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CE Article

Role of Diastole in Left Ventricular Function, I: Biochemical and Biomechanical Events

	Abstract

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Left ventricular diastolic function plays an important role in cardiac physiology. Lusitropy, the ability of the cardiac myocytes to relax, is affected by both biochemical events within the myocyte and biomechanical events in the left ventricle. ß-Adrenergic stimulation alters diastole by enhancing the phosphorylation of phospholamban, a substrate within the myocyte that increases the uptake of calcium ions into the sarcoplasmic reticulum, increasing the rate of relaxation. Troponin I, a regulatory protein involved in the coupling of excitation to contraction, is vital to maintaining the diastolic state; depletion of troponin I can produce diastolic dysfunction. Other biochemical events, such as defects in the voltage-sensitive release mechanism or in inositol triphosphate calcium release channels, have also been implicated in altering diastolic tone. Extracellular collagen determines myocardial stiffness; impaired glucose tolerance can induce an increase in collagen cross-linking and lead to higher end-diastolic pressures. The passive properties of the left ventricle are most accurately measured during the diastasis and atrial contraction phases of diastole. These phases of the cardiac cycle are the least affected by volume status, afterload, inherent viscoelasticity, and the inotropic state of the myocardium. Diastolic abnormalities can be conceptualized by using pressure-volume loops that illustrate myocardial work and both diastolic and systolic pressure-volume relationships. The pressure-volume model is an educational tool that can be used to demonstrate isolated changes in preload, afterload, inotropy, and lusitropy and their interaction.

Notice to CE enrollees: A closed-book, multiple-choice examination following this article tests your understanding of the following objectives: Describe the role of left ventricular diastolic function in cardiac physiology Discuss the influences of ion regulation in myocardial contraction and relaxation Explain components of neurohumoral regulation of left ventricular function

Left ventricular diastolic function plays an important role in myocardial performance.³ Events that occur during diastole are crucial to effective systolic function; defects in lusitropy (the ability of the myocytes to relax) have been implicated as an early sign of the development of congestive heart failure.⁴ The lusitropic state is influenced by both biochemical and biomechanical events (active relaxation) in addition to the biophysical properties of the heart (passive stiffness).⁵ In this article, we review the electrophysiology of ventricular action potentials; explain the physiological basis of myocardial contraction and relaxation, with an emphasis on diastole; and describe pressure-volume loops, a useful tool for evaluating ventricular function.

	Electrophysiology of Ventricular Action Potentials

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
A sarcolemma membrane that is uniquely permissive in its leakiness surrounds cardiac muscle myofibrils; the membrane has a very high conductance for potassium ions (K⁺) and a much lower conductance for sodium ions (Na⁺).⁶ This imbalance maintains the resting membrane potential of myocardial cells at approximately –88 mV, a figure quite close to the membrane potential of K⁺ alone. The high concentration of K⁺ inside the cell compared with outside the cell (80 mM vs 4 mM) provides both a concentration gradient and an electrical gradient that favors the movement of K⁺ from inside to outside the sarcolemma.

The membrane-bound Na⁺–K⁺–adenosine triphosphatase (Na⁺-K⁺-ATPase) pump contributes only slightly to the resting membrane potential by pumping 2 K⁺ into the cell for every 3 Na⁺ pumped out of the cell, thus maintaining the slightly negative cell interior. Under specific conditions, such as depolarization, a rapid change in voltage occurs so that current flows across the sarcolemma. Several membrane channels play a crucial role in the development of various currents during a myocardial action potential, including the Na⁺, calcium ion (Ca²⁺), and K⁺ channels. All the channels are membrane-bound proteins that span the membrane lipid bilayer.

The Na⁺, Ca²⁺, and K⁺ channels form pores within the membrane that are "gated" by changes in voltage that occur across the sarcolemma. That is, part of the channel senses the change in voltage that occurs during depolarization. The voltage sensor then alters the conformation of the channel pore to allow specific ions to cross the membrane. To initiate a cardiac action potential, depolarization of the sarcolemma induces the activation gates of the Na⁺ channel to open so that Na⁺ moves into the cell (Figure 1, phase 0). The rapid influx of Na⁺ increases the voltage across the membrane to +30 mV. In addition to their role in physiological function, the Na⁺ channels are the site of action of class I antiarrhythmics (eg, lidocaine, procainamide, quinidine); these agents inhibit the Na⁺ channel by binding to its inactivation gate. This channel is also inhibited by increased levels of extracellular K⁺ in a process used to initiate cardiac arrest during cardioplegia.

View larger version (9K): [in this window] [in a new window]   Figure 1 A ventricular action potential. Phase 0 represents the rapid increase in Na+ current (INa) that occurs at the onset of depolarization. Phase 1 represents a transient outward K+ current (Ito). Phase 2 is the plateau phase and represents the opening of a slow inward Ca2+ current (ICa).Phase 3 represents repolarization and is primarily due to a voltage-gated K+ current (IK). A background K+ current (IK1) contributes to late phase 3 and helps regulate the resting membrane potential, phase 4.

During phase 0, as the membrane voltage approaches –30 mV, the L-type Ca²⁺ channels are activated. These long-lasting Ca²⁺ channels have 2 modes of opening: mode 1, in which opening occurs as short bursts, and mode 2, in which the channel is opened for longer periods. Mode 2 channel opening allows Ca²⁺ from the extracellular space to enter the sarcoplasm (Figure 1, phase 2) and elicit additional Ca²⁺ release from the sarcoplasmic reticulum, an event that generates contraction of myofibrils. The Ca²⁺ current (I_Ca(L)) that is elicited is inactivated slowly, thus explaining the 200- to 300-ms plateau that occurs during phase 2.

Ca²⁺ channels have at least 3 identified specific sites for antagonist binding: N for nifedipine and other dihydropyridines, V for verapamil, and D for diltiazem. Ca²⁺ channel blockers cause the channel to open predominantly in mode 1, thereby decreasing Ca²⁺ conductance during phase 2 of the cardiac action potential and diminishing cardiac contractile force. In the peripheral vascular tree, Ca²⁺ antagonists cause vasodilatation and decrease afterload. L-type Ca²⁺ channels also respond to catecholamines: ß-adrenergic stimulation, via an increase in cyclic adenosine monophosphate (cAMP), leads to phosphorylation of the ₁ subunit on the Ca²⁺ channel. This process increases the probability that the Ca²⁺ channel will open and contributes to a positive inotropic response.⁶

Repolarization occurs via several other currents. First, a voltage-gated transient outward movement of K⁺ (I_to) contributes to the very early or rapid repolarization just after the peak of the action potential (Figure 1, phase 1). Second, during the gradual deactivation of the L-type Ca²⁺ channels, at a voltage of +10 mV, a small time-dependent K⁺ channel is activated. This delayed rectifier K⁺ channel slowly corrects the altered membrane potential by allowing K⁺ to escape from the cell and returning the sarcolemma membrane to resting membrane potential (Figure 1, phase 3). In addition, an inward rectifier K⁺ channel contributes K⁺ current to late repolarization; it passes outward current as long as membrane potential is greater than the normal resting potential. This background current allows K⁺ into the cell when the membrane is hyperpolarized to maintain a high K⁺ concentration and to correct the membrane polarity.

A voltage-sensitive chloride ion (Cl^–) channel provides an inward current that probably contributes little to the normal action potential. However, this channel is activated by catecholamines via cAMP; the influx of Cl^– shortens the action potential that would otherwise be lengthened by the adrenergic effect of enhanced Ca²⁺ channel opening. This modulating effect of increasing Cl^– conductance makes adrenergic stimulation more efficient both by eliciting increased contractility and by shortening the duration of contraction.⁷

Increasing chloride conductance, which is activated by catecholamines, renders adrenergic stimulation more efficient.

 

In addition to the ion fluxes that create the cardiac action potential, other membrane pumps regulate the cellular ion content. The Na⁺-K⁺-ATPase pump has a role in removing Na⁺ that entered the cell during phase 0. A Na⁺-Ca²⁺ antiporter exchanges 3 Na⁺ for 1 Ca²⁺ in response to membrane potential and the relative concentrations of Na⁺ and Ca²⁺ both inside and outside the cell membrane. During phase 2 of the cardiac action potential, this exchanger operates to move a small amount of Ca²⁺ into the cell.⁸ This antiporter also plays a major role in removing the Ca²⁺ that entered the cell during phase 2. A Ca²⁺-ATPase in the sarcolemma membrane removes a small amount of this Ca²⁺ from the sarcoplasm.⁸

Ion channels that line the sarcolemma membrane clearly play a role in cardiac electrophysiology; they are also targets of key cardioactive drugs, including antiarrhythmics, Ca²⁺ channel antagonists, and catecholamines. By controlling ionic flux and therefore the cytoplasmic concentration of Ca²⁺, they link chemical events in the myocyte to mechanical events within myofibrils.

	Myocardial Contraction

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
The links between the depolarized sarcolemma and contraction of myofibrils (excitation-contraction coupling), along with the mechanics of the interaction between myosin, actin, tropomyosin, and the troponin regulatory proteins, have been described.⁶ Briefly, the cardiac myofibrils are composed of the major contractile proteins, actin and myosin. During contraction, these interdigitated filaments slide past one another to shorten the sarcomere. This process is regulated by troponin C, troponin I, and troponin T. Troponin I is tightly bound to actin and blocks its interaction with myosin when Ca²⁺ levels are low during diastole. When released from the sarcoplasmic reticulum, Ca²⁺ binds tightly to a single site on troponin C. The Ca²⁺–troponin C complex promotes the movement of troponin I away from actin and exposes the myosin-binding site. Myosin contains myosin ATPase, an energy-consuming enzyme that catalyzes ATP during the relaxation phase of the cross-bridge cycle. The power stroke of the myosin head is elicited by the release of inorganic phosphate and adenosine diphosphate.

Both ischemia and troponin I depletion produce diastolic dysfunction and myocardial hypertrophy.

 

Evidence supports a modified theory of excitation-contraction coupling that a substantial portion of the myosin cross-bridges binds weakly to the actin filament in the relaxed state.⁹ This weak binding creates a "closed state" in which the cross-bridge interaction creates only a non–force-generating reaction.¹⁰ Troponin I appears to play a crucial role in this regard; intact troponin I is necessary to tether actin and maintain diastole. Altered function of troponin I due to either ischemia or depletion of cardiac troponin I can produce diastolic dysfunction and myocardial hypertrophy.^11,12

	Calcium Regulation During Systole

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Intracellular Ca²⁺ levels regulate the interaction between myofilaments during both the contraction and the relaxation phases of the excitation-contraction coupling cycle and therefore play a key role in the etiology of mechanical dysfunction. The proximity between the L-type Ca²⁺ channels and the Ca²⁺ release channels of the sarcoplasmic reticulum contributes to this process. Regulation of Ca²⁺ release from the sarcoplasmic reticulum has 2 proposed mechanisms: Ca²⁺-induced Ca²⁺ release (CICR) and a voltage-sensitive release mechanism (VSRM). Regardless of the mechanism, however, it is the Ca²⁺ released from the sarcoplasmic reticulum that binds to troponin C to reveal the myosin-binding site.

The voltage-sensitive release mechanism generates sustained calcium release, prolonged contraction, and thus incomplete diastolic relaxation.

 

CICR is the phenomenon by which Ca²⁺ flowing through L-type Ca²⁺ channels elicits Ca²⁺ release from the Ca²⁺ channels of the sarcoplasmic reticulum, the ryanodine receptors. The extent of CICR is graded by the magnitude of the peak of I_Ca(L), which in turn regulates the amount of Ca²⁺ release by the sarcoplasmic reticulum. Evidence supports the idea that the opening of a single L-type Ca²⁺ channel triggers a discrete release of Ca²⁺ from the ryanodine receptor called a Ca²⁺ spark.¹³ What is not known with certainty is whether a Ca²⁺ spark arises from the opening of a single ryanodine receptor or from a small group of receptors acting in concert, although most evidence points to the latter.¹⁴

Ferrier and Howlett¹⁵ recently reviewed the evidence for another mechanism of Ca²⁺ release from the sarcoplasmic reticulum, the VSRM. Like CICR, the VSRM is elicited by membrane depolarization, although the VSRM is activated at potentials near –60 mV, which is substantially lower than the potential required to elicit I_Ca(L). This mechanism generates sustained Ca²⁺ release and prolonged contraction. The magnitude of contractions elicited by VSRM is independent of the amplitude of the inward Ca²⁺ current and dependent on membrane potential. Activation and deactivation of VSRM (and therefore Ca²⁺ release and sustained contraction) are graded by membrane potentials from –20 mV to –80 mV. Thus, absence of full repolarization and/or changes in the duration of an action potential could lead to incomplete diastolic relaxation.

The VSRM is inhibited by the local anesthetic tetracaine in a manner unrelated to the blocking of Na⁺ channels.¹⁶ Tetracaine is thought to act on the ryanodine receptor, selectively blocking the VSRM. This inhibition reduces the contractile response of the myocytes by 50% at voltages that maximally initiate both CICR and VSRM. Defects in the VSRM may play a role in the etiology of congestive heart failure and/or contractile dysfunction associated with myocardial infarction. The sustained contraction elicited by VSRM may delay relaxation in conditions that result in incomplete repolarization, such as cardiac hypertrophy or heart failure.¹⁵

Along with ryanodine receptors, cardiac muscle contains other Ca²⁺ release channels, inositol triphosphate receptors. Inositol triphosphate plays a key role as a second messenger in vascular smooth muscle after activation of -adrenergic, angiotensin II, and endothelin receptors, but it seems to contribute little to normal myocardial function.¹⁷ Although the relative ratio of ryanodine receptors to inositol triphosphate receptors appears decreased in the failing myocardium, no current evidence indicates that activation of inositol triphosphate receptors induces a significant increase in cytosolic Ca²⁺.¹⁸ Inositol triphosphate receptors may have a role in regulating diastolic tone and signaling pathways within the myocardium.¹⁹

	Myocardial Relaxation

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Events that precipitate diastole include both active (intramyocardial) and passive (extramyocardial) mechanisms.²⁰ Major active events that occur within cardiac myocytes include Ca²⁺ regulation, alteration of myofilament structure and function, and neurohormonal activation. Passive events that influence relaxation include changes in early diastolic load and afterload.

	Calcium Regulation During Diastole

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Cytosolic Ca²⁺ levels regulate the active events within the myocytes; when Ca²⁺ concentrations are low, Ca²⁺ dissociates from troponin C and cross-bridge activity is inhibited. The processes by which Ca²⁺ levels are decreased to initiate diastole include (1) the uptake of Ca²⁺ by the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, (2) a sarcolemma Na⁺-Ca²⁺ exchanger (NCX), (3) a sarcolemma Ca²⁺-ATPase, and (4) a mitochondrial Ca²⁺ uniporter. It is estimated that SERCA and NCX remove 70% and 28%, respectively, of the cytosolic Ca²⁺, with the sarcolemma and the mitochondrial Ca²⁺ transport systems each accounting for approximately 1% of Ca²⁺ removal.⁸ Evidence suggests that the relative contributions of SERCA and NCX are altered in failing hearts, with a shift toward NCX and away from SERCA.¹⁷ This shift is detrimental in 2 ways. First, it reduces the Ca²⁺ stored in the sarcoplasmic reticulum, decreasing the amount of Ca²⁺ available for release during systole. Second, the NCX system is energetically more expensive than is the SERCA system; SERCA transports 2 Ca²⁺ for each ATP consumed, whereas NCX transports only 1 Ca²⁺ per ATP.

Processes that reduce myocyte calcium levels and initiate diastole are altered in heart failure. These changes decrease calcium availability for systole and require greater energy expenditure.

 

The activity of SERCA is regulated by phospholamban, a substrate key to the actions of catecholamines during diastole. Phospholamban is a reversible inhibitor of SERCA pump activity.²¹ In its dephosphorylated form, phospholamban inhibits the affinity of SERCA for Ca²⁺. (For a brief discussion of the biological role of protein phosphorylation, see Box on page 399.) Evidence from animal models of phospholamban deficiency reveal hyperdynamic contractile function, implying an important role for phospholamban in the control of basal contractility.²² In fact, the relative ratio of phospholamban to SERCA may be essential to normal contractile mechanics.²³ The phosphorylation of phospholamban relieves its inhibitory effect, increasing the Ca²⁺ sensitivity of SERCA and Ca²⁺ uptake into the sarcoplasmic reticulum, consequently regulating myocardial relaxation.²⁴ Increasing cytosolic cAMP via ß-adrenergic stimulation phosphorylates phospholamban and enhances the rate of relaxation. Increasing SERCA activity enlarges the reservoir of Ca²⁺ available during excitation-contraction coupling and thereby also improves myocardial contractility. Thus, phosphorylation of phospholamban augments both lusitropy and inotropy. Figure 2 summarizes Ca²⁺ flux within myocardial cells.

View larger version (20K): [in this window] [in a new window]   Figure 2 Ca2+ flux in cardiac myocytes during systole and diastole. During systole, both Ca2+-induced Ca2+ release (CICR) and a voltage-sensitive release mechanism (VSRM) induce Ca2+ efflux from the sarcoplasmic reticulum (SR) via ryanodine receptors (RY). Ca2+ binding to troponin C (TnC) moves troponin I (TnI) away from the myosin-binding site on actin, promoting excitation-contraction coupling. Ca2+ is regulated during diastole by uptake into the sarcoplasmic reticulum Ca2+-ATPase (SERCA) pump and mitochondria and by extrusion from the sarcolemma via the Na+-Ca2+ exchanger (NCX) and the Ca2+-ATPase pump. Phospholamban (PLB) inhibits the activity of SERCA; its phosphorylation via adrenergic stimulation enhances SERCA activity.

	Myofilament Structure and Function

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Myocardial relaxation is also influenced by the inherent viscoelastic properties of the myocardium. The extracellular matrix of the heart comprises mainly the connective tissue collagen, fibronectin, and elastin. This matrix provides structural support for the myocytes, assists in transducing myocyte shortening into a cohesive and coordinated force, and has a dynamic structure and composition that influences the mechanical properties of the myocardium.²⁵ Within the myocardium, the matrix also serves as a source of survival signals and a reservoir for growth factors.²⁶ The adhesion of myocytes to the extracellular matrix is accomplished via cell membrane receptors called integrins, which link mechanical tension outside the cell to intracellular events and play a role in bidirectional signal transduction.^27,28

The collagen matrix is a major determinant of the stiffness of myocardial tissue and, in excess, increases tissue stiffness, causing contractile dysfunction.⁶ Collagen fibers form a weblike structure, containing and supporting the myocytes while limiting to some extent dilatation and hypertrophy. Increased collagen cross-linking within the extracellular matrix induced by impaired glucose tolerance has been associated with an increase in left ventricular diastolic stiffness and higher end-diastolic pressure when volume loading occurs.^29,30

Alterations in the extracellular matrix may be a source of left ventricular remodeling after myocardial infarction and may be a result of chronic volume or pressure overload.²⁵ Remodeling may be due to pathological alterations in the matrix metalloproteinases or collagenases, enzymes that degrade components of the extracellular collagen. Inhibition of metalloproteinases in a rapid-pacing model of congestive heart failure resulted in increases in myocardial collagen and in the stiffness of the left ventricle.³¹ Conversely, increasing human matrix metalloproteinase activity in a mouse model resulted in a 2-tiered response within the myocardium that parallels the natural history of congestive heart failure.³² The cardiac myocytes initially adapted to collagen breakdown with myocardial hypertrophy, increased collagen deposition, and increased left ventricular systolic pressures. Over time, a progressive loss of collagen and the development of contractile dysfunction occurred, as indicated by marked decreases in the maximal rate of left ventricular pressure development during systole and the maximal rate of pressure decrement during diastole. Undoubtedly, ventricular remodeling plays an initially adaptive but ultimately pathological role. Thus, remodeling causes profound changes in the ability of the left ventricle to respond to altered volume and pressure loading.

Alterations in the extracellular collagen matrix, the supporting structure for myocytes, are associated with left ventricular remodeling. This remodeling is initially adaptive but ultimately pathologic.

 

	Neurohumoral Regulation of Ventricular Function

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
Two interrelated systems improve myocardial function when the heart is failing: the adrenergic nervous system and the reninangiotensin-aldosterone system.⁶ As part of the acute response to cardiac failure, adrenergic stimulation increases both heart rate and contractility. ß-Adrenergic–mediated increases in renin and antidiuretic hormone contribute to increased preload, whereas angiotensin II–mediated release of aldosterone elicits sodium and water retention. Harmful effects of norepinephrine and angiotensin II release include increased systemic vascular resistance and myocardial hypertrophy with its concomitant increase in left ventricular wall stress.

The effects of the adrenergic and the reninangiotensin-aldosterone systems are counterbalanced by the production of natriuretic peptides and prostaglandin vasodilators.

Atrial natriuretic peptide and B-type natriuretic peptide are synthesized in atrial and ventricular myocytes, respectively. Increased atrial pressure results in immediate release of atrial natriuretic peptide, whereas levels of B-type natriuretic peptide reflect long-term intravascular volume and pressure overload.³³ In response to hemodynamic stress, B-type natriuretic peptide is released, inducing natriuresis, vasodilation, and inhibition of the reninangiotensin and aldosterone responses.³⁴ B-type natriuretic peptide is a powerful biochemical marker of cardiac function that is a reliable predictor of diastolic dysfunction when no systolic dysfunction occurs.³⁵ Elevated levels of B-type natriuretic peptide are strong independent predictors of congestive heart failure³⁶ and are more accurate than clinical findings for differentiating the cause of dyspnea.³⁷ The interaction between these opposing neurohormonal systems forms a potential target for therapeutic intervention in heart failure.

Elevated levels of B-type natriuretic peptide, strong predictors of congestive heart failure, are more accurate than clinical findings in determining the cause of dyspnea.

 

	Load Dependence of Relaxation

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
The mechanics of diastole are highly interrelated with systolic loads and forces.^38,39 Diastole can be divided into 4 phases: isovolumic relaxation, rapid filling, diastasis, and atrial contraction. The isovolumic relaxation phase is generally defined as the period from closure of the aortic valve to opening of the mitral valve. The rate of decrease in left ventricular pressure that occurs here is thought to parallel the rate of actin-myosin cross-bridge inactivation.³⁸ However, the time constant for relaxation is influenced by many factors, including volume status, afterload, and inotropic state. ß-Adrenergic stimulation increases lusitropy by stimulating the phosphorylation of phospholamban and increasing Ca²⁺ uptake by SERCA. The kinetics of cross-bridge cycling allow a dual response in the rate of relaxation that depends on the timing of the increased afterload.³⁹ If afterload increases during active contraction, increases occur in sensitivity to Ca²⁺ and in cross-bridge formation; both systole and the relaxation rate are prolonged. An increase in afterload during relaxation (late systole) elicits no change in Ca²⁺ sensitivity; both systole and the relaxation rate are shortened.⁴⁰ In the absence of pathological changes, the relaxation rate may affect the early filling phase of diastole, but at heart rates less than 150/min, it does not exert significant effects on late filling and/or end-diastolic pressure.⁴¹

The rapid filling that occurs with the opening of the mitral valve accounts for 80% to 85% of total ventricular filling. Thus, the transmitral pressure gradient (left atrium to left ventricle) determines the flow into the ventricle. Left atrial pressure is primarily determined by left atrial and pulmonary vein volume and compliance, whereas left ventricular pressure is chiefly affected by the biochemical events at the myofibrillar level and the viscoelastic properties of the myocardium. The peak early transmitral filling velocity is quantified as the peak E wave on a transmitral velocity curve.⁴²

Because isovolumic relaxation and rapid filling are strongly influenced by systolic events, some authors⁴³ exclude them as phases of diastole. It is generally accepted that the passive filling characteristics of the left ventricle are most purely reflected during the diastasis and atrial contraction phases of diastole.⁴⁴ Diastasis is characterized by the addition of a very small volume to the left ventricle with little increase in left ventricular pressure. It is this interval, which at normal heart rates is 180 ms long, that is shortened by increases in heart rate.³⁸ This "static" period, when used to evaluate pressure-volume relationships in the left ventricle, is a reasonable reflection of the passive properties of the myocardium. Passive properties are independent of the effects of viscoelasticity that are prominent in other diastolic phases.

Atrial contraction contributes only 15% of left ventricular filling volume at resting heart rates but plays a key role in maintaining cardiac output during tachycardia, exercise, and impaired diastolic or systolic function. Impaired diastolic function that shifts the diastolic pressure-volume curve up and to the left increases left atrial afterload, alters left atrial systole, and impairs left ventricular filling.⁴⁵ Atrial contraction is reflected as the A wave on transmitral spectral Doppler tracings.

The isovolumic contraction phase of systole (from closure of the mitral valve to opening of the aortic valve) creates rotational left ventricular wall motion that affects diastole. The elastic energy produced by this torsion is released during isovolumic relaxation and may extend into the rapid filling phase.⁴⁶ End-systolic volume is a determinant of the minimum diastolic pressure, which makes changes in both load and systolic function variables that can modify peak transmitral velocity and the E wave.⁴²

The phases of diastole can be modeled by using pressure-volume ventricular function loops. Diastasis and atrial contraction, key components of passive filling of the left ventricle, make up one segment of the loop; the position and slope of this segment provide the underpinnings for understanding diastolic abnormalities.

	Pressure-Volume Loops: A Tool for Assessment of Ventricular Function

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 
The relationships between ventricular volume and intraventricular pressure classically have been depicted via pressure-volume loops.^2,47 These loops are used to graphically illustrate 3 key features: myocardial work, the end-systolic pressure-volume relationship, and the end-diastolic pressure-volume relationship (Figure 3). The area of the pressure-volume loop represents myocardial work independent of the effect of heart rate; for each cardiac cycle, the external work of the heart is the product of pressure and volume. The end-systolic pressure-volume relationship represents both afterload and the inotropic state of the myocardium. Inotropy is the contractile state of the myocardial tissue independent of load. The end-diastolic pressure-volume relationship represents both venous return and the lusitropic state of the myocardium. Lusitropy describes the intrinsic state of myofibril relaxation. Pressure-volume loops can also be used to illustrate the effects of both intramyocardial events (inotropy and lusitropy) and extramyocardial events (preload and afterload) on myocardial work (Figures 4A–4D).

View larger version (11K): [in this window] [in a new window]   Figure 3 Ventricular pressure-volume (P–V) relationships for a single cardiac cycle. The diastolic P–V volume line depicts the relationship between pressure and volume during diastole. Movement along the line represents changes in preload; alterations in the slope of the line indicate changes in intrinsic relaxation. Movement along the systolic P–V line represents change in after-load, whereas changes in the slope indicate altered myocardial contractility independent of load. Point A represents end-systolic volume (ESV) just before opening of the mitral valve. During the rapid filling, diastasis, and atrial contraction phases of diastole (point A to point B), as left ventricular volume increases, left ventricular pressure increases slightly. The period from closure of the mitral valve (point B) to opening of the aortic valve (point C) represents isovolumic contraction. Rapid and reduced ejection occurs from point C to point D and from point D to point E, respectively, when the aortic valve closes. Isovolumic relaxation occurs from point E to point A. Stroke volume (SV) is calculated as end-diastolic volume (EDV) minus ESV.

View larger version (16K): [in this window] [in a new window]   Figure 4 Effects of intramyocardial and extramyocardial events on pressure-volume relationships. A, Movement along the end-diastolic line (EDL) increases preload and end-diastolic volume (EDV); if afterload is kept constant, the result is an increased stroke volume and increased cardiac work (dotted line in A). Movement up the end-systolic line (ESL) represents an increase in afterload; if preload is kept constant, the result is an increased end-systolic volume (ESV) and decreased stroke volume (dashed line in A). B, Lowering the slope of the ESL represents a decrease in inotropy; at a constant preload, less ventricular pressure is generated and stroke volume is decreased. This pattern depicts pure systolic heart failure. C, Decreased lusitropy is represented by an increase in the slope of the EDL; a higher filling pressure is required to maintain the filling volume. This pattern depicts pure diastolic heart failure. D, Combined systolic and diastolic heart failure occurs when both decreased inotropy and decreased lusitropy exist. Filling pressures increase as ejection pressure decreases; reflex vasoconstriction increases afterload so that stroke volume and cardiac work are reduced at the expense of forward flow. Dash-dot indicates change in slope; short dashes show new pressure-volume loop.

View larger version (13K): [in this window] [in a new window]   Figure 5 The effects of adrenergic stimulation on the pressure-volume relationship. The slope of the end-systolic line (ESL) increases (increased inotropy) and the slope of the end-diastolic line (EDL) decreases (increased lusitropy). The shift in the end-diastolic volume (EDV) increases venous return consequent to an improved forward flow, increasing stroke volume and cardiac work. ESV indicates end-systolic volume. Dash-dot indicates change in slope; short dashes show new pressure-volume loop.

	Summary

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

Editors’ note: Part 2 of this article, titled "Role of Diastole in Left Ventricular Function, II: Diagnosis and Treatment," will appear in the November 2004 issue of the journal.

	REFERENCES

Top Abstract Electrophysiology of Ventricular... Myocardial Contraction Calcium Regulation During... Myocardial Relaxation Calcium Regulation During... Myofilament Structure and... Neurohumoral Regulation of... Load Dependence of Relaxation Pressure-Volume Loops: A Tool... Summary References

 

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