Cardiology: Cardiac Pump

What are six determinants of cardiac function?

1. Increased Contractility 2. Autonomic Nerves: This primarily the sympathetics, as parasympathetics are more involved in reducing HR. 3. Drugs Mimicking NE 4. Hormones: Epinephrine and thyroxine affect both HR and SV. 5. Hypertrophy: Cardiac muscle hypertrophy due to training increases contractility. 6. Decreased Contractility: Drugs, such as beta blockers and calcium channel blockers, an impaired cardiac muscle blood supply, and decreased blood oxygen reduced contractility.

What are four hypertrophic signals?

1. Muscle Stretch 2. Norepinephrine 3. Angiotensin II 4. Endothelin-1

What are three positive mechanisms that maintain venous return?

1. Muscular Pumps 2. Respiratory Pumps 3. Decreased Venous Compliance

Negatively-regulated (reduced gene expression) cardiac proteins by thyroid hormones include (5):

1. T3 nuclear receptor α1 2. myosin heavy chain β (slow twitch) 3. phospholamban (inhibitor of SERCA, less = ↓ SERCA activity) 4. sodium/calcium exchanger 5. adenylyl cyclase types V and VI This leads to lower inotropy.

What are five effects of T3 and T4 on cardiac function?

1. Thyroid hormones increase heart rate and contractility (chronotropy and inotropy respectively). 2. T3 and T4 increase the cardiac output by increasing the sensitivity to circulating and local catecholamines. 3. T3 and T4 increase numbers of and binding affinity of β1-adrenergic receptors in the heart. 4. The heat load generated by the calorigenic effects of thyroid hormone cause peripheral vasodilation, leading to increased cardiac demand and cardiac output. 5. Catecholamine toxicity is markedly increased when T4 is elevated.

What are three factors affecting the pressure volume loop?

1. Venous Filling Pressure (Preload) 2. Contractility 3. Aortic Pressure

What are four intrinsic factors affecting stroke volume?

1. Venous Return 2. Preload 3. Contractility 4. Afterload

What are two factors that affect afterload?

1. When aortic pressure is reduced, the velocity of the shortening of the left ventricular myocardial fibers increases because it is easier to push blood into the aorta. Therefore, with reduced afterload, the left ventricle can eject blood more rapidly. This increases stroke volume, which decreases end systolic volume. 2. The opposite is true when afterload is increased, with lower SV and greater ESV. Afterload is increased in aortic stenosis, arterial hypertension and vasoconstriction, which oppose outflow of blood from LV.

In an isolated papillary muscle stretched to its optimal length followed by applying more weight, this increase in afterload leads to _____.

1. a decreased degree of shortening. 2. a decreased velocity of shortening 3. a decreased total contraction time.

Cardiac index varies with (3).

1. age. 2. gender. 3. size.

According to the Frank-Starling mechanism, ventricular filling increases (3):

1. diastolic fiber length. 2. improves the number of possible myofilament cross-bridges. When the myofilaments are stretched, the actin-myosin complexes become closer, allowing for more cross bridges to form. The imposed stretch helps to bring the contractile components closer as tension increases to a point. 3. improves Ca+ sensitivity of myofilaments.

Positively-regulated (increased gene expression) cardiac proteins by thyroid hormones include (6):

1. myosin heavy chain α 2. β1 adrenergic receptors 3. sarcoplasmic reticulum calcium adenosine triphosphatase 4. guanine-nucleotide-regulatory proteins 5. sodium/potassium adenosine triphosphatase 6. voltage-gated potassium channels As a result, inotropy, chronotropy, and dromotropy, lusitropy are increased by thyroid hormone.

What is the effect of venous filling pressure (preload) on the pressure-volume loop?

Because the ventricles are very compliant, small changes in venous filling pressure, or preload, have a major effect on end-diastolic volume and stroke volume (SV), moving the end-diastolic volume in pressure-volume loop to right and producing a larger loop. On a curve of ventricular pressure vs. ventricular volume, at Point D, the mitral valve is opened, and there is passive filling between D and A. Between Points A and B, there is isovolumic contraction. From Point B to Point C, there is a period of ejection. At point C, the end systolic volume is reached. Point B is the end diastolic volume. However, with increased preload, the end diastolic volume is increased, and there is no change in systolic volume. Under these circumstances, stroke volume is increased because the end diastolic volume is increased. However, with no change in afterload or inotropy, the ventricle will eject blood to the same end-systolic volume despite the increase in preload. End systolic pressure volume relationship has not changed.

What is bepridil (Vascor)? What is its mechanism of action? What is it used for?

Bepridil is an anti-anginal drug which improves ventricular contractility. Bepridil enhances troponin C (TN-C) affinity for calcium and exerts a positive inotropic influence on the heart.

What is a negative mechanism that decreases venous return?

Compression of the vena cava is a negative mechanism that decreases venous return. An increase in vena cava resistance occurs when the thoracic vena cava is compressed, such as during a Valsalva maneuver and in late pregnancy. Both conditions decrease venous return.

Symptoms of Hyperthyroidism (3)

Hyperthyroidism symptoms include cardiovascular, tremor, and sweating.

A reduced ejection fraction is seen in (2).

MI and heart failure

What is the relationship of the Frank-Starling mechanism to preload?

On a plot of cardiac output (L/min) vs. right atrial pressure (RAP), normally, the RAP is around 0 mmHg, and the cardiac output is around 5 L/min. If the amount of blood returning to the ventricle increases, this increases the right atrial pressure, thereby increasing the the left ventricular and diastolic volume. This increases the cardiac output to improve contractility of the heart to about 13 L/min. If the amount of blood returning to the ventricle increases beyond a certain point, then there are diminishing returns, or lessening of the performance of the heart.

What are four ways in which T3 and T4 increase heart rate and contractility?

T3 and T4 increase heart rate and contractility by: 1. increasing the rate of calcium uptake by the SR. 2. increasing the rate of ATP hydrolysis in the SR. 3. stimulating cardiac muscular hypertrophy by causing alterations in myosin composition. 4. altering myosin composition in cardiac muscle (myosin has increased ATPase activity).

What is the Anrep effect? What is its effect on myocardial contractility?

The Anrep effect states that an increase in afterload can increase ventricular inotropy. THis is seen in denervated hearts and isolated cardiac muscle. A sudden increase in aortic pressure increases left ventricular end-diastolic volume. This can increase contractile force of the ventricle through Frank-Starling mechanisms due to increased troponin C calcium sensitivity. If increased afterload is maintained for 10 to 15 minutes, contraction increases further. This delayed increase in ventricular contractility equals an increase in inotropy, mediated by stretch activated H+/Ca+ exchanger. As a result, end-diastolic volume increases.

How does the Frank-Starling mechanism works?

The Frank-Starling mechanism states that ventricular force and pressure development varies with initial fiber length, or preload. As initial myocardial fiber length (or end diastolic volume) increases during diastole, then cardiac output, or force developed, improves in systole. Beyond a point, there is a point of diminishing returns.

What is the Frank-Starling mechanism?

The Frank-Starling mechanism states that ventricular force and pressure development varies with initial fiber length, or preload. This mechanism is an intrinsic regulator of myocardial performance and is heterometrically autoregulated, depending on preload and length. This allows the heart to adapt to alterations in venous return and pump whatever blood is receives within limits.

What is the effect of inositol 3-phosphate on contractility?

The activation of the IP3 signal transduction pathway stimulates the release of calcium by the SR through IP3 receptors located on the SR, where a larger amount of Ca+ is released.

What is the effect of phospholamban on contractility?

The activation of the cAMP-dependent protein kinase (PKA) phosphorylates phospholamban, a protein on the SR that normally inhibits calcium uptake. This disinhibition involving phospholamban leads to an increased rate of calcium uptake by the SR, thereby enhancing the speed at which the mechanism resets.

External Work

external work output during a single ventricular contraction (tan-shaded area)

An increased afterload leads to an _______ in stroke volume.

impairment

An increased contractility leads to an __________ stroke volume.

improved

An increased preload leads to an __________ stroke volume.

improved

Preload-induced hypertrophy ________ contractile function.

increases

A shift of the ESPVR up and to the left is due to an elevated _________.

inotropism of the ventricle

Afterload is __________ proportional with stroke volume.

inversely

Digitoxin is eliminated by the _______.

liver

If the heart muscle is not contracting efficiently, the EF may be __________.

reduced

Afterload-induced hypertrophy ________ contractile function.

reduces

Digoxin is _____________-acting than digitoxin.

shorter

Ejection Fraction =

stroke volume (70 mL) / end diastolic volume (120 mL) - proportion of blood ejected from the filled ventricle

Cardiac Output

the amount of blood pumped by each ventricle in one minute and is the product of heart rate and stroke volume

Stroke Volume

the amount of blood pumped out by a ventricle with each beat

Venous Return

the blood being returned to the heart in which skeletal muscle and respiratory pumps enhance blood return to heart

Cardiac Reserve (CR)

the difference between resting and max cardiac output

Left Ventricular Afterload

the force that the muscle must generate to eject blood into the aorta

Digoxin is eliminated by _________.

the kidneys

Afterload

the load against which the ventricle exerts its contractile force (aortic pressure for left heart and pulmonary artery pressure for right)

Heart Rate

the number of beats per minute

Preload

the tension (degree of stretch) of ventricular muscle in when it begins to contract (end diastolic pressure or end diastolic volume); the amount of volume presented to the ventricles before contraction, produces stretch on sarcomeres by blood delivered to it

Ejection fraction may be elevated in _______.

trained athletes due to hypertrophy

S1-S4

ventricular volumes prior to contraction

Laplace's law relates _______.

wall tension in the ventricle

The cardiovascular symptoms of hyperthyroidism can be improved by ____.

which can be reduced by β-adrenergic receptors blockers (i.e. propranolol, metoprolol)

What is the effect of β1 adrenergic receptors on contractility?

β1 adrenergic receptor stimulation increases the force and shortening velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e. positive lusitropy). Cardiac cytosolic Ca++ levels are influenced primarily by β-adrenoreceptor coupled mechanisms. Epinephrine from sympathetic nerves increases cAMP which in turn activates protein kinase A (PKA) to phosphorylate membrane L-type calcium channel (DHP-receptor) to increase calcium entry into the cell.

Laplace's Law

σ = P x r/2h σ: tension on the heart muscle fibers P: intraventricular pressure h: wall thickness

What is the effect of contractility on the pressure-volume loop?

With increased contractility, there are increases in cytosolic Ca+ in cardiomyocyte that increase force generation at any given muscle length, moving end-systolic volume (ESV) in the pressure-volume loop to left with less remaining volume after a contraction and shifts the end systolic pressure-volume relationship (ESPVR) up and to left to due elevated inotropism.

Homeometric Autoregulation

adjustments in cardiac performance that are independent of myocardial fiber length

Cardiac hypertrophy is the result of ______.

an imbalance between muscle protein biosynthesis and degradation

What is the effect of cAMP/PKA on contractility?

cAMP / PKA phosphorylation of troponin I, which sensitizes troponin-C to calcium and enhances the whole phenomenon.

Contractility

cardiac cell contractile force due to other factors besides EDV; change in developed force at a fixed resting fiber length

Cardiac Index (CI)

cardiac output/m2

When arterial pressure is decreased, stroke volume is _______.

decreased *Cardiac output does not fall until pressure exceeds 160 mmHg.

Contractility is __________ proportional with stroke volume.

directly

Preload is __________ proportional with stroke volume.

directly

Venous return is __________ proportional with stroke volume.

directly

Negative Inotropic Agents (4)

1. Acidosis 2. Ether 3. Chloroform 4. Bacterial Toxins All reduce contractility of the heart.

What are four ways in which ejection fraction is measured?

1. Echocardiogram: This is the most common method. 2. MRI 3. Nuclear Medicine: Multiple gated acquisition (MUGA) or a nuclear stress test may be used. 4. Plot ΔP/Δt. Introduce a pressure inducer into the left ventricle and measure the pressure development as the heart beats. Under normal circumstances, there are changes in the slope of the maximum developed pressure over time compared to normal. ΔP/Δt becomes steeper with the administration of sympathetics. ΔP/Δt flattens with heart failure.

What are four factors affecting contractility?

1. End-Diastolic Volume (Frank-Starling Mechanism): EDV improves contracting capacity of the heart. 2. Cardiac Innervation: The sympathetic nervous system increases contractility much more than the parasympathetic nervous system. 3. Oxygen Supply: Hypoxia decreases contractility. 4. Physical Factors: Warming increases contractility while cooling decreases contractility.

Positive Inotropic Agents (6)

1. Epinephrine 2. Norepinephrine 3. Alkalosis 4. Digitalis 5. Ca2+ 6. Caffeine All improve contractility of the heart.

How does heart rate influence myocardial contraction? (2)

1. Homeometric Autoregulation: Adjustments in cardiac performance that are independent of myocardial fiber length. 2. Bowditch Effect: Successive stimulations increase concentration of Ca+ ions in the sarcoplasm during the beginning contractions of rested muscles. If a muscle is not stimulated and then stimulated rapidly, as the contractions occur more frequently, the force developed increases to a maximum. This occurs because, when repeatedly inducing muscle contraction, there is a point at which Ca+ is not removed from the cytoplasm fast enough, leaving Ca+ in the sarcoplasm at the initiation of the next beat. Up to a point, this increases the amount of force developed.

What is the effect of Frank-Starling mechanism on contractility?

A move from Point A to Point B on the same curve is a Frank-Starling effect. In this case, the preload is increased, and there is a greater cardiac output. However, a move from Point A to Point C is a new curve called a hyperactive curve, which is an effect on contractility. With an increase in volume beyond normal limits on either curve, then there are diminishing returns.

Explain the pressure-volume loop.

A: At point A, the mitral valve opens. Early A → B: The period between A and B, there is a period of diastolic filling of ventricle. Initially, there is a decrease in ventricular pressure. Despite rapid inflow of blood from the atrium, there is progressive ventricular relaxation and distensibility. Late A → B: Gradually, the pressure increases due to ventricular filling, and its passive elastic characteristics are stretched to the maximum point. B: The ventricle is filled and begins to contract. The mitral valve closes at Point B (EDV). B → C: Between Point B and C, the isovolumic contraction occurs where pressure rises. C: The aortic valve opens. IN early C, there is rapid ejection due to pressure in the ventricle exceeding pressure of the aorta. However, in late C, when blood is ejected from the ventricle, the blood volume decreases, but the volume increases. There is reduced ejection. D: At Point D, the pressure of the aorta exceeds the pressure of the left ventricle, so the aortic valve closes (ESV). D → A: Between D and A, isovolumic relaxation occurs.

How does an increase in contractility affect the pressure-volume relationship?

An increase in contractility leads to a decreased end systolic volume, improving the contractility of the heart.

How does contractility affect the pressure-volume loop?

Any increases in cytosolic Ca+ in the cardiomyocyte increases force generation at any given muscle length, moving end-systolic volume in pressure-volume loop to left and forming a smaller loop. If contractility increases, there is no change in preload or afterload, but contraction is increased. This squeezes more blood from the ventricles, so the end systolic volume is lower. This shifts the ESPVR curve to the left and upward. As a result, the stroke volume is increased due to a reduced SV.

Autonomic: Parasympathetic Tone Cardiac Output: Heart Rate: Stroke Volume:

Autonomic: Parasympathetic Tone Cardiac Output: - Heart Rate: - Stroke Volume: no effect

Autonomic: Sympathetic Tone Cardiac Output: Heart Rate: Stroke Volume:

Autonomic: Sympathetic Tone Cardiac Output: + Heart Rate: + Stroke Volume: +

What is digitalis (digoxin)? What is the effect of this substance on Ca+ release?

Digitalis (digoxin) is a positive inotropic agent that increases the amount of Ca+ in the sarcoplasm so that more calcium is available for troponin to use. It thereby increases the force developed. This works due to alterations of Na+ concentrations. A high Na+ concentration gradient is needed to pump out sarcoplasmic calcium via the Na+/Ca+ antiporter/exchanger. By digitalis inhibiting the Na+/K+ pump, extra sodium accumulates inside the cell. The buildup of Na+ inside the cell will cause the Na+ gradient from inside the cell to the outside of the cell to decrease slightly. This make it more difficult for calcium to leave the cell via the Na+/Ca++ antiporter. When this occurs, this increases the amount of Ca+ inside the cell, making a more forceful contraction.

What is a major side effect of bepridil (Vascor)?

Due to enhanced troponin C binding to calcium induced by bepridil, bepridil may reduce the rate of ventricular relaxation, or lusitropy, causing problems with filling and leading to diastolic dysfunction.

Stroke Volume =

EDV-ESV Normally: SV (70 mL) = End Diastolic Volume (120 mL) - End Systolic Volume (50 mL)

Range of Ejection Fraction

EF 55% to 70%: normal EF 40% to 54%: slightly below normal EF 35% to 39%: moderately below normal EF Less than 35%: severely below normal

What are seven extrinsic factors that alter stroke volume?

Factors that alter stroke volume include: 1. cyclic changes during normal respiration (i.e. venous return). 2. positive end-expiratory pressure breathing increases intrapleural pressure and opposes the entrance of blood into the thorax. 3. Valsalva maneuvers (i.e. forceful expiration against closed glottis). 4. opening the thorax by increasing intrapleural pressure, making it more difficult for blood to be drawn into the thorax. 5. bleeding/filtration of fluid into the thorax. 6. extra-cardiac pressures. Increased intrapleural or pericardial pressures shift cardiac function curve to right, as cardiac filling requires greater pressure to overcome external force. For example, if intrapleural pressure is increased by 2 mmHg, then an extra 2 mmHg of RAP is needed to fill heart chambers to same extent. 8. Cardiac Tamponade

True or False: Molecular mechanisms that decrease cytosolic calcium increase the amount of ATP hydrolyzed by cardiac muscle and augment the force generated by the actin and myosin interactions, as well as the velocity of shortening.

False: increase

True or False: Cardiac hypertrophy leads reduced contractility.

False: increased contractility, leading to an increased plateau on the cardiac function curve (60-100% higher)

Cardiac Output =

HR x SV

What is the effect of aortic pressure on the pressure-volume loop?

Increasing aortic pressure increases afterload as well as the end systolic volume, leading to a reduced SV. This action moves the end-systolic volume in pressure-volume loop to right, leading to a larger loop, and higher systolic pressure.

How does an increase in afterload affect the pressure-volume relationship?

Increasing the afterload leads to an increase in systolic pressure, but aortic pressure exceeds that of the ventricles. So, systolic pressure has to rise to eject blood into the aorta, reaching a higher end systolic volume.

How does an increase in preload affect the pressure-volume relationship?

Increasing the preload increases the amount of blood into the heart; thereby, the end diastolic volume increases. Without a change in inotropy and other factors, whatever blood that is given to the heart is being ejected.

What is the clinical significance of the Anrep effect?

The clinical significance of the Anrep effect is that increased inotropy partially compensates for the increased end-systolic volume and decreased stroke volume caused by the increase in afterload. Without the Anrep effect, increases in afterload would reduce stroke volume with afterload more than what is normally observed.

What is the effect of gravity on the maintenance of venous return?

The effects of body position and gravity affect venous return. When you stand up, hydrostatic forces pull blood downward away from the right atrium and can decrease venous return. This is normally opposed by the baroreceptor reflex. This positional effect reduces venous return to the heart. This is more pronounced in hypovolemia, prolonged bed rest, and following the use of sympathetic blockers.

Flip card. Answer below. A. aortic valve opening

The following figure represents a normal left ventricular pressure-volume loop. The arrow is pointed to what event in the cardiac cycle? A. aortic valve opening B. end-systolic volume C. end of systolic ejection D. mitral valve opening

Explain the length-tension relationship.

The length of an unstretched sarcomere has little room to contract. However, when the sarcomere is stretch slightly (Point B), there is a greater capacity for the sarcomere components to pull against one another. When the sarcomere is stretched more at Point C, then there is the greatest capacity for overlap to produce tension. If the sarcomere is overstretched, then it is difficult for the components of the sarcomere to initiate contraction. Stretch in any muscle improves developed tension within limits. This also applies to ventricular muscle when preload is increased.

True or False: At any given RAP (EDV), increased sympathetic stimulation will increase cardiac output. Withdrawal of sympathetics will decrease contractility and CO.

True

True or False: Cardiac muscle hypertrophy is due to increased cell size, not increased cell number.

True

Explain Laplace's law using a normal heart, hypertrophic heart, and dilated cardiomyopathy.

Under normal circumstances, the tension within the vessel wall is developed during contraction. If the heart becomes hypertrophies, then the improvement in wall thickness makes it easier to improve ejection fraction. Conversely, if there is thinning of the heart wall, such as in dilated cardiomyopathy, then it is more difficult for the heart to develop the same amount of tension. This dilation impairs the translation of wall tension into pressure. So, stroke volume is improved in the hypereffective heart, but impaired in the hypoeffective heart.

What is the effect of decreased venous compliance on the maintenance of venous return?

When sympathetic vasoconstriction decreases the compliance of veins (i.e. during exercise), veins will decrease their holding capacity (usually 60% of blood volume). When squeezed by sympathetic activation of the muscle in the veins, it increases central venous pressure that promotes the return of venous blood via the Frank-Starling mechanism, which increases the total blood flow through the circulatory system. So, all-in-all, this increases venous return.