Heart rate response during vasodilator stress myocardial perfusion imaging: Mechanisms and implications
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Myocardial perfusion imaging (MPI) using adenosine, dipyridamole, or regadenoson (a selective A2A receptor agonist) is an established method for detecting coronary artery disease (CAD) and risk stratification.1 In high-risk populations, as in those with diabetes mellitus (DM) or chronic kidney disease, MPI has been shown to be a powerful predictor of risk, but nevertheless, patients with normal myocardial perfusion are at higher risk than those without DM or chronic kidney disease.2,3 Thus, there continues to be a need to extract more useful prognostic data from stress MPI especially in high-risk populations.
A blunted heart rate (HR) response to exercise stress has been known to be an independent predictor of poor outcome and is used clinically in conjunction with other prognostic variables such as perfusion defects, left ventricular (LV) ejection fraction (EF) and volumes, exercise time, and symptoms during exercise to derive an overall assessment of risk in a particular patient.4 In patients undergoing stress testing, for one reason or another, with adenosine or regadenoson (and dipyridamole, which acts indirectly by increasing interstitial levels of endogenous adenosine), there is a modest increase in HR and a modest decrease in blood pressure (BP). The increase in HR has been traditionally attributed to a reflex response to the vasodilatory effect on the systemic circulation and the resultant increase in sympathetic discharge.5,6 The true mechanism of HR increase, however, is more complicated and involves direct stimulation of the sympathetic nervous system.7 The administration of adenosine as a bolus, as done for the interruption of supra-ventricular tachycardias, has a negative chronotropic effect on the atrio-ventricular node via stimulation of the A1 receptor. This is in contradistinction to its effect on the A2A receptor when given as an infusion in stress MPI studies where it induces an increase in HR.5,8 The development of selective A2A receptor agonists (such as regadenoson) has allowed for the dissection of the effects of adenosine on the multiple receptors. A well-done pivotal study in rats by Dhalla et al7 that used regadenoson in combination with a selective A2A receptor antagonist, B-blocker, a ganglionic blocker (to block the sympathetic nervous system), and a direct vasodilator (nitroprusside) demonstrated the dissociation of tachycardia and hypotension (secondary to peripheral vasodilation) responses to regadenoson. This and other data (reviewed in Ref. 9) confirm that A2A receptor agonists cause a direct stimulation of the autonomic nervous system, which results in sinus tachycardia independent of the baroreflex mechanism. Thus, the change in HR in response to A2A receptor agonists can be used to evaluate autonomic function.
In the study by Mathur et al reported in this issue of the Journal 13 an increase in HR by less than 20% in response to dipyridamole was considered blunted, and this was present in 64% of the entire population (2,890 out of 4,484 patients). Therefore, caution must be exercised in the utilization of data from these multiple agents since they have different pharmacokinetic properties although they all act by stimulating the adenosine receptors. Further studies are definitely needed to characterize ideal cutoffs tailored for each reagent.
The study by Mathur et al adds to an expanding body of evidence that suggests that HR response to vasodilators is just as important as HR response during exercise and should be included in future studies of risk assessment. Ideally, the role of blunted HR response in predicting sudden death rather than all-cause mortality or composite end points should be studied, although the adjudication of whether death is sudden or non-sudden is even more difficult than whether death is cardiac or non-cardiac. The Duke investigators have examined the predictors of sudden death using the largest database available and have carefully crafted the criteria of defining sudden death.22,23
Impressively, a blunted HR response to dipyridamole in the Mathur study was independently associated with increased cardiac death even after controlling for myocardial perfusion, LVEF, age, abnormal electrocardiogram and a history of DM, myocardial infarction, and heart failure. The HR response was thus predictive of cardiac death in subgroups of patients with low, intermediate, and high summed stress score and whether or not patients were receiving beta-blocker therapy. As pointed out in their article, and as anticipated based on the data from ADVANCE MPI, more patients with DM had a blunted HR response to dipyridamole. The authors correctly point out that a blunted HR response is prognostically useful in diabetics and that DM patients with a blunted HR response had a higher event rate than non-DM patients with a blunted response. Interestingly, however, a blunted HR response predicted cardiac death just as well in non-DM patients and patients without DM with a blunted HR response had an annualized cardiac death rate of >3%, which is numerically higher than DM patients with a higher HR response. Future studies should examine the relationship between HR response and other direct measures of autonomic function including the perfusion-denervation mismatch pattern. It remains to be determined whether the HR response could be modified by life style changes or medications and whether such a modification results in a directional change in patient outcome. Finally, the relationship of HR response as a continuum and outcome and the particular cutoff point in an individual patient that defines a poor outcome need to be defined.
AEI is consultant to Gilead and received research grants from Gilead and Astellas Pharm, USA.
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