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Blunted Heart Rate Response to Lexiscan: An Independent Prognostic Indicator?

Updated by Jim McGee, BA BS CNMT RT(N)  May 29, 2018

Disclaimer: This article does not purport to be a comprehensive treatment of this subject. Please consult the references & conduct your own research before making any clinical decisions.

This article explores growing evidence that might allow risk stratification of patients with normal perfusion & LV function after undergoing regadenoson (Lexiscan) stress myocardial perfusion imaging.

Patients whose heart rate increases <15% in response to regadenoson infusion may be at significantly increased risk of cardiac events & mortality.

Keep reading to learn more.

Background: Heart Rate Response to Exercise

During an exercise tolerance test, the patient’s heart rate is expected to increase and optimally reach a protocol-specific goal.

The inability of the heart rate to appropriately elevate during this time of increased activity/demand deserves attention.

If not caused by medication, this blunted heart rate response (HRR) can be a can be a cause for concern & an independent predictor of poor outcomes.

Here are some articles about blunted HRR to exercise:

Blunted Heart Rate Response to Regadenoson (Lexiscan)

Of interest to physicians who perform, interpret (or read the final reports of) Nuclear Stress Tests:

Research is now indicating that blunted heart rate response to regadenoson (Lexiscan) may also contain valuable prognostic information … independent of perfusion & LV function results.

There is an expanding body of evidence that heart rate reponse to vasodilators is just as important as HRR to exercise.

We’ll focus on one study in particular:

A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging

Hage, F.G., Dean, P., Iqbal, F. et al. J. Nucl. Cardiol. (2011) 18: 1086.

1,156 patients underwent regadenoson MPI & were followed over the next 22 months.

The patient’s heart rate response (HRR) to regadenoson was found to be an independent predictor of death rate during the follow up period.

Heart Rate Response (HRR) was defined as:

HRR = (Max Heart Rate during regadenoson stress – Resting Heart Rate) / Resting Heart Rate *100

They divided the patients into quartiles based on their HRR:

  • Top quartile HRR = 43% or greater
  • Second quartile HRR = 28%-43%
  • Third quartile HRR = 17%-28%
  • Lowest quartile HRR = less than 17%

So the top quartile’s heart rate increased 43% or more, and the lowest quartile’s heart rate increased less than 17%.

Results of Hage et al:

After adjusting for age, gender, diabetes mellitus, renal disease & MPI findings, decreasing HRR was associated with a step-wise increase in mortality

Patients with HRR response in the lowest quartile had a five-fold increase in mortality compared to patients in the top quartile [HR 5.2, 95% CI 2.3-12.0, P < .0001].

Here’s Another Study with Similar Results:

Prognostic value of heart rate response during regadenoson stress myocardial perfusion imaging in patients with end stage renal disease

AlJaroudi, W., Campagnoli, T., Fughhi, I. et al. J. Nucl. Cardiol. (2016) 23: 560. 

In this study, Aljaroudi et al looked at the prognostic value of HRR to regadenoson in patients with end-stage renal disease (ESRD) by prognostically following patients enrolled in the ASSUAGE and ASSUAGE-CKD trials.

Results of AlJaroudi et al:

Blunted HRR was a strong and independent predictor of death & cardiovascular events

Blunted HRR adds incremental prognostic value.

Editorial in the Journal of Nuclear Cardiology:

Heart rate response to regadenoson: Making the case for its value in clinical practice

Andrikopoulou & Hage suggested that there is now sufficient data to support the use of blunted HRR to regadenoson as an independent variable when risk stratifying patients with normal perfusion results.

They proposed that:

  • Blunted HRR be defined as <15%, and
  • Normal HRR be defined as >30%

Reference:  Andrikopoulou, E. & Hage, F.G. J. Nucl. Cardiol. (2016) 23: 575. 

Mechanism of Action / Significance:

Heart rate (& blood pressure) usually goes up during vasodilator stress, whether it be dipyridamole, adenosine or regadenson.

2 Possible Mechanisms of Action:

  • A baroreflex response to vasodilation & resultant increase in sympathetic discharge .5,  6
  • Or, A2A receptor agonists directly stimulate the autonomic nervous system, which results in sinus tachycardia independent of the baroreflex mechanism

It appears that the Second Explanation is most likely. Therefore:

  • Since HRR to regadenoson is dependent on autonomic response,
  • Blunted HRR response is a reflection of cardiac autonomic dysfunction
 .

Conclusion:

Blunted HRR to Regadenoson is Associated with Cardiac Autonomic Dysfunction


.
Detailed Explanation of Mechanism of Action

The following is a direct quote from Andrikopoulou, E. & Hage, F.G. J. Nucl. Cardiol. (2016) 23: 575:

“To fully appreciate the value of incorporating the HRR in clinical practice, we need to take a step back and look at the determinants of HRR.

The increase of heart rate during vasodilator MPI has been shown to be mediated via direct sympathetic stimulation by adenosine A2A receptors.21

Therefore, HRR reflects the status of the autonomic nervous system and is independent of systemic vasodilation. Indeed, in both animals and humans, the intensity of the HRR has been shown to be dissociated from the systemic blood pressure response.22

It is also worth mentioning that the effect of regadenoson (and other vasodilator stress agents) on myocardial blood flow is directly related to its effect on the coronary microcirculation and independent of its hemodynamic effect.

Therefore, the ability of regadenoson MPI to detect myocardial perfusion abnormalities is independent of the HRR since, unlike exercise stress, the effect of regadenoson on myocardial blood flow is uncoupled from myocardial work.23

As mentioned earlier, there have been many studies published about this topic.

What follows below is a partial list of published material.

References:

Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications

Hage, F.G. & Iskandrian, A.E. J. Nucl. Cardiol. (2010) 17: 536. 

Dipyridamole myocardial SPECT with low heart rate response indicates cardiac autonomic dysfunction in patients with diabetes

Lee, KH., Yoon, J.K., Lee, M.G. et al. J Nucl Cardiol (2001) 8: 129. 

A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging

Hage, F.G., Dean, P., Iqbal, F. et al. J. Nucl. Cardiol. (2011) 18: 1086. 

Abnormal heart rate response with vasodilator stress myocardial perfusion imaging: Relevance to clinical practice

Dakik, H.A. J. Nucl. Cardiol. (2017) 24: 1672.

Impact of integrating heart rate response with perfusion imaging on the prognostic value of regadenoson SPECT myocardial perfusion imaging in patients with end-stage renal disease

Gomez, J., Fughhi, I., Campagnoli, T. et al. J. Nucl. Cardiol. (2017) 24: 1666.

Blunted heart rate response as a predictor of cardiac death in patients undergoing vasodilator stress technetium-99m sestamibi gated SPECT myocardial perfusion imaging

Mathur, S., Shah, A.R., Ahlberg, A.W. et al. J. Nucl. Cardiol. (2010) 17: 617.

Prognostic Impact of Hemodynamic Response to Adenosine in Patients Older Than Age 55 Years Undergoing Vasodilator Stress Myocardial Perfusion Study

Circulation. 2003;107:2894-2899  

Reclassification of cardiovascular risk in patients with normal myocardial perfusion imaging using heart rate response to vasodilator stress.

Iqbal, Fahad M. et al. American Journal of Cardiology , Volume 111 , Issue 2 , 190 – 195

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