Re-evaluating Stress Testing Paradigms in Older Adults

By 2050, the US population aged 65 and older is expected to double, reaching 83.7 million(1). Cardiovascular disease is the leading cause of morbidity and mortality in older adults(2). With advancing age, patients accumulate a lifetime of cardiovascular risk factors as well as age-related physiological changes that promote atherosclerosis. Consequently, older adults are at a higher risk for incident and progressive coronary artery disease and subsequent adverse cardiac outcomes(3). Paradoxically, these patients have been under-represented in cardiovascular imaging trials and imaging registries(4). Much of the evidence guiding ischemia evaluation and management has been derived from younger or middle-aged populations. Consequently, clinicians often face uncertainty when applying standard testing algorithms to patients over 75 or 80 years of age – the same group of patients who most frequently undergo noninvasive imaging(5). In this group, invasive testing may have high procedural risk and poor long term outcomes due to frailty and comorbidities(6, 7). Noninvasive imaging, particularly myocardial perfusion imaging (MPI), plays an important role by helping identify which older patients have coronary artery disease, risk stratifying this population to potentially identify those who may benefit from further therapies while potentially avoiding unnecessary invasive procedures.

Traditional exercise stress testing is often limited in older patients. Many older adults cannot achieve sufficient workload because of reduced functional capacity, orthopedic or neurologic issues, or baseline ECG abnormalities. As a result, the diagnostic yield of exercise ECG testing alone falls with age. For example, the Duke treadmill score, which predicts cardiac events in younger populations, performs poorly beyond age 75 where most older patients fall into intermediate-risk categories, and even “low-risk” older adults have annual cardiac mortality ~2% (8). Given these limitations, MPI has become a valuable tool in evaluating ischemia among older patients. Yet, much of the foundational MPI data were generated decades ago, using conventional SPECT technology in a population with higher cardiovascular disease prevalence. Since then, technology and population demographics have changed dramatically.

New-generation cadmium–zinc–telluride (CZT) SPECT systems offer higher temporal and spatial resolution, faster acquisition times, and reduced radiation exposure compared to conventional systems. These advances enhance image quality, reduce motion artifacts, and allow for quicker and more accurate quantification of perfusion defects. However, despite these advantages, data specifically evaluating the diagnostic and prognostic performance of CZT SPECT MPI in older adults remain limited.

The sub-analysis of the AMICO registry by Liga et al.(9) specifically addresses how well modern MPI done on CZT systems performs in older patients (>70 years) compared to younger patients, with a focus on different stress modalities. This study included 627 older patients aged >70 years and an equally sized matched cohort of younger patients under the age of 70, all of whom underwent state-of-the-art SPECT MPI with a CZT camera and subsequent coronary angiography. Older cases and younger controls were matched for sex, risk factors, and type of stress test (exercise vs. pharmacologic) to isolate the effect of age on test performance. This large prospective dataset provides a robust examination of diagnostic and prognostic value of SPECT MPI in older adults. Overall, SPECT MPI was effective in diagnosing obstructive CAD across the entire cohort (AUC ~0.79). However, test accuracy declined with advancing age, driven specifically by a drop in specificity in older patients. In the >70 year age group, specificity for obstructive CAD was only 64% versus 72% in younger patients. The same pattern was also noted with advancing age within the older adult subgroup. In other words, older individuals had more false-positive perfusion results. Importantly, this age-related gap in specificity was entirely attributable to exercise stress testing. When analyzed by stress modality, the authors found that among those who underwent treadmill exercise imaging, older patients had significantly lower diagnostic accuracy than younger patients (ROC AUC 0.75 vs 0.82, p = 0.03). By contrast, in patients who underwent pharmacologic vasodilator stress, the diagnostic accuracy in older adults was just as high as in younger patients (AUC 0.84 vs 0.80, with no significant difference). In fact, no age-related drop in diagnostic performance was seen with vasodilator SPECT – the diminished specificity was observed only in exercise MPI.

Why might exercise stress MPI be less specific in older adults? Liga et al. provide important mechanistic insights(9). While a majority of older patients in the AMICO sub-study underwent exercise stress testing (63%), their achieved stress level was markedly lower than younger adults. Specifically, older patients demonstrated significantly lower peak rate-pressure product (RPP stress) and lower RPP reserve (stress/rest RPP ratio) indicating blunted myocardial workload during stress testing. Additionally, a smaller proportion of older patients reached ≥85% of their maximum predicted heart rate, further suggesting suboptimal exercise effort. These hemodynamic limitations may reduce the differential perfusion signal required for accurate ischemia detection on MPI, increasing the likelihood of false-positive results. Multivariable analyses support this mechanism: both increasing age and lower RPP reserve were independent predictors of reduced diagnostic specificity of exercise MPI. This suggests that inadequate myocardial stress associated with exercise stress, rather than imaging limitations, is the main driver of lower test specificity in older adults. Pharmacologic vasodilator stress, on the other hand, does not depend on patient effort and can detect perfusion abnormalities even in patients who cannot exercise maximally. It makes sense, then, that vasodilator MPI maintained high accuracy irrespective of age in this study. Furthermore, these “false positives” on perfusion imaging may reflect clinically meaningful microvascular dysfunction or diffuse subendocardial ischemia which is prevalent in older adults, which are not captured by epicardial stenosis alone. Although coronary microvascular dysfunction was not directly assessed in the study, the observed prognostic significance of non-obstructive CAD and perfusion defects in this cohort suggests that these findings should not be dismissed as artifacts. Rather, they underscore that a positive MPI in an older patient often signals a true ischemic substrate even if coronary anatomy does not show focal high-grade lesions.

What do these results mean for the clinicians? The current guidelines appropriately emphasize that exercise should remain the preferred stress modality when patients can achieve adequate workload, given the valuable functional information obtained including exercise capacity, symptoms, and hemodynamic response(10). However, the AMICO data suggest we need more nuanced criteria for selecting stress protocols in older adults. Achieving 85% of predicted maximal heart rate may not ensure sufficient myocardial workload if RPP is low or functional capacity is poor. Stress imaging protocols in older adults should therefore be individualized according to age and functional capacity rather than rigid thresholds. For patients under 70 years with preserved fitness, exercise stress remains appropriate. For those aged 70–80 years, assessment of functional capacity using the Duke Activity Status Index (DASI) or a similar screening tool can guide selection of type of stressor. For patients older than 80 years or any older adult with borderline exercise capacity, pharmacologic vasodilator stress should be strongly considered. When exercise testing is initiated but inadequate workload or RPP is achieved, conversion to vasodilator stress during the same visit is advisable to maintain diagnostic accuracy.

Another important clinical question is whether myocardial perfusion imaging (MPI) meaningfully stratifies risk in very old adults, for whom age and comorbidities often dominate outcomes. Despite lower diagnostic specificity of exercise MPI in older adults, Liga et al. demonstrate that the prognostic value of perfusion abnormalities remains preserved across age groups. In the present study, the summed difference score (SDS) was a strong, independent predictor of major adverse cardiac events (MACE) in both younger and older cohorts (HR 1.11 per SDS unit, 95% CI 1.07–1.14). The gradient of risk held true even in the oldest subgroups (70s and 80s), with higher SDS correlating with significantly worse outcomes. This apparent paradox of reduced diagnostic accuracy but preserved prognostic power reflects a broader shift in how ischemia manifests with aging. In older adults, exercise-induced perfusion defects may not always correspond to focal epicardial stenoses. Instead, they likely reflect an integrated cardiovascular stress response that includes diffuse subendocardial ischemia, diastolic dysfunction, and coronary microvascular disease along with epicardial atherosclerosis—substrates that remain prognostically meaningful even when angiography shows non-obstructive CAD. Supporting this, the study also found that non-obstructive CAD independently predicted adverse events in older adults, reinforcing the importance of diffuse atherosclerosis and microvascular dysfunction as risk drivers in aging hearts.

Prior studies have shown similar findings (11). Nair et al. reported that patients ≥80 years with a normal MPI and no major comorbidities had event rates near 1% per year, comparable to younger population(12). However, event rates increased sharply to 9.6% per year among those with moderately to severely abnormal MPI. Collectively, these data validate the finding that a normal MPI confers low risk even in very old patients, while an abnormal scan remains an important warning sign. The AMICO cohort confirms these findings, demonstrating that even in the oldest adults above 80, inducible ischemia identified those at highest risk of adverse cardiac events. As such, age should not be a barrier to ischemia evaluation. MPI offers prognostic insight that may guide personalized care by identifying high-risk patients who may benefit from more intensive therapy, and sparing low-risk older adults from unnecessary invasive procedures.

The authors are to be congratulated for addressing a critical evidence gap with scientific rigor and clinical relevance. With a matched younger age cohort, integration of imaging, angiographic, and outcome data, the authors provide a nuanced understanding of how SPECT MPI performs across age. Future efforts must refine how we tailor imaging to this diverse population. An older adults’ functional status and biological age rather than chronological age alone would be ideal to inform the choice of stress modality, imaging protocol, and therapeutic thresholds. There is an urgent need for validation of such protocols that incorporate these variables to optimize the diagnostic yield while accommodating the needs and changes of an aging population. PET MPI with absolute myocardial blood flow and flow reserve quantification may outperform traditional SPECT in identifying diffuse and microvascular disease in older adults and requires formal evaluation in this population. Importantly, as older patients often prioritize functional status and quality of life over procedural endpoints or survival(13), future studies must integrate these patient-centered outcomes alongside adverse cardiac events. Finally, imaging must not only risk-stratify but guide management – by identifying which older adults may benefit from revascularization or intensive medical therapy, and which patients may be safely managed conservatively. Until such data are available, clinicians should individualize decisions, but the insights from studies like AMICO provide confidence that identifying ischemia is meaningful at any age.

As the population ages and cardiovascular disease burden rises, nuclear cardiology must evolve to meet the distinct needs of older adults. It is time to move beyond one-size-fits-all testing and toward precision imaging by developing strategies that account for the wide variability in functional capacity, comorbidity, and clinical goals. The current study compellingly shows that the traditional “exercise-first” paradigm needs to be reconsidered in older adults. While exercise stress remains valuable for its comprehensive physiologic assessment, its reduced diagnostic specificity in older adults cannot be ignored. The preserved prognostic power of ischemia across modalities is reassuring, yet it reinforces the need to tailor stress selection to each patient’s functional status, biological age, and therapeutic priorities. In the future, we need to adopt a personalized, biology-informed approach that integrates frailty, functional reserve, and patient-centered outcomes such as quality of life and independence over traditional end-points and methods of evaluation. Only by doing so can we fulfill the promise of delivering accurate, actionable, and compassionate imaging care for our most vulnerable patients.