The Anrep Effect Reconsidered R. G. Monroe, … , C. Phornphutkul, M. Davis J Clin Invest. 1972;51(10):2573-2583. https://doi.org/10.1172/JCI107074. Research Article Evidence is presented supporting the hypothesis that the positive inotropic effect after an abrupt increase in systolic pressure (Anrep effect) is the recovery from subendocardial ischemia induced by the increase and subsequently corrected by vascular autoregulation of the coronary bed. Major evidence consists of data obtained from an isolated heart preparation showing that the Anrep effect can be abolished with coronary vasodilation, and that with an abrupt increase in systolic pressure there is a significant reduction in the distribution of coronary flow to subendocardial layers of the ventricle. Furthermore, the intracardiac electrocardiogram shows S-T segment and T wave changes after an abrupt increase in ventricular pressure similar to that noted after coronary constriction. Major implications are that normally there may be ischemia of the subendocardial layers tending to reduce myocardial contractility which may account, in part, for the positive inotropic effect of various coronary vasodilators; that with an abrupt increase in ventricular pressure the subendocardium is rendered temporarily ischemic, placing the heart in jeopardy from arrhythmias until this is corrected; and that end-diastolic pressure and the intracardiac electrocardiogram may provide a means of evaluating the adequacy of circulation to subendocardial layers in diseased ventricles when systolic pressure is abruptly increased. Find the latest version: https://jci.me/107074/pdf rhe Anrep Effect Reconsidered R. G. MONROE, W. J. GAMBLE, C. G. LAFARGE, A. E. KUMAR, J. STARK, G. L. SANDERS, C. PHORNPHUTKUL, and M. DAVIS From the Department of Pediatrics, Harvard Medical School, and the De- partments of Cardiology and Radiology, Children's Hospital Medical Center, Boston, Massachusetts 02115 A B S T R A C T Evidence is presented supporting the hy- abruptly increased in a heart lung preparation by in- pothesis that the positive inotropic effect after an abrupt creasing resistance to outflow, a positive inotropic effect increase in systolic pressure (Anrep effect) is the re- developed subsequent to the increase, as manifested by a covery from subendocardial ischemia induced by the in- decrease in left ventricular end-diastolic pressure and crease and subsequently corrected by vascular autoregu- volume while systolic pressure was maintained constant. lation of the coronary bed. Major evidence consists of As Starling observed this effect to be accompanied by an data obtained from an isolated heart preparation showing increase in coronary flow he later attributed it to "im- that the Anrep effect can be abolished with coronary vaso- proved nourishment of the muscle" (3, 4). In 1959 dilation, and that with an abrupt increase in systolic Rosenblueth, Alanis, Lopex, and Rubio (5) noted that pressure there is a significant reduction in the distribu- the effect was independent of changes in coronary flow tion of coronary flow to subendocardial layers of the and in 1960 Sarnoff, Mitchell, Gilmnore and Remensnyder ventricle. Furthermore, the intracardiac electrocardio- (6) showed the effect to persist even when coronary flow gram shows S-T segment and T wave changes after an was maintained constant thereby casting doubt on the abrupt increase in ventricular pressure similar to that hypothesis proposed by Starling. noted after coronary constriction. Major implications A thought-provoking review of this phenomenon, are that normally there may be ischenia of the suben- termed by Sarnoff and Mitchell the "Anrep" effect (7), docardial layers tending to reduce myocardial contrac- was published by Blinks and Koch-Weser in 1963 (8). tility which may account, in part, for the positive ino- Essentially, they concluded that the mechanism of the tropic effect of various coronary vasodilators; that with Anrep effect still remained obscure. They, too, dismissed an abrupt increase in ventricular pressure the subendo- the coronary flow hypothesis of Starling, in view of the cardium is rendered temporarily ischemic, placing the findings of Rosenblueth et al. (5) and Sarnoff et al. (6). heart in jeopardy from arrhythmias until this is cor- As the effect was noted in reserpinized preparations (8, rected; and that end-diastolic pressure and the intra- 9) they were disinclined to implicate catacholamines in cardiac electrocardiogram may provide a means of its mechanism. Despite the fact that Sarnoff et al. evaluating the adequacy of circulation to subendocardial showed an efflux of potassium from the heart after a layers in diseased ventricles when systolic pressure is sudden increase in systolic pressure (10) Blinks and abruptly increased. Koch-Weser pointed out differences between the Anrep effect and the Bowditch effect, making it doubtful that INTRODUCTION similar mechanisms were involved. Foremost in these differences was the observation that the Anrep effect is In 1912 Knowlton and Starling (1) as well as Anrep not found in cardiac muscle strip preparations (8, 11). (2) noted that if left ventricular systolic pressure was Later, a report from this laboratory showed the effect This work was performed during Dr. Monroe's tenure- to be decreased, but not abolished in an isolated heart ship of a Career Development Award from the National In- preparation treated with propranolol (9). Here it was stitutes of Health. postulated that at least part of the mechanism could be Dr. Davis is a Scholar in Radiological Research of the James Picker Foundation. attributed to catacholamines as norepinephrine has been Received for publication 8 March 1972 and in revised form shown to be released by the ventricle in quantities 10 June 1972. roughly proportional to systolic pressure (12, 13). Ad- The Journal of Clinical Investigation Volume 51 October 1972 2573 mittedly, however, these authors were unable to ascribe coronary sinus pressure was maintained at a constant, a single mechanism to explain completely the "Anrep" slightly negative pressure. After cannulation of tlle pulmonary artery, the peri- effect (9). cardium was incised and the right atrium opened. The Mindful of the findings of Blinks and Koch-Weser (8) bundle of His was ligated and electrocoagulated to insure as well as Gilmore, Cingolani, Taylor, and McDonald a complete heart block. A selected ventricular rate could (11) that the effect is not seen in muscle strip prepara- then be maintained by electrical stimulation of the distal that portion of the ligated His bundle with a pulse generator. tions, but only seen in intact hearts, and mindful Through the opening in the right atrium a plastic covered, coronary flow is not present in muscle strip preparations stranded, stainless steel wire snare was positioned circum- it was decided to attempt to study, in depth, the inter- ferentially around the outside of the left ventricle and relationships of coronary flow and the "Anrep" effect septum at the maximum diameter of the ventricle and heart preparation. From these studies maintained in position with loose sutures. As shown in using an isolated Fig. 1 the snare was mechanically attached to a linear evidence was obtained which suggests that the "Anrep" displacement transducer (Hewlett-Packard Co., Walthami, effect, rather than being due to an increased state of Mass., Linearsyn 585 DT) thereby allowing the transducer to contractility or intrinsic adaptation that appears subse- mneasure the circumferenice of the left ventricle continuously. quent to an abrupt increase in ventricular pressure After closure of the riglht atriotomy a small cardiac catlheter (I.D. 1.0 mm) and a large canniula (I.D. 5.0 mnm ) (5-11, 14), is more accurately described as the recovery were inserted into the left ventricle by way of the pulmo- from a negative inotropic effect caused by the abrupt in- nary veins. The catheter was attached to a linear differential crease. Further evidence was obtained suggesting that transducer (Sanborn 267B, Hewlett-Packard Co.) for con- subendocardial ischemia is responsible for the negative tinuous measurement of left ventricular pressure. The can- cor- nula was attached to the Starling resistance shown on the inotropic effect, a condition which is stubsequently upper right of Fig. 1. By adjusting the pressure applied rected by vascular autoregulation of the coronary bed to the Starling resistance the peak left ventricular pressure with a redistribution of coronary flowr. could be maintained at a predetermined level. This hypothesis, far from being novel, was at least After perfusion was established and the catheters inserted, in by Starling and others who used the the individual pulmonary lobes were ligated at the hilus and part implied removed, and the heart immersed to the level of the coronary term "recovery" when describing the effect (2, 3). The ostia in a bath of normal saline maintained at 37'C. Cor- object of this report is to present evidence supporting onary perfusion pressure was monitored at the level of the this position and discuss its physiological and clinical coronary ostia with a pressure transducer (Sanborn 267B, implications. Hewlett-Packard Co.). In some experiments the intraven- tricular electrocardiogram was obtained from a bipolar elec- trode catheter inserted into the left ventricular cavity METHODS through a pulmonary vein. The perfusion pressure, ven- The isolated heart prcparation. The basic preparation has tricular pressure, ventricular circumference