B P6 C47 Pathophysiology of Heart Failure

Question 1

HFrEF is initiated after an _____ either damages the heart muscle, with a resultant loss of functioning cardiac myocytes or, alternatively, disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally.

Answer 1

Index event

Question 2

The decrease _____ in HF activates a series of compensatory adaptations that are intended to maintain cardiovascular homeostasis.

Answer 2

Decrease in cardiac output

Question 3

In healthy persons, “high-pressure” _____ and “low- pressure” ____- provide inhibitory signals to the central nervous system (CNS) that repress the sympathetic outflow to the heart and peripheral circulation.

Answer 3

High pressure: carotid sinus and aortic arch baroreceptors

Low pressure: cardiopulmonary mechanoreceptors

Question 4

Under normal conditions, inhibitory inputs from _____ are the principal inhibitors of sympathetic outflow, whereas discharge from the _____ are the major excitatory inputs to sympathetic outflow.

Answer 4

Inhibits sympathetic outflow:
High-pressure carotid sinus & Aortic arch baroreceptors
Low-pressure cardiopulmonary mechanoreceptors

Excitatory inputs to sympathetic flow:
Nonbaroreflex peripheral chemoreceptors & muscle metaboreceptors

Question 5

Healthy persons display low sympathetic discharge at rest and have a high heart rate variability. In patients with HF, however, inhibitory input from baroreceptors and mechanoreceptors decreases and excitatory input increases, with the net result that there is a generalized increase in sympathetic nerve traffic and blunted parasympathetic nerve traffic, leading to _____.

Answer 5

Loss of heart rate variability
Increased peripheral vascular resistance

Question 6

As a result of the increase in _____, there is an increase in circulating levels of NE, a potent adrenergic neurotransmitter. The elevated levels of circulating NE result from a combination of increased release of NE from adrenergic nerve endings and its consequent “spillover” into the plasma, as well as reduced uptake of NE by adrenergic nerve endings

Answer 6

Sympathetic tone

Question 6

In patients with advanced HF, the circulating levels of NE in resting patients are _____ times those found in normal persons. Indeed, plasma levels of NE predict mortality in patients with HF

Answer 6

2-3x

Question 7

Whereas the normal heart usually extracts NE from the arterial blood, in patients with moderate HF the _____ NE concentration exceeds the arterial concentration, indicating increased adrenergic stimulation of the heart

Answer 7

Coronary sinus NE

Question 8

However, as HF progresses there is a significant decrease in the myocardial concentration of NE. The mechanism responsible for cardiac NE depletion in severe HF is not clear and may relate to an “_____” phenomenon resulting from the prolonged adrenergic activation of the cardiac adrenergic nerves in HF.

Answer 8

Exhaustion phenomenon

Question 9

In addition, there is decreased activity of myocardial _____, which is the rate-limiting enzyme in the synthesis of NE.

Answer 9

Tyrosine hydroxylase

Question 10

In patients with cardiomyopathy, iodine 131 (131I)–labeled metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by adrenergic nerve endings, is not taken up normally, suggesting that _____ is also depressed.

Answer 10

NE reuptake

Question 11

Increased sympathetic activation of the _____ receptor results in increased heart rate and force of myocardial contraction, with a resultant increase in cardiac output

Answer 11

Beta1-adrenergic

Question 12

In addition, the heightened activity of the adrenergic nervous system leads to stimulation of myocardial _____ receptors,which elicits a modest positive inotropic effect, as well as peripheral arterial vasoconstriction

Answer 12

Alpha1-adrenergic

Question 13

The augmented adrenergic outflow from the CNS also may trigger _____, particularly in the presence of myocardial ischemia.

Answer 13

VT or SCD

Question 14

Withdrawal of parasympathetic nerve stimulation has been associated with _____. Several clinical trials with direct vagal nerve stimulation did not meet their primary endpoint but additional studies are ongoing.

Answer 14

(1) Decreased nitric oxide (NO) levels
(2) Increased inflammation
(3) Increased sympathetic activity
(4) Worsening LV remodeling

Question 15

In contrast with the SNS, the components of the ____ are activated comparatively later in HF.

Answer 15

Renin-Angiotensin system (RAS)

Question 16

The presumptive mechanisms for RAS activation in HF include _____, leading to increased renin release from juxtaglomerular apparatus.

Answer 16

(1) Renal hypoperfusion
(2) Decreased filtered sodium reaching the macula densa in the distal tubule
(3) Increased sympathetic stimulation of the kidney

Question 17

Most ACE activity (approaching 90%) in the body is found in _____; the remaining 10% is found in a soluble (non–membrane-bound) form in the interstitium of the heart and vessel wall.

Answer 17

Tissues

Question 18

The importance of tissue ACE activity in HF is suggested by the observation that ACE messenger RNA (mRNA) and ACE-binding sites and ACE activity are increased in _____ human hearts.

Answer 18

Explanted human hearts

Question 19

_____ has also been identified as the cellular receptor of SARS-CoV-2

Answer 19

ACE2

Question 20

Cellular localization of the AT1 receptor in the heart is most abundant in _____, whereas the AT2 receptor is localized more specifically in _____.

Answer 20

AT1r: nerves distributed in the myocardium
AT2r: fibroblasts and the interstitium

Question 21

Activation of the AT1 receptor leads to _____, whereas activation of the AT2 receptor leads to _____.

Answer 21

AT1r:
Vasoconstriction
Cell growth
Aldosterone secretion
Catecholamine release

AT2r:
Vasodilation
Inhibition of cell growth
Natriuresis
Bradykinin release

Question 22

Studies have shown that the AT1 receptor and mRNA levels are _____ in failing human hearts, whereas AT2 receptor density is increased or unchanged, so that the ratio of AT1 to AT2 receptors decreases.

Answer 22

Downregulated

Question 23

Angiotensin II has several important actions that are critical to maintaining short-term circulatory homeostasis.The sustained expression of angiotensin II is maladaptive, however, leading to _____ of the heart, kidneys, and other organs

Answer 23

Fibrosis

Question 24

Angiotensin II can also lead to worsening neurohormonal activation by enhancing the release of _____ from sympathetic nerve endings, as well as stimulating the zona glomerulosa of the adrenal cortex to produce _____.

Answer 24

Sympathetic nerve endings: NE

Adrenal cortex: Aldosterone

Question 25

Analogous to angiotensin II, ________ provides short-term support to the circulation by promoting the reabsorption of sodium in exchange for potassium in the distal segments of the nephron.

However, the sustained expression of aldosterone may exert harmful effects by provoking _______ within thr vasculature and myocardium, contributing to reduced vascular compliance and increased ventricular stiffness.

In addition, aldosterone provokes ___________, any of which may lead to worsening HF.

Answer 25

Aldosterone

Hypertrophy and fibrosis

Endothelial cell dysfunction
Baroreceptor dysfunction
Inhibition of NE uptake

Question 26

The mechanism of action of aldosterone in the cardiovascular system appears to involve oxidative stress,with resultant inflammation in target tissue.

Although the exact role of angiotensin III (2 to 8), angiotensin IV (3 to 8), and angiotensin 1 to 7 in HF are not known, experimental studies suggest that ____________ counteracts the effects of angiotensin II, and attenuates LV remodeling.

Answer 26

Angiotensin 1 to 7

Question 27

In contrast, ___________ directly stimulates the zona glomerulosa of the adrenal glands to produce aldosterone, which promotes sodium resorption in the distal collecting duct of the kidney.

Angiotensin III also has an important role in ____________ release in the brain, which controls water retention in the distal collecting duct of the kidney.

Angiotensin III in the brain can also modulate cardiac nervous sympathetic hyperactivity, as well as LV remodeling after MI.

Answer 27

Angiotensin III

Vasopressin

Question 28

In the heart, the potential sources for ROS include the _____.

Answer 28

Mitochondria
Xanthine oxidase
NADPH oxidase

Question 29

Oxidative stress in the heart may be caused by reduced antioxidant capacity and increased production of ROS, which may arise secondary to ____.

Answer 29

• Mechanical strain of the myocardium
• Neurohormonal stimulation (angiotensin II, alpha-adrenergic agonists, endothelin-1 [ET-1]), or inflammatory cytokines (tumor necrosis factor [TNF], interleukin [IL]-1).

Question 30

ROS stimulate myocyte hypertrophy, reexpression of fetal gene programs, and apoptosis.

ROS also can modulate fibroblast proliferation and collagen synthesis and trigger increased matrix metalloproteinase (MMP) abundance and activation.

ROS also can affect the peripheral vasculature in HF by decreasing the bioavailability of ________

These and other observations have led to the suggestion that strategies to reduce ROS may be of thera- peutic value in patients with HF.

Answer 30

Nitric oxide

Question 31

However, xanthine oxidase inhibition with ____ to reduce oxidative stress in hyperuremic patients with HF did not improve clinical status or cardiac function in a clinical trial.

Answer 31

Allopurinol

Question 32

One of the signatures of advancing HF is increased salt and water retention by the kidneys.

Traditional theories have ascribed this increase to either ______, which attributes sodium retention to ______ as a consequence of impaired cardiac output, or ______, which emphasizes the importance of increased venous pressure in favoring __________________ from the intravascular to the extracellular compartment.

Answer 32

“Forward” failure - inadequate renal perfusion

“Backward” failure - transudation of salt and water

Question 33

These mechanisms have largely been supplanted by the concept of ___________________________, which postulates that despite blood volume expansion in HF, inadequate cardiac output sensed by baroreceptors in the vascular tree leads to a series of compensatory neurohormonal adaptations that resemble the homeostatic response to acute blood loss.

Answer 33

Decreased effective arterial blood volume

Question 34

An implantable barostimulation device that activates the carotid baroreceptors to decrease sympathetic activation and increase vagal tone improved quality of life, exercise capacity, and NT-proBNP in patients with symptomatic HF in the ______________________________

Answer 34

BeAT-HF (Barostimulation for Heart Failure).

Question 35

Volume overload in HF is multifactorial and is secondary, at least in part, to several factors that have the potential to cause increased sodium reabsorption, including _________________________

Answer 35

Activation of the SNS, activation of RAS, reduced renal per- fusion pressures, and blunting of renal responsiveness to natriuretic peptides

Question 36

Increased renal __________________________ leads to decreased renal blood flow, as well as increased renal tubular sodium and water reabsorption throughout the nephron

Answer 36

Sympathetic nerve–mediated vasoconstriction

Question 37

Renal sympathetic stimulation also can lead to the nonosmotic release of _____________________ from the posterior pituitary,which reduces the excretion of free water and contributes to worsening peripheral vasoconstriction, as well as increased ________________ production

Answer 37

Arginine vasopressin (AVP)

Endothelin (ET)

Question 38

___________________ can also lead to renal interstitial hypertension,with the development of tubular injury and renal fibrosis.

Answer 38

Increased renal venous pressure

Question 39

Of note, circulating AVP is elevated in many patients with HF, even after correction for plasma osmolality (i.e., nonosmotic release),1 and may contribute to the hyponatremia that occurs in HF

Question 40

The ______________ mediate vasoconstriction, platelet aggregation, and stimulation of myocardial growth factors, whereas V3 modulates adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary.

The _______________ mediates antidiuretic effects by stimulating adenyl cyclase to increase the rate of insertion of water channel−containing vesicles into the apical mem- brane

Answer 40

V1 receptors

V2 receptor

Question 41

Because the vesicles contain preformed functional water channels, termed aquaporins, their localization in the apical membranes in response to V2 stimulation,_______________________ of the api- cal membrane, leading to water retention.

The “vaptans,” vasopressin receptor antagonists with V1 (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or nonselective V1/V2 activity (conivaptan), have been shown to reduce body weight and reduce hyponatremia in clinical trials

Answer 41

Increases the water permeability

Question 42

Angiotensin II facilitates retention of sodium and water by multiple renal mechanisms, includ- ing a direct proximal tubular effect, as well as through activation of aldosterone, which leads to increased sodium resorption in the distal tubule.Angiotensin II also stimulates the thirst center of the brain and provokes the release of AVP and aldosterone, both of which can lead to further dysregulation of salt and water homeostasis.

Question 43

Neurohormonal regulation of vascular tone: Vasoconstrictors

Answer 43

Catecholamine:
Norepinephrine: peripheral a1-adrenergic stimulation

Peptide:
Angiotensin II
Arginine vasopressin
Endothelin
Neuropeptide Y
Urotensin II

Lipid:
Thromboxane A2

Question 44

Neurohormonal regulation of vascular tone: Vasodilators

Answer 44

Catecholamine:
Norepinephrine: central alpha2-adrenergic stimulation Epinephrine: beta2-adrenergic stimulation
Dopamine

Peptide:
Bradykinin
Adrenomedullin
Apelin

Gas:
NO (i.e., “endothelium-derived relaxing factor” [EDRF])

Lipid:
Prostacyclin (PGI2) Prostaglandin E2 (PGE2)

Question 45

Under physiologic conditions, ANP and BNP function as natriuretic hormones that are released in response to increases in atrial and myocardial stretch, often secondary to excessive sodium intake. Once released, these cardiac peptides act on the kidney and peripheral circulation to unload the heart, through:

Answer 45

(1) increased excretion of sodium and water
(2) inhibiting the release of renin and aldosterone

Question 46

In the setting of RAAS activation, the release of ANP and BNP may serve as an important counterregulatory mech- anism that maintains sodium and water homeostasis. However, for reasons that are not entirely clear, the renal effects of the natriuretic peptides appear to become blunted with advancing HF, leaving the effects of RAAS unopposed. Potential reasons for this blunting include:

Answer 46

(1) Low renal perfusion pressure
(2) Relative deficiency or altered molecular forms of the natriuretic peptides
(3) Decreased levels of natriuretic peptide receptors

Question 47

NEP inhibition of degradation of natriuretic peptides results in _____. On the other hand, inhibition of degradation of other vasoactive peptides, such as angiotensin II, angiotensin 1 to 7, and ET, opposes the vasodilatory effects of natriuretic peptides

Answer 47

NEP inhibition: vasorelaxation, natriuresis, inhibition of hypertrophy, and fibrosis

Question 48

However, the use of a combined AT1 receptor antagonist and a neprilysin inhibitor (valsartan/sacubitril, LCZ696) was shown to have a favorable impact on HF outcome, including quality of life, exercise capacity, and more importantly, HF hospitalization and total mortality, in the _____ trial

Answer 48

PARADIGM-HF

Question 49

The infusion of a recombinant human ANP and BNP exerts beneficial hemodynamic effects, characterized by _____, resulting in their clinical development as therapeutic agents for human HF. In addition to their important biologic role, the natriuretic peptides have provided important diagnostic and prognostic information in HF

Answer 49

(1) Decreases in arterial and venous pressures
(2) Increase in cardiac output
(3) Suppression of neurohormonal activation in humans

Question 50

The most powerful stimulus for peripheral vasoconstriction is _____, which releases the potent vasoconstrictor __. Other vasoconstrictors that contribute to maintaining circulatory homeostasis include angiotensin II, ET, neuropeptide Y, urotensin II, thromboxane A2, and AVP

Answer 50

Sympathetic activation

NE

Question 51

The increased sympathetic adrenergic stimulation of the peripheral arteries and the increased concentrations of circulating vasoconstrictors contribute to the arteriolar vasoconstriction and to the maintenance of arterial pressure.The sympathetic stimulation of the veins contributes to an increase in venous tone, which helps to :

Answer 51

Maintain venous return and ventricular filling
Support cardiac performance by Starling’s law of the heart

Question 52

As noted, the vasoconstricting neurohormones activate counterregulatory vasodilator responses, including release of:

Answer 52

Natriuretic peptides, NO, bradykinin, adrenomedullin, apelin, and vasodilating PGI2 and PGE2

Question 53

Under normal circumstances, the continuous release of NO (endothelium-derived relaxing factor) from the endothelium counteracts these vasoconstricting factors and allows for appropriate vasodilatory responses during exercise. As HF advances, however, the endothelial cell–mediated vasodilatory responsiveness is lost, which contributes to the excessive _____ that is emblematic of advanced HF. Of interest, the vasodilator response can be restored by the administration of L-arginine, a precursor of endothelium-derived NO.

Answer 53

Peripheral arterial vasoconstriction

Question 54

NOS1 has been detected in _____. NOS2 is an inducible isoform that is not normally expressed in the myocardium but is _____. NOS3 is expressed in _____.

Answer 54

NOS1: cardiac conduction tissue, intracardiac neurons, SR of cardiac myocytes

NOS2: synthesized de novo in virtually all cells in the heart in response to inflammatory cytokines

NOS3: coronary endothelium and endocardium, sarcolemma and transverse (T)-tubule membranes of cardiac myocytes.

Question 55

Vericiguat, an oral soluble guanylate cyclase stimulator, reduced the composite of death from cardiovascular causes and first HF hospitalization in the _____ trial

Answer 55

VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial

Question 56

Numerous studies have suggested that failing human cardiac myocytes undergo a number of important changes that might be expected to lead to a progressive loss of contractile function. These include:

Answer 56

(1) Decreased alpha-myosin heavy chain gene expression with a concomitant increase in beta-myosin heavy chain expression
(2) Progressive loss of myofilaments in cardiac myocytes
(3) Alterations in cytoskeletal proteins
(4) Alterations in excitation-contraction coupling and in energy metabolism
(5) Desensitization of beta-adrenergic signaling

Question 57

In pressure overload hypertrophy (e.g., with aortic stenosis or hypertension),increased systolic wall stress leads to the _____.This pattern of remodeling has been referred to as “_____” hypertrophy and has been linked with alterations in _____.

Answer 57

(1) Addition of sarcomeres in parallel
(2) Increase in myocyte cross-sectional area
(3) Increased LV wall thickening

“Concentric” Hypertrophy

Ca2+/calmodulin-dependent protein kinase II–dependent signaling

Question 58

By contrast, in volume over-load hypertrophy (e.g., with aortic and mitral regurgitation), increased diastolic wall stress leads to an _____. This pattern of remodeling has been referred to as “_____” hypertrophy (because of the position of the heart in the chest), or a “dilated” phenotype, and has been linked with _____.

Answer 58

Increase in myocyte length with the addition of sarcomeres in series, thereby engendering increased LV ventricular dilation

Eccentric hypertrophy

Protein kinase B (Akt) activation

Question 59

Patients with HF classically present with a _____.The myocytes from these failing ventricles have an elongated appearance that is characteristic of myocytes obtained from hearts subjected to chronic volume overload.

Answer 59

Dilated left ventricle with or without LV wall thinning

Question 60

The early stage of cardiac myocyte hypertrophy is characterized morphologically by _____. At this stage, the cardiac myocytes are larger than normal, but with preservation of cellular organization.

Answer 60

Increases in the number of myofibrils and mitochondria
Enlargement of mitochondria and nuclei

Question 61

As hypertrophy continues, there is an increase in the number of mitochondria, as well as the addition of new contractile elements in localized areas of the cell. Cells subjected to longstanding hypertrophy show more obvious disruptions in cellular organization, such as _____.

Answer 61

Extremely enlarged nuclei with highly lobulated membranes, accompanied by the displacement of adjacent myofibrils with loss of the normal registration of the Z-bands.

Question 62

The late stage of hypertrophy is characterized by:

Answer 62

(1) Loss of contractile elements (myocytolysis) with marked disruption of Z-bands and severe disruption of the normal parallel arrangement of the sarcomeres

(2) accompanied by dilation and increased tortuosity of T tubules.

Question 63

Impaired contraction and relaxation of the failing heart is most prominent at _____, which results in a depressed force-frequency relationship.

Answer 63

High heart rates

Question 64

Normally, higher contraction frequency increases cardiac performance because of a frequency-dependent augmentation of intracellular Ca2+ transients.

By contrast, in the failing myocardium, a decline in force generation is seen with higher heart rates that is secondary to _____.

Answer 64

(1) Decrease in amplitude of intracellular Ca2+
(2) Prolonged decline of the Ca2+ transient
(3) Increased levels of diastolic calcium

Question 65

The reduced intracellular Ca2+ transient is secondary to depletion of Ca2+ from the SR, the result of three major defects in calcium cycling that occur in the failing heart:

Answer 65

(1) increased Ca2+ leak through RyRs
(2) impaired SR Ca2+ uptake from reduced SERCA2a (SR calcium pump) protein levels and function
(3) increased expression and function of the sarcolemmal Na+/ Ca2+ exchanger (NCX).

Question 66

Ca2+ enters the cell during the action potential through _____ calcium channels and triggers a release of a much larger amount of calcium from the SR through RyRs

Answer 66

L-type Ca channels

Question 67

Experimental studies suggest that PKA-dependent phos- phorylation of the RyR may provoke Ca2+ leak by destabilizing the association between calstabin and FKB. Interestingly, in dogs, beta-adrenergic blockers prevent the development of Ca2+ leak by restoring RyR stabilization by FKBP12.6. This observation has led to the suggestion that the increase in contractile function following treatment with beta blockers is secondary to _____.

Answer 67

RyR stabilization

Question 68

In addition to its contribution to reduced SR Ca2+ content, increased leak seems to be relevant for arrhythmias in HF.This results from activation of NCX: Ca2+ leaking out of the SR activates NCX to remove Ca2+ from the cytosol in exchange of Na+. Because NCX is electrogenic (3 Na+ versus 1 Ca2+), the increased influx of ___ results in a net inward current generating the so-called delayed afterdepolarizations (DADs),which serve as a trigger of arrhythmias

Answer 68

Increased influx of Na

Question 69

In the human heart, there are two main mechanisms responsible for elimination of Ca2+ from the cytosol: _____. Under normal conditions, approximately 75% of Ca2+ is taken up by the SR and 25% extruded from the cell through NCX.

In HF there is decreased uptake of Ca2+ by the SR secondary to _____.

Answer 69

(1) SR uptake of Ca2+ by the SERCA2a Ca2+ pump
(2) Transsarcolemmal Ca2+ elimination through NCX

Decreased SERCA2a protein levels and SERCA2a function