Introduction

Gleb von Anrep, a Russian-born Egyptian physiologist, observed in the year 1912 the gradual partial recovery of left ventricular dilation following acute aortic constriction. Anrep effect deals with epicardial to endocardial redistribution of blood flow. Recovery from ischemia is the primary mechanism of the Anrep effect.

Developed Force is the force because of an increase in the troponin C sensitivity to the influx of calcium (L-type channel). When a cardiac muscle stretches, there is an expeditious rise in the developed force known as the Frank-Starling mechanism. After an initial rapid response to stretch, there is a slow (gradual) increase in the developed force, called slow flow response, over 10 to 15 minutes because of the rise in calcium-transient amplitude, called the Anrep effect.[1]

A vast number of mechanisms are responsible for the rise in the calcium transient during the Anrep effect. A cardinal mechanism is the increased sarcolemmal calcium influx through the sodium-calcium exchanger operating in a reverse mode.

The prolongation of the action potential duration by cardiac myocyte stretch could favor reverse-mode sodium-calcium exchange and escalate calcium influx. A greater action potential duration will approve the reverse-mode sodium-calcium exchanger activity.[2]

Cellular Level

Myocardial stretch releases angiotensin II and activates endothelin type-I receptor. There is simultaneous activation of angiotensin I receptors, activation of the mineralocorticoid receptor, transactivation of the epidermal growth factor receptor, increased formation of mitochondrial reactive oxygen species, upstream activation of redox-sensitive kinases, myocardial sodium/hydrogen exchanger I, and an increase in calcium transient amplitude through the sodium/calcium exchanger in reverse.[1]

The release of angiotensin II/endothelin type-I is responsible for cardiac myocyte hypertrophy, and the blockade of angiotensin II abolishes the Anrep effect. For example, the drug losartan blocks the angiotensin I receptors.  According to previous studies, angiotensin II and endothelin type-I have a one-way direction and an upstream process, as the blockade of endothelin type-I receptors eventually causes the blockade of angiotensin II. The Anrep effect is not related to any genomic mechanisms as the mechanical response occurs in a very brief period.

The oxide ion is very unstable, and it is rapidly converted by superoxide dismutase into hydrogen peroxide, a more stable, membrane-permeant reactive oxygen species with wide recognition as a signaling molecule. In the myocardium, a membrane-bound extracellular superoxide dismutase, a cytoplasmic copper-zinc superoxide dismutase, and a mitochondrial manganese superoxide dismutase perform the dismutation. Therefore, the oxide ion is easily converted into hydrogen peroxide at different cellular locations, upstream or downstream of the mitochondria. Sabri et al.[3] and Rothstein et al.[4] showed that hydrogen peroxide was the intracellular signal that led to the activation of kinases that phosphorylated the sodium-hydrogen antiporter I. Promoting an increased conversion of oxide ion into hydrogen peroxide leads to an enhanced slow flow response (Caldiz et al. 2007).[5] Therefore, hydrogen peroxide plays an essential role in the development of the slow flow response or Anrep effect.

Stretching of the myocardium leads to mineralocorticoid activation by releasing preformed angiotensin II from the myocyte, which begins the release of aldosterone through angiotensin I receptor activation. Aldosterone activates the mineralocorticoid receptors in an autocrine/paracrine fashion. The chain of events started by the myocardial stretch is the release of angiotensin II followed by endothelin release, mineralocorticoid receptor activation, and epidermal growth factor receptor transactivation. These steps cause upstream mitochondrial reactive oxygen species release, which is responsible for activation of extracellular signal-related kinases (ERK)/90-kDa ribosomal S6 kinase (p90) signaling pathway (ERK1/2-p90) stimulating sodium-hydrogen antiporter I.[1] Once epidermal growth factor receptor transactivation takes place, aldosterone activates sodium-hydrogen antiporter I. Post-translational enhancement of sodium-hydrogen antiporter I activity results from a stretch-mediated release of preformed angiotensin II/endothelin type-I leading to activation (phosphorylation) of kinases.

Mechanism

The variable behavior of myocardial intracellular pH in the presence of bicarbonate is because of the increase in myocardial intracellular pH caused by stretch. Myocardial stretch induces angiotensin II and endothelin release, which causes the release of endothelin type-I and activates the sodium-hydrogen antiporter I. The expected intracellular alkalization is minimized in the presence of bicarbonate because angiotensin II also activates the sodium-independent chloride/bicarbonate exchanger. However, an increase in sodium is caused by hyperactivity of the sodium-hydrogen antiporter I after stretch, despite the compensation in myocardial intracellular pH by the simultaneous activation of the sodium-independent chloride/bicarbonate exchanger. The slow increase in developed force occurs when there is an increase in sodium, and its suppression also prevents the slow flow response.

The increase in sodium, induced by the activation of the sodium-hydrogen antiporter I, causes a secondary rise in the calcium transient via sodium/calcium exchanger. The increase in the calcium transient, which underlies the slow flow response, is secondary to the rise in sodium. Previous studies showed that there are no significant changes in the calcium transient during the fast response in developed force, whereas the slow flow response accompanies an increase in both the peak systolic calcium and the calcium transient.[2] The increase in the calcium transient is in agreement with published results and rationalizes the increase in the contractility that takes place during the slow phase. A small decrease in diastolic calcium occurs immediately after stretch, and no further changes in diastolic calcium happen during the development of the second phase in force response. Similar small changes in diastolic calcium after stretch are consistent with increased calcium binding to troponin C.

Therefore, the increase in the calcium transient after muscle stretch is a consequence of the rise in sodium. The increase in sodium results from sodium-hydrogen antiporter I activation by an autocrine-paracrine mechanism.

Pathophysiology

A sudden increase in arterial blood pressure and left ventricular pressure during thoracic aortic clamping may lead to acute compression of subendocardial blood vessels and ischemia, causing a decrease in myocardial contractility. Vascular autoregulation regulates subendocardial blood distribution increasing the blood flow to the affected areas, which increases the otherwise compromised contractility of the heart.[6][7]

Physiologically, the Anrep effect lets the heart adapt to an abrupt increase in afterload, occurring just after the Frank-Starling mechanism. Crucial intracellular signals for the development of the Anrep effect like increased oxidative stress, sodium-hydrogen antiporter I hyperactivity, and augmented calcium concentration play critical roles in the progression of pathological cardiac hypertrophy.[8][9]

Clinical Significance

Vasodilators such as nitroglycerin increase the cardiac output by decreasing the afterload and preload and increasing coronary perfusion, thus facilitating the Anrep effect.