Reactive hyperemia

Reactive hyperemia: a review of methods, mechanisms, and considerations

Reactive hyperemia is a technique for noninvasive assessment of peripheral microvascular function and a predictor of all-cause and cardiovascular morbidity and mortality. 

RH is the rapid and exaggerated reperfusion following a period of ischemia. 

Vasodilation in response to ischemia markedly reduces resistance in the microvasculature, allowing the hyperemic surge to reperfuse the oxygen-starved tissue, thus correcting the ischemic error signal before recovering to a basal state. 

It represents the magnitude of limb reperfusion following a brief period of ischemia induced by arterial occlusion. 

A blunted reactive hyperemia is believed to reflect impaired microvascular function. 

Venous occlusion plethysmography was initially used to measure RH.

Venous occlusion plethysmography

measurement is prognostically significant.

Measurement of RH by venous occlusion plethysmography is commonly reported by peak forearm blood flow (FBF) measured as the highest FBF detected during the hyperemic response, and total FBF, measured as the area under the FBF curve throughout the hyperemic response and recovery.

Reactive hyperemia by venous occlusion plethysmography technique: 

A cuff placed around the upper arm is inflated to induce ischemia. 

A gauge is placed around the largest part of the forearm to detect changes in limb volume. 

Near the end of the ischemic period, a cuff placed around the wrist  to suprasystolic pressures, preventing blood from flowing into the hand.

The upper arm cuff is deflated and then quickly reinflated at a lower pressure to arrest the venous circulation while allowing the higher-pressure arterial circulation to perfuse the forearm. 

The low-pressure cuff is then rapidly inflated and deflated at short, regular intervals over the following minutes. 

During each low-pressure inflation, arterial blood floods into the limb while venous blood is prevented from exiting. 

The engorged vasculature causes the limb to swell sufficiently to increase limb volume. 

By measuring the rate of change in forearm volume, arterial blood flow can be inferred. 

Venous occlusion plethysmography is accurate and has high reproducibility.

Venous occlusion plethysmography has several limitations. 

Doppler ultrasound has become the clinical standard for measuring RH. 

Doppler US finds reductions in peak hyperemic blood flow in subjects with hypercholesterolemia, elevated systemic inflammation and in subjects exposed to high levels of air pollution.

Reactive hyperemia is the transient increase in organ blood flow that occurs following a brief period of ischemia.

RH occurs following the removal of a tourniquet, unclamping an artery during surgery, or restoring flow to a coronary artery after reopening a closed artery using an angioplasty balloon or clot dissolving drug.

In general, the ability of an organ to display reactive hyperemia is similar to its ability to display autoregulation.

Reactive hyperemia occurs because during the period of occlusion, tissue hypoxia and a build up of vasodilator metabolites, such as adenosine, dilate arterioles and decrease vascular resistance. 

Then when perfusion occlusion is released, flow becomes elevated because of the reduced vascular resistance. 

With RH the tissue becomes reoxygenated and vasodilator metabolites are washed out of the tissues, vessels regain their normal vascular tone, thereby returning flow to control. 

The longer the period of occlusion, the greater the metabolic stimulus for vasodilation leading to increases in peak reactive hyperemia and duration of hyperemia.  

Depending upon the organ, maximal vasodilation as indicated by peak flow.

Vasodilation may occur following less than one minute: coronary circulation of complete arterial occlusion, or may require several minutes of occlusion, gastrointestinal circulation.

The peak velocity-time is integral to be predictive of cardiovascular disease and future cardiac events.

There is no universally agreed upon analytical approach for quantifying RH by Doppler ultrasound: peak velocity, peak blood flow, velocity-time integral, average hyperemic velocity and average hyperemic flow.

Measurement of reactive hyperemia can be achieved by Doppler ultrasound, and 

Near-Infrared Spectroscopy is an alternative.

Near-Infrared Spectroscopy operates by emitting near-infrared light at wavelengths that are differentially absorbed by oxygenated hemoglobin/myoglobin (HbO2) and deoxygenated hemoglobin/myoglobin (HHb): quantifying the concentration of both HbO2 and HHb in the tissue and calculate tissue oxygen satus.

In patients with sepsis, reperfusion rate is significantly blunted compared with controls and that a lack of improvement in reperfusion rate over a 48-h period was predictive of mortality.

Peripheral artery tonometry (PAT) has ease of use and portability, coupled with the simplicity of the analysis. 

RH in peripheral artery tonometry is measured by the changes in the amplitude of pulsations in finger pressure. 

The primary outcome measure, the RH index (RHI), has been proven useful for predicting endothelial dysfunction, coronary atherosclerosis, coronary artery disease, microvascular dysfunction secondary to sepsis, and coronary plaque formation.

Blunting RHI is correlated with risk factors for developing cardiovascular disease, as well as increased risk of future adverse cardiac events.

Peripheral artery tonometry (PAT)

derived RH (RH-PAT) is often described as a measure of endothelial function.

The dilation of the microvasculature decreases resistance downstream, allowing for the hyperemic surge of blood to reperfuse the limb.

The fundamental stimulus driving RH is tissue hypoxia, a potent stimulus for vasodilation.

Hypoxia stimulates vasodilation through mechanisms involving prostacyclin (PGI2)-, adenosine-, nitric oxide (NO)-, and K+ channel-mediated hyperpolarization. 

NO rapidly diffuses out of the endothelial cell and into the underlying vascular smooth muscle, where it activates guanylyl cyclase (GC). 

GC converts GTP to cGMP, which then activates protein kinase G (PKG). 

Protein kinase G (PKG) mediates vasorelaxation by activating KCa channels, causing K+ efflux. 

The resulting hyperpolarization causes voltage-sensitive Ca2+ channels to close, preventing Ca2+influx. 

PKG activates Ca2+-ATPase pumps, increasing expulsion of Ca2+ from the myocyte and sequestration of Ca2+ into the sarcoplasmic reticulum.

The decreased intracellular Ca2+ concentration, shifts  the balance in activity between myosin light chain kinase and myosin light chain phosphatase to favor phosphatase activity. 

Under hypoxic conditions, intracellular Ca2+ concentration rises, leading to the stimulation of phospholipase A, which catalyzes the production of arachidonic acid, the substrate for PGI2 synthesis by cyclooxygenase (COX).

PGI2 can bind to receptors on the luminal surface of the endothelium, stimulating production of cAMP and subsequent activation of protein kinase A. 

COX then activates K+ channels, inducing hyperpolarization and smooth muscle relaxes.

However, the role of prostaglandins in mediating RH remains unclear.

Adenosine elicits its vasoactive effects by binding to membrane-bound receptors, activating an internal G protein-mediated cascade..

Binding of adenosine activates adenyl cyclase, stimulating production of cAMP. 

cAMP a second messenger then activates protein kinase A, opening K+ channels and resulting in hyperpolarization of the endothelium and vascular smooth muscle

Adenosine, prostaglandins, and NO,  are metabolic vasodilators that function by activating an enzymatic signaling cascade.

K+ contributes to the regulation of vascular tone through alterations in the polarization state of both endothelial and vascular smooth muscle cells. 

In endothelial cells, ATP-sensitive K+ channels are inhibited by ATP.

Under conditions that lower ATP concentration, such as hypoxia, K+ channels begin to open, and the efflux of K+ hyperpolarizes the endothelial cell and raises the driving force for Ca2+ to enter the cell, leading to the subsequent production of NO and PGI2, respectively .

Potassium channels can also be opened by protein kinase A, which is activated following adenosine and PGI2 binding their respective receptors.

 Vascular smooth muscle cells express multiple isoforms of K+ channels that participate in vasomodulation iincreasi g K+ efflux, leading to myocyte hyperpolarization and closure of voltage-gated Ca2+ channels. 

As a result  there is decreased intracellular Ca2+ concentration, leading to vasorelaxation

The rate or magnitude of reperfusion is proportional to the microvasculature’s ability to dilate during ischemia.

RH reflects the microvasculature’s ability to dilate in response to a period of acute ischemia. 

RH is a negative-feedback loop, the purpose of which is to correct the ischemic error signal and restore the tissue to a homeostatic state. 

RH predicts cardiovascular events and mortality because of its ability to detect impaired vasodilatory function. 

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