Dr.Arati Mohan Badgandi

Moderator :Dr. Asha

Sequence of electrical and mechanical events during course of a single heartbeat.

Heart consists of two atria and two ventricles that provide two separate circulations in series.

Pulmonary circulation, a low-resistance and high-capacitance vascular bed, receives output from right side of heart, and chief function is bidirectional gas exchange.

Left side of heart provides output for systemic circulation - delivers oxygen & nutrients, removes CO2 & metabolites from various tissue beds

Begins with initiation of heartbeat (specialized property of cardiac pacemaker tissues is automaticity & rhythmicity).

SAN - natural pacemaker; generating impulses at greatest frequency.

Describes pressure, volume & flow phenomena in ventricles as function of time.

Cycle similar for both ventricles, with differences in timing due to differences in the depolarization sequence & levels of pressure in pulmonary & systemic circulations.

(A) Isovolumic Contraction Phase Represents 1st portion of systolic activity,

just after QRS complex on ECG - myocardial fibers begin to shorten.

Contraction continues - ventricular pressure increases rapidly, exceeding atrial pressure –forcing AV valve to close.

AV valve balloons into atrium – chordal apparatus tenses, preventing regurgitation –sealed chamber.

Bulging of MV into LA - slight increase in LA pressure (c wave).

(B) Ejection phase

When developed pressure > resting pressure of aorta or pulmonary artery, semilunar valves open - ejection phase.

Actual opening of valves due to movement of blood across valve leaflets caused by pressure gradient.

Ejection phase leads to marked decrease in ventricular volume and slight increase in pressure initially that rapidly decreases to the dicrotic notch pressure.

Equalization of pressure gradient between ventricular and aortic pressures - end of ejection phase & closure of semilunar valves.

This is the point of smallest ventricular volume, known as end-systolic volume (ESV) - dependent on contractile state of ventricle and properties of vascular system.

In clinical practice, end-diastolic volume EDV & ESV are relatively easy to measure. The difference between these two is the SV.

By using SV equation, divided by the EDV, ejection fraction (EF) can be obtained.

EF = (EDV-ESV)/EDV

EF well-known estimation of global cardiac function- allows application of Starling principle in study of cardiac function based on changes in EDV as they relate to SV.

LA pressure rises during ventricular systole (v wave) as blood returns to the LA via pulmonary veins.

(C) Isovolumic Relaxation Phase

Isovolumic relaxation begins to occur before blood has stopped flowing out of ventricle, energy-consuming process.

Refers to period immediately after closure of semilunar valves, in which ventricle undergoes rapid decrease in pressure and no change in volume - precontractile configuration.

Pressure declines exponentially during isovolumic relaxation, when semilunar valves are closed.

(D) Filling Phase (Diastolic Filling) As relaxation continues, ventricular

pressure drops. Atria receive blood flow from pulmonary

veins (LA) or SVC & IVC (RA), thus experiencing rise in pressure & volume.

As atrial pressure rises & ventricular pressure drops, a crossover point is reached where AV valves open and blood flows down pressure gradient to ventricles.

2 phases : (1)Rapid phase based solely on pressure

gradient (2)Slower active phase, based on atrial

contraction (atrial kick), producing a wave.

During this filling, ventricular volume increases rapidly but pressure changes very little.

At low ESV, ventricular early rapid filling facilitated by ventricular suction/elastic recoil.

Measured by end-diastolic pressure-volume relation (EDPVR), which describes ventricular distensibility - strong relationship to the compliance of ventricle, extrinsic factors, & determinants of ventricular relaxation.

This process continues until next electrical signal - starting contraction phase again.

•Valve closure & rapid-filling phases - audible with a stethoscope. •S1- vibrations with closure of AV valves - ventricular systole.• S2, shorter & higher frequency than S1- closure of semilunar valves (aortic and pulmonic) at end of ventricular ejection. •S3, S4 - low-frequency vibrations due to early, rapid filling & late diastolic atrial contractile filling respectively. Heard in normal children, but in adults usually indicate disease.

Alternative time-independent representation of cardiac cycle obtained by plotting instantaneous ventricular pressure and volume.

During ventricular filling, pressure and volume increase nonlinearly (phase I).

Instantaneous slope of pressure-volume (P-V) curve during filling (dP/dV) is diastolic stiffness, & inverse (dV/dP) is compliance.

Thus, as chamber volume increases, ventricle becomes stiffer.

In a normal ventricle, operative compliance is high, as ventricle operates on flat portion of its diastolic P-V curve.

During isovolumic contraction (phase II) pressure increases - volume remains constant.

During ejection (phase III) pressure rises & falls until minimum ventricular size is attained.

Maximum ratio of pressure to volume (maximal active chamber stiffness/elastance) usually occurs at end of ejection.

Isovolumic relaxation follows (phase IV), & when left ventricular pressure falls below left atrial pressure, ventricular filling begins.

End diastole is at lower right hand corner of loop, & end systole is at upper left corner.

Heart provides driving force for delivering blood throughout CVS to supply nutrients & remove metabolic waste.

Due to complexity of RV anatomy, description of systolic function usually limited to the LV.

Systolic performance of heart is dependent on loading conditions & contractility.

Preload & afterload are two interdependent factors extrinsic to heart - govern cardiac performance.

CO - amount of blood entering circulation/minute.

Reflects condition of heart & entire vascular system, subject to autoregulatory systems of vasculature and tissues.

CO=SV X HR Primary determinants for CO – HR & SV. Also dependent on secondary factors -

venous return, SVR, peripheral oxygen use, total BV, respiration & body position.

Normal range of CO 5-6 L/min in 70-kg man, with SV 60-90mL/beat & HR 80beats/min.

CO highly variable in normal healthy individual, being able to increase upto 25-30 L/min during high metabolic demand.

Cardiac index (CI) -used to compare different sizes of individuals.

Done by correcting standard CO equation for body surface area (BSA). CI = CO/BSA

Normal values 2.5-3.5L/min/m2 for normal 70kg man. By correcting for BSA, it is possible to compare patients at common level of function, despite differences in body habitus.

Preload - ventricular wall stress at end-diastole.

Determined by ventricular EDV, end-diastolic pressure EDP & wall thickness.

To apply preload principle to clinical practice, following adjustments can be made:

1.Substituting ventricular volumes for preload

stress In clinical practice, ventricular volumes most

closely approximate muscle fiber length. In normal humans, a straight-line relationship

has been demonstrated between EDV and SV. 

2.Substituting ventricular pressures for ventricular volumes

Ventricular pressures often substituted for

ventricular volumes when assessing filling conditions of the ventricle.

Clinically used substitutes for LVEDP & LVEDV

left atrial pressure (LAP) pulmonary artery occlusion/capillary wedge

pressure (PAOP/PCWP) pulmonary artery diastolic pressure (PADP) right atrial pressure (RAP) central venous pressure (CVP)

Accuracy in predicting LV preload - distensibility of ventricle, integrity of MV, presence of normal pulmonary conditions, integrity of pulmonary, tricuspid valves & RV function.

LVEDP can be measured with placement of a catheter into the LA.

LA catheter commonly inserted surgically through one of the pulmonary veins.

LAP provides good approximation of LVEDP, provided the MV is normal.

Commonest technique for estimation of LVEDP during cardiac surgery - placement of pulmonary artery (PA) catheter. PCWP - good approximation of LVEDP.

Marked alterations in airway pressure (ie.during use of high levels PEEP) may disturb relationship between PCWP & LAP.

Depending on compliance of pulmonary parenchyma, part/all of airway pressure may be transmitted to PA catheter.

Must be considered when evaluating LV filling pressure with PA catheter in patients receiving mechanical ventilation & PEEP.

When catheter cannot be advanced into wedge position, PADP may be used to estimate LVEDP -usually quite accurate, unless pulmonary vascular resistance (PVR) markedly elevated.

CVP - poorest estimate of LVEDP, although frequently used in patients with good function of RV & LV.

2nd major determinant of mechanical properties of cardiac muscle fibers & performance.

Afterload can be considered as stress imposed on ventricular wall during systole or as arterial impedance to the ejection of SV.

Measurements of Afterload

WALL STRESS

Can be expressed & quantified by Laplace equation: σ=(P.r)/2h

where σ is the stress (dynes·cm-2), P is pressure generated by LV throughout systole, r & h are corresponding radius & thickness of RV/LV wall.

IMPEDANCE

Afterload – extracardiac forces (impedance) in systemic circulation that oppose ventricular ejection & pulsatile flow.

As LV is coupled to systemic circulation through open aortic valve, pulsatile flow (SV) & pressure generated by LV will be hindered by compliance & resistance of arterial system.

Determined by physical properties of aorta & its branches (viscoelastic properties and diameter) & by properties of their content (blood).

SVR clinically obtained as ratio of pressure differential between mean arterial pressure (MAP) & RAP or CVP & CO - oversimplified version of resistance.

Based on circulatory analog of Ohm's law: P=QXR

Determines that pressure (P) generated during ejection of given flow (Q) is proportional to that flow and to the resistance (R) encountered by it.

Resistance mainly determined by arteriolar resistance SVR= (MAP-RAP)/CO

3rd determinant of SV. Contractility - intrinsic property of cardiac cell that defines amount of work heart can perform at a given load.

DETERMINANTS(A) Isovolumic Contraction Phase Indices prototype of such indices - dP/dt. obtained by placing a catheter with a

micromanometer at tip into LV. LV pressure continuously sampled while an

electronic differentiator calculates the first derivative of pressures, or dP/dt (mm Hg/s).

Highest value of dP/dt, or peak dP/dt - proportional to contractility.

Because heart's developed tension/pressure is dependent on initial length of cardiac muscle, it is predictable that dP/dt will be preload dependent.

(B) Ejection Phase Indices Standard ejection phase index of contractility -

EF.

(C) Load-Independent Indices Ratio of ventricular pressure over volume is

ventricular elastance - varies throughout cycle. For each cardiac cycle, researchers defined the

maximal value of this ratio as the end-systolic elastance (EES) & point at which it was reached - end-systolic point.

Noted - with rapid decreases in preload all consecutive end-systolic points were positioned on a single straight line, known as the end-systolic pressure-volume relation (ESPVR)

Slope of this line (EES) is proportional to contractility; steeper at higher contractility, flatter at lower contractility.

Major determinant of CO. Controlled by multiple systems - conduction

system, CNS & ANS, which respond via complex pathways to changes in internal & external conditions.

Besides neural & hormonal factors, many pharmacologic controls available.

HR itself can increase contractility of heart -treppe/step (Bowditch) phenomenon, which shows that at increased HRs, slope of ESPVR increases in stepwise fashion related to increased rate.

Thought to be due to increase in level of intracellular calcium.

Diastolic dysfunction - 40%-50% of patients with CHF despite normal systolic function.

Use of TEE greatly improved knowledge of diastole by showing actual real-time activities in the heart related to filling pressures, shape & relaxation.

Possible to relate diastolic dysfunction (which is increased impedance to ventricular filling) to structural & pathologic causes of CHF.

Determinants of Diastolic Function(A) PASSIVE VENTRICULAR FILLING Main determinants of transmitral flow are

LV compliance & rate of rise of transmitral gradient.

Numerous drugs & cardiac revascularization improve dysfunction/stiffness.

(B) ATRIAL OR ACTIVE FILLING More than 75% flow - passive portion of

diastole. In severe diastolic dysfunction where this

cannot take place - atrial kick important to maintain SV & CO.

Two waves obtained: 1.E wave - early passive flow across MV 2.A wave - atrial systole. Small area of no flow between E and A

waves - diastasis. Ratios change with disease & age. In early diastolic failure, E/A wave ratio <1,

& waves reverse, E being shorter than A- delayed relaxation pattern.

As failure progresses, E/A ratio reverts to normal pattern >1.

Final stage - high, rapidly decelerating E wave with small A wave - restrictive pattern.

The Action Potential Normal heartbeat initiated by complex flow of

electrical signals - action potentials.

Myocardial cell membrane normally permeable to K+, relatively impermeable to Na+.

Membrane-bound Na+–K+-ATPase concentrates K+ intracellularly in exchange for extrusion of Na+.

Intracellular Na+ concentration kept low, whereas intracellular K+ concentration kept high relative to extracellular space.

Relative impermeability of membrane to Ca also maintains high extracellular to cytoplasmic Ca gradient.

Movement of K+ out of cell & down concentration gradient results in net loss of + charge from cell.

Electrical potential established across cell membrane, with inside of cell negative with respect to extracellular environment .

Thus, resting membrane potential represents balance between 2 opposing forces: movement of K+ down its concentration gradient & electrical attraction of negatively charged intracellular space for positively charged K.

Normal ventricular cell resting membrane potential –80 to –90mV.

As with other excitable tissues (nerve & skeletal muscle), when cell membrane potential becomes less negative & reaches threshold value - action potential (depolarization) develops.

AP transiently raises membrane potential of myocardial cell to +20 mV.

In contrast to AP in neurons, spike in cardiac is followed by plateau phase lasting 0.2–0.3s.

While AP in skeletal muscle & nerves due to abrupt opening of fast Na channels in cell membrane, in cardiac muscle it is due to opening of both fast Na channels (spike) & slower Ca channels (plateau).

Depolarization is accompanied by transient decrease in K permeability.

Subsequent restoration of normal K permeability & closure of Na & Ca channels restores membrane potential to normal.

After depolarization, cells are refractory to subsequent normal depolarizing stimuli until phase 4.

Effective refractory period is minimum interval between 2 depolarizing impulses.

In fast-conducting myocardial cells, this period is closely correlated with duration of AP.

In contrast, effective refractory period in slowly conducting myocardial cells can outlast duration of AP.

Some channels activated by change in cell membrane voltage, whereas others open when bound by ligands.

Voltage-gated fast Na+ channel has outer (m) gate that opens at –60 to –70mV & inner (h) gate that closes at –30 mV.

T-type (transient) voltage-gated Ca channels play role in phase 0 of depolarization.

During plateau phase (phase 2), Ca inflow occurs through slow L-type (long-lasting), voltage-gated channels.

3 major types of K+ channels responsible for repolarization.

1st results in transient outward K current (ITo), 2nd is responsible for short rectifying current (IKr), & 3rd produces slowly acting rectifying current (IKs) that restores cell membrane potential to normal

Originates in SAN, group of specialized pacemaker cells in sulcus terminalis, posteriorly at junction of right atrium & SVC.

They cells appear to have outer membrane that leaks Na (& possibly Ca).

Slow influx of Na, results in less negative, resting membrane potential (–50 to –60mV) – has 3 important consequences:

1.constant inactivation of fast Na channels 2.AP with threshold of –40 mV, primarily due

to ion movement across slow Ca channels 3.Regular spontaneous depolarizations.

During each cycle, intracellular leakage of Na causes cell membrane to become progressively less negative - threshold potential reached - Ca channels open, K permeability decreases – AP develops.

Restoration of normal K permeability returns cells in SAN to their normal resting membrane potential.

Impulse generated at SAN normally rapidly conducted across atria AVN – specialized fibers may speed up conduction.

AVN - located in septal wall of RA just anterior to opening of coronary sinus, above insertion of septal leaflet of tricuspid valve -3 distinct areas:

1.Upper junctional (AN) region 2.Middle nodal (N) region 3.Lower junctional (NH) region N region – no automaticity, only junctional

areas. Normally slower rate of spontaneous

depolarization in AV junctional areas (40–60 times/min) allows faster SAN to control HR.

Any factor that decreases rate of SAN depolarization or increases automaticity of AV junctional areas allows junctional areas to function as pacemaker.

Impulses from SAN normally reach AVN after about 0.04s, but leave after another 0.11s.

Delay - result of slowly conducting small myocardial fibers within AVN, which depend on slow Ca channels for propagation of AP.

In contrast, conduction of impulse between adjoining cells in atria & ventricles is due to activation & inactivation of fast Na channels.

Lower fibers of AVN form common bundle of His.

Passes into interventricular septum before dividing into left & right branches - complex network of Purkinje fibers depolarizing ventricles.

In contrast to AVN tissue, His–Purkinje fibers have fastest conduction velocities - nearly simultaneous depolarization of entire endocardium of both ventricles (normally within 0.03s).

Spread of impulse from endocardium to epicardium through ventricular muscle - additional 0.03 s.

Thus, impulse from SAN requires < 0.2 s to depolarize entire heart.

Cascade of biological processes beginning with cardiac action potential, ending with myocyte contraction and relaxation.

E-C related to 1.calcium homeostasis 2.myofilament calcium sensitivity 3.functions of cytoskeletal & sarcomeric

proteins

Myocardial cells contract due to interaction of two overlapping, rigid contractile proteins, actin & myosin.

These proteins fixed in position within each cell during contraction & relaxation.

Dystrophin, large intracellular protein, connects actin to cell membrane (sarcolemma).

Cell shortening occurs when actin & myosin fully interact & slide over one another.

This interaction normally prevented by 2 regulatory proteins – troponin & tropomyosin

Troponin - 3 subunits - troponin I, C & T. Troponin - attached to actin at regular

intervals. Tropomyosin - within the center of actin

structure.

Increase in intracellular Ca concentration (from about 10–7 - 10–5 mol/L) promotes contraction as Ca ions bind troponin C.

Resulting conformational change in these regulatory proteins exposes active sites on actin - allows interaction with myosin bridges (overlapping).

Active site on myosin functions as Mg-dependent ATPase – activity enhanced by increase in intracellular Ca concentration.

Series of attachments & disengagements occur as each myosin bridge advances over successive active sites on actin.

ATP consumed during each attachment.

Relaxation occurs as Ca actively pumped back into SR by Ca2+–Mg2+-ATPase.

Resulting drop in intracellular Ca allows troponin–tropomyosin complex to again prevent interaction between actin & myosin.

Decline of Ca2+ transient is caused by following:

(1) Ca2+ reuptake into SR by SERCA2

(modulated by phosphorylatable regulatory protein termed phospholamban)

(2) Ca2+ extrusion from cell by NCX (3) Ca2+ extrusion from cell by sarcolemmal

Ca2+-ATPase (4) Ca2+ accumulation by mitochondria (5) Ca2+ binding to intracellular buffers

(including fluorescent indicators that are used in experimental systems to measure transient).

Fundamentals of Myocardial Contractility

Relations between force & muscle length, velocity of shortening, calcium & heart rate.

Maximal force developed at any sarcomere length is determined by degree of overlap of thick & thin filaments, & number of available crossbridges.

Force increases linearly until a sarcomere length with maximal overlap (~2.2 m) is achieved, beyond which force & overlap gradually declines to zero.

Ascending limb of length-tension relationship (equivalent to Frank-Starling relationship that relates preload to cardiac performance) also caused by length-dependent increase in myofilament calcium sensitivity .

Explained by enhanced calcium binding to TnC, narrower interfilament gaps at long sarcomere length, increased SR calcium release & uptake at longer sarcomere lengths.

Relation between force & velocity of contraction is hyperbolic.

At maximum force (isometric force), shortening cannot occur.

At zero force (i.e., unloaded muscle), velocity is at max, Vmax, reflecting maximum turnover rate of myosin ATPase.

Therefore, alterations in myosin isoform such as those seen in response to pressure overload, have an effect on Vmax.

Shorter sarcomere lengths decrease Ca2+ sensitivity, caffeine & various inotropic drugs (e.g., levosimendan) - potent Ca sensitizers.

Adrenergic stimulation - cAMP-dependent phosphorylation of cardiac TnI & resultant decrease in myofilament Ca sensitivity.

Thus for a positive -adrenergic receptor (AR)–inotropic effect, amplitude of Ca transient must more than compensate for reduced AR-mediated myofilament sensitivity.

Increasing HR increases contractility - related to Ca2+ capacity & load of SR.

Frequency-dependent acceleration of relaxation (FDAR) results from CaMKII phosphorylation of phospholamban (or by some other mechanism that increases SR Ca2+ transport).

CaMKII might be activated by increased [Ca2+]i - occurs with increased stimulation rates.(precise mechanisms unresolved)

When a strip of heart muscle is attached at both ends - length is fixed & then electrically stimulated, muscle develops force without shortening.

Fundamental property of striated muscle -strength of this isometric twitch is dependent on initial resting muscle length, or preload.

As cardiac muscle is stretched passively, resting tension rapidly rises & prevents overstretching of sarcomeres.

If additional load is applied before contraction (i.e. preload), stimulation causes contraction with increased peak tension & rate of tension development (dT/dt). Thus, total tension includes both active & passive tension.

Inotropic state - defined operationally as change in rate or extent of force development that occurs independently of loading conditions.

Biophysical basis of inotropic state includes

subcellular processes that regulate myocyte cytosolic Ca & actin-myosin crossbridge cycling.

In isolated cardiac muscle, changes in inotropic state measured by changes in peak isometric tension & dT/dt at a fixed preload.

Tension-time curves of isometric twitches at 3 levels of preload. With increased preload, peak tension (T) & maximum rate of tension development (dT/dt) are increased. Time to peak tension unchanged.

If isolated cardiac muscle allowed to shorten, contraction is termed isotonic.

Initial muscle length determined by applying a preload; additional load known as the afterload, affects muscle behavior after stimulation.

Muscle shortening occurs when tension development equals the total load (preload plus afterload).

During shortening, tension remains constant. With dissipation of active state, the muscle returns to initial preloaded length, & tension finally declines.

If preload is altered while afterload is kept constant, length-shortening & length-velocity curves analogous to length-tension curve seen in isometric muscle.

Force-velocity curve describes an inverse hyperbolic curve relating afterload & initial velocity of shortening, can be obtained from a series of variably afterloaded contractions.

When afterload is so great that muscle cannot shorten, contraction becomes isometric (P0).

Velocity of an unloaded contraction (Vmax) is determined by physicochemical properties unique to cardiac muscle & therefore considered a measure of inotropic state.

However, because load always exists, Vmax must be extrapolated from force-velocity curve.

Although changes in preload shift P0 without changing Vmax, a +ve inotropic agent increases Vmax & P0 by means of parallel upward shift of force-velocity curve; -ve inotropic agent causes opposite effect.

Similar operational definitions of inotropic state can be applied to preloaded isotonic contraction, in that a +ve inotropic agent produces upward shift of length-shortening & length-velocity curves.

Tension at end of isotonic contraction is same as tension developed from an isometric contraction at same resting muscle length.

Besides load & contractile state, cardiac muscle performance is influenced by frequency of stimulation.

An increase in stimulation frequency causes an increase in tension in isolated cardiac muscle, known as Bowditch phenomenon.