Anrep effect

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The Anrep effect describes the rapid increase in myocardial contractility in response to the sudden rise in afterload, the pressure the heart must work against to eject blood. [1] [2] This adaptive mechanism allows the heart to sustain stroke volume and cardiac output despite increased resistance. It operates through homeometric autoregulation, meaning that contractility adjustments occur independently of preload (the initial stretch of the heart muscle) or heart rate. [1] [2] [3]

Contents

The Anrep effect is characterized by a two-step elevation in myocardial contractility, in response to elevated afterload, involving two distinct mechanistic phases: a primary, rapid rise in contractility driven by sarcomeric strain sensing, and a secondary, sustained phase of contraction mediated by post-translational modifications of contractile proteins. [3] [4] First described by Gleb von Anrep in 1912 [5] and further elaborated in the 1960s by Sarnoff et al., [1] [2] the Anrep effect represents a distinct cardiac regulation mechanism, differing fundamentally from the Frank-Starling mechanism, [6] the slow force response, [7] [8] and the Gregg effect. [9]

While traditionally considered a short-term adaptation, recent studies suggest that the Anrep effect may also occur in chronic conditions involving persistent afterload elevation, such as hypertrophic obstructive cardiomyopathy. [4]

The heart adjusts its pumping efficiency through changes in muscle length and load. When the cardiac muscle is stretched, it triggers a biphasic rise in force generation. The initial phase, governed by the Frank-Starling law (heterometric autoregulation), results in an immediate increase in contractile strength due to increased end-diastolic volume. This adjustment helps balance cardiac output with changes in filling pressure. The second phase, termed the slow force response, unfolds over several minutes, reflecting a sustained increase in contractility when preload remains constant following the initial stretch. In contrast, the Anrep effect (homeometric autoregulation) enhances ventricular contractility in response to acute afterload elevation, independent of preload or heart rate variations. The Anrep effect is often confused with other regulatory processes (e.g., the slow force response, the Gregg phenomenon) but has unique, very distinct, characteristics:

Frank-Starling mechanism

The Frank-Starling mechanism describes how increased preload (ventricular filling) stretches cardiac muscle fibers, enhancing stroke work through length-dependent activation of the myofilaments. This process aligns actin and myosin filaments for efficient cross-bridge formation while also recruiting myosin heads from dormant states into contraction-ready configurations. [6] [10] Additionally, stretching the sarcomeres sensitizes the thin (actin) filaments to calcium, promoting stronger and more sustained contractions. [6] By contrast, the Anrep effect occurs at constant preload, triggered solely by afterload. [1] [2] [3] It is characterized by increased contractility (steeper end-systolic pressure-volume relationship) and higher stroke work, without changes in stroke volume or end-diastolic volume. [3] [4]

Slow force response

This stretch-related (preload) response involves a gradual rise in contractility over several minutes (from 2 to 15 minutes, depending on species and experimental conditions) [7] [8] [11] due to stretch-activated ion channels and G-protein-coupled receptors. [7] [12] It is mediated by angiotensin II and endothelin-1, which increase intracellular sodium and calcium concentrations through sodium-calcium exchangers. In contrast, the afterload-dependent response of the Anrep effect is initiated in milliseconds and concludes within 10 seconds, bypassing extracellular calcium regulation through the slow force response. [3] Additionally, streptomycin, an inhibitor of stretch-activated ion channels, blocks the slow force response but does not affect the Anrep effect, reinforcing that the two mechanisms operate through distinct pathways. [3]

Gregg Effect

This effect describes increased contractility due to improved coronary perfusion. [9] It originates from changes in microvascular volume that trigger stretch-activated ion channels, resulting in increased intracellular calcium transient. [13] The Gregg phenomenon generally begins to affect contractility approximately 5 seconds after onset, reaching peak force development within 40 seconds of sustained perfusion. [3] However, the Anrep effect persists even in denervated, isolated hearts with constant coronary flow, eliminating perfusion-based explanations. [3] Like the slow force response, the Gregg effect is sensitive to streptomycin, while the Anrep effect remains unaffected. [3]

Mechanistic basis of the Anrep effect

The activation of the Anrep effect involves recruiting a significant portion of dormant myosin motors within cardiomyocytes, as most myosin heads in each heart cell remain in a resting state. [4] This recruitment transitions myosin from its inactive configuration to a contraction-ready state through a biphasic activation process that increases contractility in response to the afterload, and consequently elevates energy consumption:

Immediate (rapid) phase: myofilament strain-sensitive activation

Sustained phase: post-translational modifications

Hemodynamic description

The Anrep effect can be understood in terms of its hemodynamic impact on the heart during afterload increases: [3] [4]

  1. Elevated afterload: reflected by increased effective arterial elastance and ventricular end-systolic pressure.
  2. Enhanced myocardial contractility: demonstrated by a leftward shift and steepening of the end-systolic pressure-volume relationship, along with a higher maximum rate of pressure rise (dP/dtmax).
  3. Prolonged systole: represented by a longer systolic ejection time due to sustained activation of contractile elements.

These responses ensure the heart maintains stroke volume' and cardiac output, despite increased afterload, at the cost of higher energy consumption. [4]

Historical perspective

The Anrep effect was first described by Gleb von Anrep in 1912 [5] during experiments involving splanchnic nerve stimulation in dogs. He observed that stimulating the splanchnic nerve caused peripheral vasoconstriction, which increased blood pressure and afterload. In response, cardiac contractility increased, a phenomenon Anrep attributed to the release of adrenaline from the suprarenal glands, independent of preload changes. Later, Ernest Starling suggested that enhanced coronary flow, improving myocardial nourishment (a concept later termed the Gregg effect [9] ), might explain the observed increase in contractility. [15] However, both historical and recent research has demonstrated that the Anrep effect arises from an intrinsic property of the myocardium, independent of adrenaline release or coronary flow. [1] [2] [3] In the mid-20th century, Sarnoff et al. [1] [2] introduced the term homeometric autoregulation to describe the heart’s ability to augment contractility in response to elevated afterload, independent of preload or hormonal stimulation. This concept distinguished the Anrep effect from the Frank-Starling law, which involves heterometric autoregulation, where increased preload enhances contractility by stretching myocardial fibers. Despite Sarnoff’s clarification, some of his experiments reported a brief, transient increase in preload following afterload elevation. He dismissed this effect as non-essential for triggering the Anrep effect, yet this observation led to persistent confusion. To this day, some studies mistakenly associate the Anrep effect with the slow force response, despite clear differences in their underlying physiology.

Clinical implications

Although originally considered an acute and transient response, recent research suggests that the Anrep effect may persist in chronic conditions involving sustained afterload increases. One example is hypertrophic obstructive cardiomyopathy, where left ventricular outflow tract obstruction results in persistent afterload elevation, potentially activating the Anrep effect chronically. [4] Understanding this mechanism has important implications for cardiac physiology, heart failure management, and therapeutic interventions targeting afterload reduction.

Related Research Articles

In cardiovascular physiology, stroke volume (SV) is the volume of blood pumped from the ventricle per beat. Stroke volume is calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood in the ventricle at the end of a beat from the volume of blood just prior to the beat. The term stroke volume can apply to each of the two ventricles of the heart, although when not explicitly stated it refers to the left ventricle and should therefore be referred to as left stroke volume (LSV). The stroke volumes for each ventricle are generally equal, both being approximately 90 mL in a healthy 70-kg man. Any persistent difference between the two stroke volumes, no matter how small, would inevitably lead to venous congestion of either the systemic or the pulmonary circulation, with a corresponding state of hypotension in the other circulatory system. A shunt between the two systems will ensue if possible to reestablish the equilibrium.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Frank–Starling law</span> Relationship between stroke volume and end diastolic volume

The Frank–Starling law of the heart represents the relationship between stroke volume and end diastolic volume. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction, when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches cardiac muscle, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.

<span class="mw-page-title-main">Afterload</span> Pressure in the wall of the left ventricle during ejection

Afterload is the pressure that the heart must work against to eject blood during systole. Afterload is proportional to the average arterial pressure. As aortic and pulmonary pressures increase, the afterload increases on the left and right ventricles respectively. Afterload changes to adapt to the continually changing demands on an animal's cardiovascular system. Afterload is proportional to mean systolic blood pressure and is measured in millimeters of mercury.

<span class="mw-page-title-main">Endocardium</span> Innermost layer of tissue lining the chambers of the heart

The endocardium is the innermost layer of tissue that lines the chambers of the heart. Its cells are embryologically and biologically similar to the endothelial cells that line blood vessels. The endocardium also provides protection to the valves and heart chambers.

<span class="mw-page-title-main">Preload (cardiology)</span> Heart muscle stretch at rest

In cardiac physiology, preload is the amount of sarcomere stretch experienced by cardiac muscle cells, called cardiomyocytes, at the end of ventricular filling during diastole. Preload is directly related to ventricular filling. As the relaxed ventricle fills during diastole, the walls are stretched and the length of sarcomeres increases. Sarcomere length can be approximated by the volume of the ventricle because each shape has a conserved surface-area-to-volume ratio. This is useful clinically because measuring the sarcomere length is destructive to heart tissue. It requires cutting out a piece of cardiac muscle to look at the sarcomeres under a microscope. It is currently not possible to directly measure preload in the beating heart of a living animal. Preload is estimated from end-diastolic ventricular pressure and is measured in millimeters of mercury (mmHg).

In cardiology, ventricular remodeling refers to changes in the size, shape, structure, and function of the heart. This can happen as a result of exercise or after injury to the heart muscle. The injury is typically due to acute myocardial infarction, but may be from a number of causes that result in increased pressure or volume, causing pressure overload or volume overload on the heart. Chronic hypertension, congenital heart disease with intracardiac shunting, and valvular heart disease may also lead to remodeling. After the insult occurs, a series of histopathological and structural changes occur in the left ventricular myocardium that lead to progressive decline in left ventricular performance. Ultimately, ventricular remodeling may result in diminished contractile (systolic) function and reduced stroke volume.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.

<span class="mw-page-title-main">Milrinone</span> Chemical compound

Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the heart's contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.

Impedance cardiography (ICG) is a non-invasive technology measuring total electrical conductivity of the thorax and its changes in time to process continuously a number of cardiodynamic parameters, such as stroke volume (SV), heart rate (HR), cardiac output (CO), ventricular ejection time (VET), pre-ejection period and used to detect the impedance changes caused by a high-frequency, low magnitude current flowing through the thorax between additional two pairs of electrodes located outside of the measured segment. The sensing electrodes also detect the ECG signal, which is used as a timing clock of the system.

<span class="mw-page-title-main">Autoregulation</span> Adjustment within a biological system

Autoregulation is a process within many biological systems, resulting from an internal adaptive mechanism that works to adjust that system's response to stimuli. While most systems of the body show some degree of autoregulation, it is most clearly observed in the kidney, the heart, and the brain. Perfusion of these organs is essential for life, and through autoregulation the body can divert blood where it is most needed.

<span class="mw-page-title-main">Pulsus alternans</span> Medical condition

Pulsus alternans is a physical finding with arterial pulse waveform showing alternating strong and weak beats. It is almost always indicative of left ventricular systolic impairment, and carries a poor prognosis.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">Coronary perfusion pressure</span>

Coronary perfusion pressure (CPP) refers to the pressure gradient that drives coronary blood pressure. The heart's function is to perfuse blood to the body; however, the heart's own myocardium must, itself, be supplied for its own muscle function. The heart is supplied by coronary vessels, and therefore CPP is the blood pressure within those vessels. If pressures are too low in the coronary vasculature, then the myocardium risks ischemia with subsequent myocardial infarction or cardiogenic shock.

Cardiac physiology or heart function is the study of healthy, unimpaired function of the heart: involving blood flow; myocardium structure; the electrical conduction system of the heart; the cardiac cycle and cardiac output and how these interact and depend on one another.

A plot of a system's pressure versus volume has long been used to measure the work done by the system and its efficiency. This analysis can be applied to heat engines and pumps, including the heart. A considerable amount of information on cardiac performance can be determined from the pressure vs. volume plot. A number of methods have been determined for measuring PV-loop values experimentally.

<span class="mw-page-title-main">Omecamtiv mecarbil</span> Chemical compound

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is an experimental drug being studied for a potential role in the treatment of left ventricular systolic heart failure.

<span class="mw-page-title-main">Rottlerin</span> Chemical compound

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.

<span class="mw-page-title-main">Pathophysiology of heart failure</span>

The main pathophysiology of heart failure is a reduction in the efficiency of the heart muscle, through damage or overloading. As such, it can be caused by a wide number of conditions, including myocardial infarction, hypertension and cardiac amyloidosis. Over time these increases in workload will produce changes to the heart itself:

References

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  10. ↑ Ma, Weikang; Henze, Marcus; Anderson, Robert L.; Gong, Henry; Wong, Fiona L.; del Rio, Carlos L.; Irving, Thomas (2021-09-03). "The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium". Circulation Research. 129 (6): 617–630. doi:10.1161/CIRCRESAHA.120.318647. ISSN   0009-7330. PMC   8416939 . PMID   34365814.
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  12. ↑ Calaghan, Sarah; White, Ed (August 2004). "Activation of Na + –H + exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart". The Journal of Physiology. 559 (1): 205–214. doi:10.1113/jphysiol.2004.069021. ISSN   0022-3751. PMC   1665066 . PMID   15235080.
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  14. ↑ Nickel, AG; von Hardenberg, A; Hohl, M; Löffler, JR; Kohlhaas, M; Becker, J; Reil, JC; Kazakov, A; Bonnekoh, J; Stadelmaier, M; Puhl, SL; Wagner, M; Bogeski, I; Cortassa, S; Kappl, R; Pasieka, B; Lafontaine, M; Lancaster, CR; Blacker, TS; Hall, AR; Duchen, MR; Kästner, L; Lipp, P; Zeller, T; Müller, C; Knopp, A; Laufs, U; Böhm, M; Hoth, M; Maack, C (1 September 2015). "Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure". Cell Metabolism. 22 (3): 472–84. doi:10.1016/j.cmet.2015.07.008. PMID   26256392.
  15. ↑ Patterson, S. W.; Piper, H.; Starling, E. H. (1914-10-23). "The regulation of the heart beat". The Journal of Physiology. 48 (6): 465–513. doi:10.1113/jphysiol.1914.sp001676. ISSN   0022-3751. PMC   1420509 . PMID   16993269.
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