Table of Contents
Cardiologists who perform or interpret Nuclear Stress Tests may have a new prognostic indicator.
When a patient’s heart rate increases less than normal in response to Lexiscan (Regadenoson), they may be at increased risk of cardiac events & mortality.
This is most likely due to cardiac autonomic dysfunction.
Heart Rate Response to Exercise
Blunted heart rate response (HRR) to exercise is widely known to be a cause for concern.
If not caused by medication, this blunted HRR can be a predictor of poor outcomes, independent of myocardial perfusion imaging results.
- Impaired heart rate response to graded exercise: prognostic implications of chronotropic incompetence in the Framingham Heart Study. | Lauer MS, Okin PM, Larson MG, Evans JC, Levy D. | Circulation. 1996;93: 1520—1526. FREE Full Text
- Chronotropic incompetence: the implications of heart rate response to exercise (compensatory parasympathetic hyperactivity?). | Ellestad MH. | Circulation. 1996; 93: 1485—1487. FREE Full Text
- Chronotropic incompetence in clinical exercise testing. | Wiens RD, Lafia P, Marder CM, Evans RG, Kennedy HL. | Am J Cardiol. 1984; 54: 74—78. Abstract Only
Heart Rate Response to Regadenoson
There is an expanding body of evidence that heart rate reponse to vasodilators is just as important as HRR to exercise.
Let’s take a quick look at 2 studies.
Study: Hage, et al.
- 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%.
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]
Study: AlJaroudi et al.
- 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.
Blunted HRR was a strong and independent predictor of death & cardiovascular events.
Blunted HRR adds incremental prognostic value.
JNC Editorial: Andrikopoulou & Hage
- Heart rate response to regadenoson: Making the case for its value in clinical practice Andrikopoulou, E. & Hage, F.G. J. Nucl. Cardiol. (2016) 23: 575.
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%
Mechanism of Action / Significance
Heart rate (& blood pressure) usually goes up during vasodilator stress, whether it be dipyridamole, adenosine or regadenson.
There are 2 possible reasons that heart rate typically increases:
- A baroreflex response to vasodilation & resultant increase in sympathetic discharge .5, 6
- 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.
Conclusion: Cardiac Autonomic Dysfunction
Andrikopoulou & Hage concluded that heart rate response to regadenoson is dependent on autonomic response.
Therefore, blunted HRR response is likely a reflection of cardiac autonomic dysfunction.
Here’s how they summed it up:
“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“
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.
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