the medulla and pons.
explain what is meant by “compensated” heart failure
Compensated heart failure refers to a state in which the heart, despite some dysfunction (e.g., weakened pump function), is able to maintain near-normal cardiac output at rest through various compensatory mechanisms.
These mechanisms include:
Frank-Starling mechanism: The heart increases preload (end-diastolic volume, EDV), which stretches the myocardial fibers, leading to stronger contractions and increased stroke volume (SV), as per the Frank-Starling law.
Neurohormonal activation: Systems like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) increase heart rate, contractility, and blood pressure to maintain CO.
Cardiac remodeling: Structural changes, such as eccentric hypertrophy (dilation with added sarcomeres in series), allow the heart to accommodate a larger blood volume
explain what is meant by “decompensated” heart failure
Decompensated heart failure occurs when the compensatory mechanisms are no longer sufficient to maintain adequate cardiac output, leading to worsening symptoms like fluid retention (congestion), dyspnea, and fatigue.
Contributing factors include:
Increased oxygen demand and inefficiency: Over time, the compensatory mechanisms (e.g., hypertrophy, neurohormonal activation) increase the metabolic demands of the heart muscle, leading to a mismatch between oxygen supply and demand.
Progressive cardiac dysfunction: The heart becomes less responsive to preload, meaning that the Frank-Starling mechanism no longer works effectively, and increased preload may lead to pulmonary and systemic congestion.
Ischemia: In some cases, increased oxygen demand can lead to ischemic damage, further impairing contractility. However, ischemia is not always the cause of decompensation.
Neurohormonal overload: Chronic activation of systems like the SNS and RAAS can lead to adverse effects, including increased afterload (pressure the heart must pump against) and harmful remodeling, further decreasing cardiac output.
list 3 adaptations seen in HF to try maintain CO
- Frank-starling mechanism - increasing preload and EDV
- Neurohormonal activation
-> SNS release of norepinephrine (increase HR, contractility and PVR)
-> RAAS to increase vascular tone (ANG II) and offset “perceived hypovolemia” and hypoperfusion of tissues and organs.
-> ANP to mediate the effects of RAAS through diuresis. - Concentric of Eccentric hypertrophy
- Eccentric hypertrophy to to accommodate greater volumes (preload). Initially, this helps increase stroke volume, but it can lead to maladaptive changes, including dilation of the left ventricle and fluid overload, worsening heart failure.
-Concentric hypertrophy to try combat pressure overload/increases in afterload: Over time, concentric hypertrophy can reduce ventricular compliance, leading to diastolic dysfunction, reduced preload, and worsening cardiac output.
what are the 3 phenotypes of cardiomyopathies
Cardiomyopathies are diseases intrinsic to the cardiac muscle itself.
- Dilated cardiomyopathies: due to alcoholism, toxin exposure, pregnancy, mutations in cytoskeleton proteins -> causes systolic HF
- Hypertrophic cardiomyopathies: mutations in contractile proteins particularly Beta-myosin heavy chains -> causes diastolic HF
- Restrictive cardiomyopathies: amyloid deposition, interstitial fibrosis due to radiation, endomyocardial scarring.
Explain how the laplace equation is effected in systolic heart failure
The Laplace equation states that tension in the muscle wall = (pressure in the chamber x radius) / wall thickness.
In systolic heart failure, there is reduced contractility of the heart muscle cells, which may have undergone eccentric hypertrophy to compensate for increased end-diastolic volume (EDV), or preload. Eccentric hypertrophy involves the dilation of the ventricular chamber, leading to an increase in its radius.
However, according to the Laplace equation, an increase in the chamber radius (as seen in eccentric hypertrophy) means that the wall tension must also increase in order to generate enough force during contraction to expel the blood.
As tension increases, the stress on the muscle wall also rises, since stress = tension / wall thickness. Stress is further increased due to ventricular wall thinning. To manage the increased pressure within the ventricle, the heart muscle requires more oxygen to maintain function. However, in heart failure, this oxygen demand cannot be adequately met.
This mismatch between oxygen supply and demand leads to further myocyte dysfunction, a continued loss of contractility, and progressive thinning of the ventricular wall. Ultimately, this cycle exacerbates systolic heart failure, as the heart’s ability to pump blood efficiently continues to decline.
why must potassium levels be monitored when on digoxin?
Hypokalemia can increase the effects of digoxin on the heart, resulting in digoxin toxicity and arrhythmias.
Digoxin is a cardiac glycoside which works by partially inhibiting the Na+/K+ ATPase pump on the myocyte, which increases intracellular sodium concentrations. This, in turn, reduces the activity of the Na+/Ca2+ exchanger, leading to more calcium being retained in the cell and in the sarcoplasmic reticulum (SR), promoting stronger contractile forces. Therefore, when plasma potassium concentrations are reduced, there is less potassium available extracellularly for normal Na+/K+ ATPase activity. This enhancement of digoxin’s effects on the intracellular environment can lead to an increased risk of arrhythmias
This is particularly important to consider if a patient is on diuretics which are not “potassium-sparing” as they increase potassium secretion.
mechanism of action and 2 ADRS of Ivabradine
Ivabradine is a selective inhibitor of the funny current of the SA node, which is carried primarily by sodium ions (with a smaller contribution from potassium) through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
It works to slow the heart rate by binding to the HCN channels, thereby reducing the inward flow of sodium into the pacemaker cells of the SA node. This action slows the rate of depolarization toward the threshold potential, thereby increasing the time between successive action potentials and reducing the heart rate
ADRs:
Bradycardia and AVN heart block
Luminous phenomena by blocking retinal currents which involve channels very similar to funny sodium channels.
Patients must have a heart rate > 70BPM to get ivabradine.
MOA of ARNI’s
Angiotensin II receptor Neprilysin inhibitors contain valsartan and sacubitril.
Valsartan blocks the angiotensin II receptor (AT 1) thereby preventing downstream effects of angiotensin II including vasoconstriction, sodium and water reabsorption, aldosterone and ADH release, and ventricular remodelling.
Sacubitril works by inhibiting neprilysin, the enzyme responsible for the degradation of natriuretic peptides ANP, BNP, CNP. By preventing their breakdown it prolongs their effects within the body such as: vasodilation, renin and aldosterone inhibition, natriuresis and diuresis, anti-hypertrophic and anti-fibrotic effects.
ADRs:
Hypotension
Hyperkalemia
Renal impairement
Angioedema
How do beta blockers help in heart failure?
(1) Inhibition of Sympathetic Overactivation:
Beta-blockers reduce the harmful effects of chronic catecholamine stimulation by blocking beta-1 receptors, slowing disease progression and reducing myocardial stress.
(2) Reduction in Heart Rate and Oxygen Demand:
By lowering heart rate and contractility, beta-blockers decrease oxygen consumption and improve diastolic filling, enhancing overall cardiac efficiency.
(3) Prevention of Ventricular Remodeling:
Beta-blockers help reverse or limit adverse structural changes in the heart, leading to improved ejection fraction and better left ventricular function.
(4) Reduction of Arrhythmias and Sudden Death:
Beta-blockers stabilize cardiac electrical activity, reducing the risk of life-threatening arrhythmias and sudden cardiac death.
(5) Additional Benefits of Carvedilol:
Carvedilol, with alpha-1 blocking effects, reduces afterload via vasodilation, further improving cardiac output and hemodynamics.
(6) Beta 1 blockade in the JGA can inhibit renin release and subsequent fluid overload via RAAS
What class of drug is digoxin? What are its 2 mechanisms by which it is useful in HFrEF?
Digoxin in a cardiac glycoside
Beneficial effects
(1) It increases myocyte contractility without increasing the hearts oxygen consumption
(2) It slows the HR by increasing vagal tone of the heart by an unknown mechanism.
MOA:
-Increases calcium (and sodium) concentrations within the myocyte by reducing the driving force behind the Na+/Ca2+ exchanger.
-It inhibits the Na+/K+ ATPase pump on the myocyte thereby maintaining a high intracellular Na+ concentration.
-This reduces the driving force behind the Na+/Calcium exchanger which normally passively exchanges both ions as sodium diffuses back into the cell having been pumped out by the ATPase pump.
outline the synthesis and degradation of BNP
Synthesis
-Produced in the ventricles in response to increased wall stress (e.g., heart failure).
-NPPB gene encodes pre-proBNP (134 amino acids).
-Pre-proBNP is cleaved to proBNP (108 amino acids) in the endoplasmic reticulum, by Corin enzyme.
-ProBNP is split into:
Active BNP-32 (32 amino acids) – biologically active.
NT-proBNP (76 amino acids) – inactive diagnostic marker.
Degradation
-Neprilysin (NEP): Cleaves BNP into inactive fragments.
-NPR-C Receptors: Mediate cellular uptake and degradation.
-Renal Excretion: BNP and NT-proBNP cleared by the kidneys.
Describe the MOA of exogenous nitrates
- converted to nitric oxide in the body.
- NO activates guanylyl cyclase which increases cGMP production.
- cGMP activates protein kinase G
- Protein kinase G decreases calcium influx into smooth muscle cell and increases storage of calcium in sarcoplasmic reticulum
- This results in smooth muscle relaxation
Exogenous nitrates mostly cause venous dilation at low doses, this reduces preload and oxygen demand on the heart which reduces ischemic pain.
Higher doses can act on aterioles thereby reducing afterload and reducing oxygen demand
They can also improve oxygen supply to myocardium by dilating coronary arteries.
in HF isosorbide dinitrate is typically used with hydralazine which predominantly dilates arterioles
isosorbide dinitrate –> isosorbite mononitrate (given orally or IV)
Explain the MOA of Empagliflozin and Dapagliflozin in HF
These are SGLT-2 inhibitors which block this sodium-glucose transporter on the apical surface of the PCT epithelial cells.
This causes glycosuria and natriuresis as well as osmotic diuresis.
The overall result is reduced blood volume which reduces preload, afterload and pulmonary congestion.
These drugs may also improve heart health by reducing oxidative stress and epicardial fat.
Describe the MOA of spirnolactone/Elperenone in HFrEF
Reduction of Sodium and Water Retention:
Spironolactone blocks the cytoplasmic mineralocorticoid receptor, thereby preventing binding of aldosterone preventing its downstream effects, particuarly sodium + water reabsorption in the collecting duct (and K+ secretion) through expression of ENAC channels and Na+/K+ ATPase pumps in the principal cells.
This alleviates volume overload, decreases preload, and helps control congestion in HFrEF patients.
Potassium Preservation:
By inhibiting potassium excretion in the kidney, spironolactone acts as a potassium-sparing diuretic, countering hypokalemia often caused by other diuretics like loop or thiazide diuretics. This effect is critical in maintaining electrolyte balance and reducing arrhythmia risk.
Prevention of Myocardial Fibrosis and Remodeling:
Aldosterone contributes to adverse structural changes in the heart, including fibrosis and ventricular hypertrophy. Spironolactone reduces collagen deposition and prevents further deterioration in myocardial structure, allowing for improvements in left ventricular ejection fraction (LVEF) and overall cardiac function.
Attenuation of Renin-Angiotensin-Aldosterone System (RAAS) Overactivation:
Chronic RAAS activation in HFrEF drives fluid retention, vasoconstriction, and cardiac remodeling. Spironolactone inhibits aldosterone’s role in perpetuating this cycle, leading to reduced afterload (via decreased vascular stiffness and resistance) and preload (via improved fluid balance).
Spironolactone is Progestogenic and anti-androgenic and so may cause gyanaecomastia, impotence and menstrual changes
Elperonone has less of these effects
