CARDIOVASCULAR PHYSIOLOGY

LECTURE 5

Heart as a pump – cardiac performance

Coronary circulation. Particularities of the cardiac muscle metabolism.

Ana-Maria Zagrean MD, PhD

 Cardiac dynamics -
comparison of the dynamics of the left and right ventricles

The heart is a system of 2 pumps linked in series.

The muscular wall of the left ventricle (LV) is thicker and more powerful than that
of the right ventricle (RV), and the interventricular septum is even thicker.
The thick muscular walls of the ventricles are responsible for exerting the heart’s
pumping action.

The two ventricles share a

common envelope of spiral and
circular muscle layers.
This arrangement ensures that
ventricular contraction virtually
wrings the blood out of the
heart, although incompletely.

The apex contracts before some

of the basal portions of the
ventricle, a sequence that
propels blood upward to the
aortic and pulmonary valves.
 Right ventricular contraction

- the free wall has such a large surface area that a small movement
of the free wall toward the septum, in a bellows-like motion, ejects a large volume.
- the longitudinal axis of the RV shortens when spiral muscles pull the tricuspid
valve ring toward the apex.
- the contraction of the deep circular fibers of the LV forces the septum into a
convex shape, so that the septum bulges into the RV.
→ ejection of blood from RV, at lower intraventricular pressure than LV
for the same stroke volume.
 Left ventricular contraction

- constriction of the circular muscle layers reduces the diameter of the

chamber, progressing from apex to base (squeezing a tube of toothpaste);
responsible for the high pressures developed by the LV;
- contraction of the spiral muscles pulls the mitral valve ring toward the apex,
thereby shortening the long axis.
- The conical shape of the lumen gives the LV a smaller surface-to-volume
ratio than the RV and contributes to the ability of the LV to generate high
pressures.
 Atrial contraction
- normally makes only a minor contribution to the filling of the two ventricles at rest
- is a useful safety factor in case of
-tachycardia - the diastolic interval/time for passive filling is short, and
atrial contraction can provide a much-needed boost.
-certain pathological conditions, like narrowed/stenotic AV valve, when the
atrial pump can make an important contribution to ventricular filling

- the relative importance of atrial contraction to overall cardiac function is evident

in patients who develop atrial fibrillation - arrhythmia with atria chaotic
electrical activity (500 impulses/min)
 The right atrium (RA) contracts before the left atrium (LA), but the left
ventricle contracts before the right
- SA node is located in the RA
→ atrial contraction begins and ends earlier in the RA than in the LA
-Ventricular contraction starts slightly earlier on the left side
→ mitral valve closes before the tricuspid valve.
-RV has a briefer period of isovolumetric contraction (it does not need to build up as
much pressure to open its semilunar valve and to initiate ejection)
→ pulmonary valve opens slightly ahead of the aortic valve
-Ejection from the RV lasts longer than that from the LV
→ aortic valve (higher downstream press.) closes before the
pulmonary valve
→ pulmonary valve (lower downstream pressure) opens first and
closes last.
! Normal physiological splitting of S2 due to the
timing difference in the closure of the semilunar
valves.
During inspiration, the relatively negative
intrathoracic pressure enhances filling of the right
heart, causing it to have a larger end-diastolic
volume and more blood to eject (more time
required for ejection from RV)
Ventricular Relaxation

- Isovolumetric relaxation is briefer in the right heart than in the left.

- the pulmonary valve closes after the aortic valve, and the tricuspid
valve opens before the mitral valve

→ The right ventricle begins filling before the left.

 Cardiac volumes & myocardial contractility/inotropism
- Inotropism = the intrinsic ability of the cardiac muscle to contract and to
develop force at a given muscle length
- estimated by the ejection fraction (EF)
= stroke vol./end-diastolic vol.
= 0.55 - 0.60 (55-60%)

- End-diastolic volume: EDV = 110-120 ml → 150-180 ml

- End-systolic volume: ESV = 40-50 ml → 10-20 ml
- Stroke volume (SV): volume of blood pumped with each contraction
SV = EDV - ESV ~ 120 ml – 50 ml = 70 ml
- Heart rate (HR) = number of beats per minute
- Cardiac output (CO) = volume of blood per minute
= Stroke volume x Heart rate
- Pulse: rhythmic stretching of arteries by heart contraction
- Measurement of cardiac volumes & flows by echocardiography & Doppler ultrasound
technique. As a rule, ejection fractions of LV and RV are equal, but clinicians
normally measure left ventricular ejection fraction (LVEF).
 *
*wedge pressure -index of left atrial pressure
Pressure-Volume loop for the left ventricle – ejection work of the ventricle

Graphical Analysis of Ventricular The "pressure-volume loop” (red lines),

Pumping. Relationship between LV demonstrating changes in intraventricular
volume and intraventricular pressure volume and pressure during the normal
during the cardiac cycle (diastole and cardiac cycle. EW, external work (the area
systole). subtended by the volume-pressure diagram).
 "Pressure-Volume Diagram" during the cardiac cycle - LV

- Diastolic pressure curve:

*shows gradual filling of LV up to the end-
diastolic pressure (EDP)
*pressure greatly rises after 150 ml
ventricular filling … (no more stretch,
pericardial limit)

- Systolic pressure curve:

*shows systolic pressure during LV
contraction at each volume of filling;
*increases even at low ventricular vol.
*reaches a max. 250-300 mmHg (LV),
and 60-80 mmHg (RV) at 150 -170 ml.
* for volumes > 170 ml, the systolic
pressure actually decreases (actin and
myosin filaments interrelation decreases)
The 4 phases of the "pressure-volume diagram", during the normal
cardiac cycle:
Phase I: Period of filling.
-initial ventricular volume ~50 ml (end-systolic volume),
diastolic pressure ~0 mm Hg.
-ventricular volume normally increases with 70 ml, up to ~120 ml (end-
diastolic volume), and the diastolic pressure rise to about 5 mm Hg.
Phase II: Period of isovolumic contraction.
-volume of the ventricle constant (all valves closed) ~120 ml, the pressure
inside the ventricle increases to equal the pressure in the aorta, at ~80 mm Hg.
Phase III: Period of ejection.
-systolic pressure rises higher during contraction of the ventricle (from 80 up to
~120 mmHg), while the volume of the ventricle decreases during ejection.
Phase IV: Period of isovolumic relaxation.
-aortic valve closes, no change in volume (~50 ml ESV), decrease of ventricular
pressure back to diastolic pressure (~0 mm Hg).
 Preload and Afterload

Preload
- the degree of tension on the muscle when it begins to contract.
- is usually considered to be the end-diastolic pressure (EDP)
when the ventricle has become filled.
- depends on the incoming blood in the right atrium (RA)
= venous return

Afterload
- the load against which the muscle exerts its contractile force.
- is the systolic pressure in the artery leading from the ventricle,
(relation with the vascular resistance).
Pressure-Volume curve for the left ventricle during cardiac cycle

(EDV-ESV)

ejection Aortic valves open

(Afterload- arterial
pressure)
Isovolumic
relaxation

contraction
Isovolumic
(Preload– EDP,
degree of stretch in
filling the resting state)

Stroke volume is determined by: 1) preload (EDP), 2) afterload (arterial

pressure) and 3) intrinsic inotropic state of the myocardium.
Frank-Starling low of the heart:

Within physiological limits, the heart pumps all the blood that
returns to it.
- Preload: the wall tension that corresponds to ED pressure →
venous return - skeletal mm pump & respiratory pump
- sympathetic constriction of veins
→ EDV → length of sarcomere at beginning of contraction;

→ length-tension relationship in cardiac muscle

optimal sarcomere lengths – max. no. of A-M cross-bridges,
troponin affinity for Ca
increase Ca uptake from extracellular fluid and release from SR
- Afterload – arterial blood pressure
- Inotropic state of the heart
- Stretch of the right atrial wall directly increases the heart rate
by 10-20 % → increase the amount of blood pumped each minute
 Frank-Starling law of the heart

More blood in the ventricle at the beginning of contraction (EDV),

the greater the stroke volume. Stroke volume is proportional to force.
 The tension generated (force) is directly
proportional to the initial length of the muscle fiber.
Length-Tension Relationship

Factors that influence

this relationship:
• Intracellular Ca2+
• Changes in force due
to fiber length
• Changes in force
created by catechol-
amines discharges

The ability of stretched muscle, up to an optimal length,

to contract with increased work output is characteristic
of all striated muscle.
 Frank-Starling law of the heart
End-systolic pressure-volume relation
Left Ventricular Pressure

D”
D’ C”
D C’
C
↑ EDV

Normal EDV

↓ EDV

A A’ A” B B’ B”
Left Ventricular Volume
Assessment of contractility by the use
of a ventricular pressure-volume loop.
The purple pressure-volume loop is
the normal curve.
 Chemical energy required for cardiac contraction

Efficiency of cardiac contraction

- most of the expended chemical energy is converted into heat (75-80%)

- a much smaller portion is converted into work output (WO) (20-25%).

Efficiency or performance of cardiac contraction

= WO / total chemical energy expenditure

Maximum efficiency of the normal heart ~ 20-25 %.

In heart failure, it decreases to as low as 5 -10 %.
 Cardiac Work Output (WO)
• Stroke work output of the heart
= amount of energy converted to work / heartbeat (stroke).
• Minute work output
= total amount of energy converted to work /1 minute (stroke work output x HR)

• Work output (WO) of the heart is used:

1) to move the blood from the low-pressure veins to the high-pressure
arteries - volume-pressure work or External Work (EW)
(WOLV ~ 6 x WORV , given the different systolic pressures in the 2 pumps).

2) a minor proportion of energy is used to accelerate the blood to its

velocity of ejection through the aortic and pulmonary valves
– Kinetic energy of blood flow  mass of blood ejected x vejection2.
normally 1% of WO, increases up to 50% in Aortic Stenosis
 Myocardial contractility – myocardial cell structure
Cardiac myocytes are shorter then the skeletal ones, branched, interconnected
from end to end by intercalated disks (desmosomes, gap junctions) in a
mechanical and electrical syncytium:
AP generated in the sinoatrial node travel in the entire heart in ~ 0.22 sec
Contraction of a cardiac muscle cell ~ 0.3 sec

Sarcolema -T tubules & terminal cisternae Triad and its role in the
- sarcoplasmic reticulum (SR) excitation-contraction coupling
 Myocardial contractility – myocardial cell structure

-Transverse T-tubule
-particular to myocardium: radial, but also axial T tubules
-invagination of the sarcolemma; extension of extracellular fluid…
-more developed in the ventricles;
-scanty in atrial & Purkinje cells
-oriented at the Z lines
-enable fast impulse transmission / almost simultaneously
stimulation of myofibrils

-Sarcoplasmic reticulum
-developed from ER, important as Ca store
-closed set of anastomosing tubules wandering through the
myofibrils:
network SR (important for Ca re-uptake by Ca-ATPase pumps,
inhibited by phospholamban)
junctional SR (close to sarcolemma/T-tubules, Ca store)
corbular SR (sac-like expansion) along the SR network, in I band
(Ca storage enabled by calsequestrin)
 Myocardial contractility – myocardial cell structure

• Sarcoplasme: contains myoglobin (3.4 g/l), an O2 store, which is

50% saturated at pO2=5 mmHg; it facilitates the diffusion of O2
through the sarcoplasme

• Single central nucleus

• Mitochondria: up to 30% of the volume of the heart

→ great oxidative capacity

• Rich capillary supply: ~ 1 capillary / myocardial cell; short diffusion

distances

• Cardiac myocytes receive sympathetic and parasympathetic

innervation that modulate cardiac muscle function.
 Myocardial contractility – myocardial cell structure

Sarcomere - contractile unit, located between two Z lines, 1.8-2 mm in resting

myocytes, give the striated appearance, contains myofibrilary proteins:
- contractil: myosin (thick), actin (thin); each myosin is surrounded by 6 actin filam.
- regulatory: tropomyosin, troponin complex
- accesory, non-contractile cytoskeletal filaments:
titin/connectin, tropomodulin, nebulin
Cardiac sarcomere: major components

Troponin C (TnC): binds to Ca2+ to produce a conformational change in TnI

Troponin T (TnT): binds to tropomyosin, interlocking them to form a troponin-
tropomyosin complex
Troponin I (TnI): binds to actin and cover its myosin binding sites, to hold the troponin-
tropomyosin complex in place and to inhibit A-M binding and contraction.
TnI phosphorylation by beta1 agonists accelerates relaxation
 Cardiac sarcomere and contraction

Actin has ATP and Ca/Mg binding sites; interaction with tropomyosin-
troponin complex; present myosin binding sites

Myosin - ATP-ase activity, interact with actin

Contraction = shortening of the sarcomeres; sliding filament mechanism

(repeated making and breaking of crossbridges between A & M filaments, in
the presence of ATP).
The crossbridges are the heads of the myosin molecules, which change
their angles by binding to the actin sites, after tropomyosin Ca-dependent
displacement .
 Cardiac muscle is generally similar to skeletal muscle in the interaction
of the actin and myosin during cross-bridge cycling, the resynthesis of ATP,
and the termination of contraction/relaxation.
Excitation-Contraction Coupling in Cardiac Muscle
STEPS:

1. AP from SAN travels through gap junctions in adjacent

myocytes/conductive tissue. AP spreads over cell membranes and deep
into the T tubules

2. AP-triggered voltage change opens L-type Ca channel on cardiac

myocytes membrane → inward Ca current (during the AP’s plateau)

3. ↑ [Ca]i (10%) triggers the Ca-induced Ca release from SR Ca channels

(ryanodine receptors) → critical dependence of cardiac contraction
on extracellular Ca

4. ↑↑ [Ca]i (90%) from SR stores → Ca binds to troponin C → tropomyosin

is moved out and release the myosin binding sites on the actin filaments
→ promotes actin-myosin interaction and contraction
Excitation-Contraction Coupling in Cardiac Muscle
5. Myosin cross-bridges bind to the underlying actin → one direction
movement of the myosin head, which pulls the actin filament toward the
center of the sarcomere
6. Actin & myosin binding → myocardial cells contract, developing a
tension proportional to [Ca]i
7. Late stage of AP phase 2 (plateau): influx of Ca2+ through L-type Ca2+
channels decreases → less Ca2+ released by the SR - prevent a further
increase in [Ca2+]i
8. Relaxation occurs when [Ca]i is restored/decreased to resting values by
-Ca-ATPase pump (SERCA)- disinhibited by phospholamban phosphorylation
-sarcolemmal Ca pump
-electrogenic 3Na-1Ca antiporter
9. ATP is needed for relaxation, to release myosin from the actin
(if not → rigor status). Partial hydrolysis of ATP and release of ADP
energizes the myosin head for another cross-bridge cycle.
AP plateau: opening of the voltage-
dependent L-type Ca2+ channels.
Ca2+ influx is small but critical for the
opening of SR Ca2+ channels.

Ca2+ release from the SR increases [Ca2+]i

to allow contraction.

Relaxation occurs as the [Ca2+]i is

lowered from the combined actions of the
sarcolemmal 3Na+-1Ca2+ antiporter, Ca2+
uptake by the SR and Ca2+ extrusion by the
sarcolemmal Ca2+ pump.

AP in cardiac muscle (≈0.3 sec) overlaps

the contraction, resulting in a long
refractory period; modulation of L-type
Ca2+ channel can be used as an alternative
strategy to increase the force of contraction
 Myocardial relaxation and intracellular Ca2+

(1) Extrusion of Ca2+ into the Extracellular Fluid

! Even during the plateau of AP the myocyte extrudes some Ca2+.

After the membrane potential returns to more negative values, the

extrusion processes trigger a [Ca2+]i fall.

The cells extrude all the Ca2+ that enters the cytosol from the
extracellular fluid through L-type Ca2+ channels.

Ca2+ extrusion into the extracellular fluid occurs by

(1) sarcolemmal Na-Ca exchanger (NCX1), which operates
at relatively high levels of [Ca2+]i;
Effect of cardiac glycosides (digitalis) to ↑ [Ca2+]i

(2) a sarcolemmal Ca2+ pump, which may function at even

low levels of [Ca2+]i, but contributes only modestly to
relaxation.
 Myocardial relaxation and intracellular Ca2+

(2) Re-uptake of Ca2+ into the SR

Even during the plateau of AP, some of the
Ca2+ accumulating in the cytoplasm is
sequestered into the SR by the Ca2+ pump
SERCA. Regulated by phospholamban.

(3) Dissociation of Ca2+ from Troponin C

As [Ca2+]i falls, Ca2+ dissociates from

troponin C, blocking actin-myosin
interactions and causing relaxation.

β1-Adrenergic agonists accelerate

relaxation by promoting phosphorylation of
troponin I, which in turn enhances the
dissociation of Ca2+ from troponin C.
 Phospholamban effect on heart activity

Phospholamban, an integral SR membrane protein with a single

transmembrane segment, is an important regulator of SR Ca-pump (SERCA).

Its phosphorylation by any of several kinases (like protein kinase A – PKA,

secondary to β1-adrenergic stimulation) relieves phospholamban's inhibition of
SERCA, allowing Ca2+ resequestration in the SR to accelerate.

The net effect of its phosphorylation is an increase in the rate of cardiac muscle
relaxation. Also, a positive inotropic effect (more Ca available in the SR).
 What is specific to cardiac muscle

APs that propagate between adjacent cardiac myocytes through gap

junctions initiate contraction of cardiac muscle.

Cardiac contraction requires Ca2+ entry through L-type Ca2+ channels,

that will locally determine important Ca-induced Ca release

The regulatory protein troponin C (TNNC1 subtype) has just a single,

active low-affinity Ca2+ binding site, rather than the two high-affinity and
two low-affinity sites of troponin C TNNC2 in skeletal muscle.

Note the importance of SR Ca2+ pump activity and its inhibition by the
regulatory protein phospholamban.
When phospholamban is phosphorylated by cAMP-dependent protein
kinase (PKA), its ability to inhibit the SR Ca2+ pump is lost.
Thus, activators of PKA, such as epinephrine, may enhance the rate of
cardiac myocyte relaxation.
 What is specific to cardiac muscle
• In cardiac muscle, the strength of contraction is not regulated by frequency
summation or multiple-fiber summation possible, but through modulating
the contractile force generated during each individual muscle twitch.
• The contractile force is enhanced (positive inotropic effect) by:
- modulating the magnitude of the rise in [Ca2+]i :
Norepinephrine (NE) acts on β-type adrenergic receptor to increase
cAMP, activate PKA and phosphorylate the L-type Ca2+ channels,
thereby increasing Ca2+ influx and contractile force.
- cAMP pathway also increase the Ca2+ sensitivity of the
contractile apparatus by phosphorylating one or more
of the regulatory proteins.
- NE increase the Ca2+ permeability of voltage-gated Na+ channels
- prolongation of AP through inhibition of K channels increase Ca inflow
• The contractile force is decreased (negative inotropic effect) by:
Ach acts on muscarinic receptors, increase cGMP →
phosphorylation of L-type Ca2+ channels at distinct sites →
decrease in Ca2+ influx during the cardiac AP → decrease in the
force of contraction.
Duration of contraction:
function of AP duration
~ 0.2 sec in A
~ 0.3 sec in V

When cardiac muscle is stretched, it contracts more forcefully:

length-tension relationship in cardiac muscle
(Frank-Starling Low of the Heart: optimal sarcomere lengths, number
of A-M cross-bridges, troponin affinity for Ca, increase Ca uptake and
release from SR)
 Coronary Circulation

Main L & R coronary arteries: left for the anterior & left lateral portions of LV,
and right for most of the RV and the posterior part of the LV.
- epicardial arteries on the surface of the heart;
- intramuscular arteries penetrate from the surface into the cardiac muscle
mass; compressed during systole
- subendocardial arterial plexus
- ! inner 0.1 mm of the endocardial surface is also nourished directly from the
intracardiac blood
 Coronary Circulation
Coronary venous blood flow:
- from the LV returns to the RA by way of the coronary sinus (~75%
of the total coronary blood flow);
- from the RV returns through small anterior cardiac veins that flow
directly into the RA.
- ! a very small amount of coronary venous blood also flows back
into the heart through very minute thebesian veins, which empty
directly into all chambers of the heart.
Collateral Circulation in the Heart.
In a normal heart, almost no large communications exist among the larger
coronary arteries, but many anastomoses do exist among the smaller arteries sized
20 - 250 µm in diameter.

The degree of damage to the heart muscle (secondary to atherosclerotic coronary

constriction or by sudden coronary occlusion) is determined to a great extent by
the degree of collateral circulation that has already developed or that can open
within minutes after the occlusion.

Minute anastomoses in the normal coronary arterial system

 Coronary Blood Flow
In resting conditions coronary blood flow in adults averages about 225 ml/min
(4 – 5 % of the total CO).

During strenuous exercise:

→ 4-7 fold increase CO together with increased arterial pressure
→ 6-9 fold increased work output of the heart, with only 3-4 times increase in
coronary blood flow
! increase of the ratio (heart energy expenditure / coronary blood flow) shows a
relative deficiency of coronary blood supply →the need for increasing the "efficiency"
of cardiac utilization of energy.

Phasic flow of blood through the coronary capillaries of the LV during cardiac
systole and diastole: strong compression of the LV muscle around the intramuscular
vessels during systolic contraction. For the RV the phasic changes are partial, because
the force of contraction of the RV muscle is far less than that of the LV.
 Control of Coronary Blood Flow
1. Regulation through Local Muscle Metabolism

Metabolic factors, especially myocardial oxygen consumption/oxygen demand, are

the major controllers of myocardial blood flow.
Normally ~70% of the oxygen in the coronary arterial blood is removed
as the blood flows through the heart muscle→ little additional oxygen can be
supplied to the heart musculature → the need to increase the coronary blood flow,
through local arteriolar vasodilation, proportional to cardiac muscle
metabolism/ degree of activity.

Vasodilator substances released from the muscle cells in response to

increased metabolism:
-Adenosine: low oxygen conc. in the muscle cells→ ATP degrades to adenosine
monophosphate→ further degraded to adenosine → adenosine release into the
tissue fluids of the heart muscle→ vasodilation (action maintained for only 1-3 hrs)
Most of adenosine is reabsorbed into the cardiac cells to be reused.
Obs: Blockers of adenosine do not prevent coronary vasodilation caused by
increased heart muscle activity.
- Other vasodilators: adenosine phosphate compounds, potassium ions,
hydrogen ions, carbon dioxide, bradykinin, prostaglandins, nitric oxide.
 Control of Coronary Blood Flow
2. Autonomic Nervous Control of Coronary Blood Flow: Direct & Indirect
effects

Direct effects: action of Ach (vagus nerves) and NE/E (sympathetic nerves) on the coronary
vessels
Ach has a direct effect to dilate the coronary arteries, even the distribution of vagal nerve fibers
to the ventricular coronary system is reduced.
NE has either vascular constrictor or vascular dilator effects, depending on the presence or
absence of constrictor receptors (alpha receptors, > on epicardial coronary vessels) and dilator
receptors (beta receptors, > on intramuscular arteries). Both alpha and beta receptors exist in
the coronary vessels →sympathetic stimulation cause slight overall coronary constriction or
dilation, but usually constriction.
Excess sympathetic drive → severe alpha vasoconstrictor effects →vasospastic myocardial
ischemia.

Indirect effects: secondary changes in coronary blood flow caused by increased/decreased

activity of the heart, mostly opposite to the direct effects, that play a major role in normal
control of coronary blood flow.

Sympathetic stimulation increases both HR and contractility →increases the rate of

metabolism → vasodilation of coronary vessels through local blood flow regulatory mechanisms
→ blood flow increases.
Vagal stimulation slows the heart and has a slight depressive effect on heart contractility
→ decrease cardiac oxygen consumption
 Particularities of Cardiac Muscle Metabolism

- derives mainly from oxidative metabolism of fatty acids (70%) and, to a

lesser extent, of lactate and glucose (anaerobic conditions, ischemic cardiac
pain due to production of lactate and pH decrease)
- is measured by the rate of oxygen consumption in the heart
- is used to provide the work of contraction.

- >95% of the metabolic energy is used to form ATP in the mitochondria. ATP
is then used for cardiac muscular contraction and other cellular functions.

-in severe coronary ischemia, ATP degrades to adenosine diphosphate →

adenosine monophosphate → adenosine → dilation of the coronary arterioles
during coronary hypoxia.
Adenosine diffusion from the muscle cells into the circulating blood with serious
cellular consequence. Within 30 min. of severe coronary ischemia, about one
half of the adenine base can be lost from the affected cardiac muscle cells.
New synthesis of adenine is only possible at a rate of 2%/hour. For a coronary
ischemia that persisted for ≥30 minutes, relief of the ischemia may be too late
for the cardiac cells to survive.