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.<ref name=":0">{{Cite journal |last1=Sarnoff |first1=S. J. |last2=Mitchell |first2=J. H. |last3=Gilmore |first3=J. P. |last4=Remensnyder |first4=J. P. |date=September 1960 |title=Homeometric Autoregulation in the Heart |journal=Circulation Research |volume=8 |issue=5 |pages=1077–1091 |doi=10.1161/01.res.8.5.1077 |issn=0009-7330}}</ref><ref name=":1">{{Cite journal |last1=Sarnoff |first1=Stanley J. |last2=Mitchell |first2=Jere H. |date=May 1961 |title=The regulation of the performance of the heart |journal=The American Journal of Medicine |volume=30 |issue=5 |pages=747–771 |doi=10.1016/0002-9343(61)90211-x |pmid=13746561 |issn=0002-9343}}</ref> 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.<ref name=":0" /><ref name=":1" /><ref name=":2">{{Cite journal |last1=Reil |first1=Jan-Christian |last2=Reil |first2=Gert-Hinrich |last3=Kovács |first3=Árpád |last4=Sequeira |first4=Vasco |last5=Waddingham |first5=Mark T. |last6=Lodi |first6=Maria |last7=Herwig |first7=Melissa |last8=Ghaderi |first8=Shahrooz |last9=Kreusser |first9=Michael M. |last10=Papp |first10=Zoltán |last11=Voigt |first11=Niels |last12=Dobrev |first12=Dobromir |last13=Meyhöfer |first13=Svenja |last14=Langer |first14=Harald F. |last15=Maier |first15=Lars S. |date=August 2020 |title=CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect |journal=The Journal of Physiology |language=en |volume=598 |issue=15 |pages=3129–3153 |doi=10.1113/JP279607 |issn=0022-3751 |pmc=7657994 |pmid=32394454}}</ref>
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.<ref name=":2" /><ref name=":3">{{Cite journal |last1=Sequeira |first1=Vasco |last2=Maack |first2=Christoph |last3=Reil |first3=Gert-Hinrich |last4=Reil |first4=Jan-Christian |date=2024-01-05 |title=Exploring the Connection Between Relaxed Myosin States and the Anrep Effect |journal=Circulation Research |volume=134 |issue=1 |pages=117–134 |doi=10.1161/circresaha.123.323173 |pmid=38175910 |issn=0009-7330}}</ref> First described by Gleb von Anrep in 1912<ref name=":4">{{Cite journal |last=von Anrep |first=G. |date=1912-12-09 |title=On the part played by the suprarenals in the normal vascular reactions of the body |journal=The Journal of Physiology |volume=45 |issue=5 |pages=307–317 |doi=10.1113/jphysiol.1912.sp001553 |pmid=16993158 |pmc=1512890 |issn=0022-3751}}</ref> and further elaborated in the 1960s by Sarnoff et al.,<ref name=":0" /><ref name=":1" /> the Anrep effect represents a distinct cardiac regulation mechanism, differing fundamentally from the Frank-Starling mechanism,<ref name=":8">{{Cite journal |last1=de Tombe |first1=Pieter P. |last2=Mateja |first2=Ryan D. |last3=Tachampa |first3=Kittipong |last4=Ait Mou |first4=Younss |last5=Farman |first5=Gerrie P. |last6=Irving |first6=Thomas C. |date=May 2010 |title=Myofilament length dependent activation |journal=Journal of Molecular and Cellular Cardiology |volume=48 |issue=5 |pages=851–858 |doi=10.1016/j.yjmcc.2009.12.017 |issn=1095-8584 |pmc=2854194 |pmid=20053351}}</ref> the slow force response,<ref name=":5">{{Cite journal |last1=Dowrick |first1=Jarrah M. |last2=Tran |first2=Kenneth |last3=Loiselle |first3=Denis S. |last4=Nielsen |first4=Poul M. F. |last5=Taberner |first5=Andrew J. |last6=Han |first6=June-Chiew |last7=Ward |first7=Marie-Louise |date=May 2019 |title=The slow force response to stretch: Controversy and contradictions |url=https://onlinelibrary.wiley.com/doi/10.1111/apha.13250 |journal=Acta Physiologica |language=en |volume=226 |issue=1 |article-number=e13250 |doi=10.1111/apha.13250 |pmid=30614655 |issn=1748-1708|hdl=2292/49478 |hdl-access=free |url-access=subscription }}</ref><ref name=":6">{{Cite journal |last1=Alvarez |first1=Bernardo V. |last2=Pérez |first2=Néstor G. |last3=Ennis |first3=Irene L. |last4=Camilión de Hurtado |first4=María C. |last5=Cingolani |first5=Horacio E. |date=1999-10-15 |title=Mechanisms Underlying the Increase in Force and Ca<sup>2+</sup> Transient That Follow Stretch of Cardiac Muscle |journal=Circulation Research |volume=85 |issue=8 |pages=716–722 |doi=10.1161/01.res.85.8.716 |issn=0009-7330}}</ref> and the Gregg effect.<ref name=":7">{{Cite journal |last=Gregg |first=Donald E. |date=December 1963 |title=Effect of Coronary Perfusion Pressure or Coronary Flow on Oxygen Usage of the Myocardium |journal=Circulation Research |volume=13 |issue=6 |pages=497–500 |doi=10.1161/01.res.13.6.497 |pmid=14120967 |issn=0009-7330}}</ref>
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.<ref name=":3" />
== Distinguishing the Anrep effect from related cardiac mechanisms == 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.<ref name=":8" /><ref>{{Cite journal |last1=Ma |first1=Weikang |last2=Henze |first2=Marcus |last3=Anderson |first3=Robert L. |last4=Gong |first4=Henry |last5=Wong |first5=Fiona L. |last6=del Rio |first6=Carlos L. |last7=Irving |first7=Thomas |date=2021-09-03 |title=The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium |journal=Circulation Research |language=en |volume=129 |issue=6 |pages=617–630 |doi=10.1161/CIRCRESAHA.120.318647 |issn=0009-7330 |pmc=8416939 |pmid=34365814}}</ref> Additionally, stretching the sarcomeres sensitizes the thin (actin) filaments to calcium, promoting stronger and more sustained contractions.<ref name=":8" /> By contrast, the Anrep effect occurs at constant preload, triggered solely by afterload.<ref name=":0" /><ref name=":1" /><ref name=":2" /> 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.<ref name=":2" /><ref name=":3" />
===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)<ref name=":5" /><ref name=":6" /><ref>{{Cite journal |last1=Parmley |first1=Ww |last2=Chuck |first2=L |date=1973-05-01 |title=Length-dependent changes in myocardial contractile state |url=https://www.physiology.org/doi/10.1152/ajplegacy.1973.224.5.1195 |journal=American Journal of Physiology. Legacy Content |language=en |volume=224 |issue=5 |pages=1195–1199 |doi=10.1152/ajplegacy.1973.224.5.1195 |pmid=4700639 |issn=0002-9513|url-access=subscription }}</ref> due to stretch-activated ion channels and G-protein-coupled receptors.<ref name=":5" /><ref>{{Cite journal |last1=Calaghan |first1=Sarah |last2=White |first2=Ed |date=August 2004 |title=Activation of Na + –H + exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart |journal=The Journal of Physiology |language=en |volume=559 |issue=1 |pages=205–214 |doi=10.1113/jphysiol.2004.069021 |issn=0022-3751 |pmc=1665066 |pmid=15235080}}</ref> 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.<ref name=":2" /> 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.<ref name=":2" />
===Gregg Effect=== This effect describes increased contractility due to improved coronary perfusion.<ref name=":7" /> It originates from changes in microvascular volume that trigger stretch-activated ion channels, resulting in increased intracellular calcium transient.<ref>{{Cite journal |last1=Lamberts |first1=R. R. |last2=van Rijen |first2=M. H. P. |last3=Sipkema |first3=P. |last4=Fransen |first4=P. |last5=Sys |first5=S. U. |last6=Westerhof |first6=N. |date=2002-04-01 |title=Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels |url=https://www.physiology.org/doi/10.1152/ajpheart.00327.2001 |journal=American Journal of Physiology. Heart and Circulatory Physiology |language=en |volume=282 |issue=4 |pages=H1334–H1340 |doi=10.1152/ajpheart.00327.2001 |pmid=11893569 |issn=0363-6135|url-access=subscription }}</ref> The Gregg phenomenon generally begins to affect contractility approximately 5 seconds after onset, reaching peak force development within 40 seconds of sustained perfusion.<ref name=":2" /> However, the Anrep effect persists even in denervated, isolated hearts with constant coronary flow, eliminating perfusion-based explanations.<ref name=":2" /> Like the slow force response, the Gregg effect is sensitive to streptomycin, while the Anrep effect remains unaffected.<ref name=":2" />
== 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.<ref name=":3" /> 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===
* An acute rise in afterload increases ventricular wall tension, activating resting myosin heads due to afterload-dependent mechanosensing. This transition involves super-relaxed state myosin shifting into the contraction-ready state (i.e, disorder-relaxed), allowing myosin to bind to actin and form force-generating cross-bridges.<ref name=":2" /><ref name=":3" />
===Sustained phase: post-translational modifications===
* Persistent afterload triggers oxidative stress, activating calcium/calmodulin-dependent protein kinase II.<ref>{{cite journal |last1=Nickel |first1=AG |last2=von Hardenberg |first2=A |last3=Hohl |first3=M |last4=Löffler |first4=JR |last5=Kohlhaas |first5=M |last6=Becker |first6=J |last7=Reil |first7=JC |last8=Kazakov |first8=A |last9=Bonnekoh |first9=J |last10=Stadelmaier |first10=M |last11=Puhl |first11=SL |last12=Wagner |first12=M |last13=Bogeski |first13=I |last14=Cortassa |first14=S |last15=Kappl |first15=R |last16=Pasieka |first16=B |last17=Lafontaine |first17=M |last18=Lancaster |first18=CR |last19=Blacker |first19=TS |last20=Hall |first20=AR |last21=Duchen |first21=MR |last22=Kästner |first22=L |last23=Lipp |first23=P |last24=Zeller |first24=T |last25=Müller |first25=C |last26=Knopp |first26=A |last27=Laufs |first27=U |last28=Böhm |first28=M |last29=Hoth |first29=M |last30=Maack |first30=C |title=Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure. |journal=Cell Metabolism |date=1 September 2015 |volume=22 |issue=3 |pages=472–84 |doi=10.1016/j.cmet.2015.07.008 |pmid=26256392|doi-access=free }}</ref> Myosin light chain 2 and cardiac myosin-binding protein C are phosphorylated, strengthening myosin-actin cross-bridge formation and prolonging systolic ejection time to maintain stroke volume.<ref name=":2" /><ref name=":3" />
== Hemodynamic description == The Anrep effect can be understood in terms of its hemodynamic impact on the heart during afterload increases:<ref name=":2" /><ref name=":3" />
# Elevated afterload: reflected by increased effective arterial elastance and ventricular end-systolic pressure. # 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/dt<small>max</small>). # 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.<ref name=":3" />
== Historical perspective == The Anrep effect was first described by Gleb von Anrep in 1912<ref name=":4" /> 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<ref name=":7" />), might explain the increase in contractility observed by von Anrep.<ref>{{Cite journal |last1=Patterson |first1=S. W. |last2=Piper |first2=H. |last3=Starling |first3=E. H. |date=1914-10-23 |title=The regulation of the heart beat |journal=The Journal of Physiology |volume=48 |issue=6 |pages=465–513 |doi=10.1113/jphysiol.1914.sp001676 |pmid=16993269 |pmc=1420509 |issn=0022-3751}}</ref> 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.<ref name=":0" /><ref name=":1" /><ref name=":2" /> In the mid-20th century, Sarnoff et al.<ref name=":0" /><ref name=":1" /> 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.<ref name=":3" /> Understanding this mechanism has important implications for cardiac physiology, heart failure management, and therapeutic interventions targeting afterload reduction.
==References== {{reflist}}
Category:Cardiology