Comparison of long-term mortality risk following normal exercise vs adenosine myocardial perfusion SPECT

A higher frequency of clinical events has been observed in patients undergoing pharmacological vs exercise myocardial perfusion single-photon emission computed tomography (SPECT). While this difference is attributed to greater age and co-morbidities, it is not known whether these tests also differ in prognostic ability among patients with similar clinical profiles. We assessed all-cause mortality rates in 6,069 patients, followed for 10.2 ± 1.7 years after undergoing exercise or adenosine SPECT. We employed propensity analysis to match exercise and adenosine subgroups by age, gender, symptoms, and coronary risk factors. Within our propensity-matched cohorts, adenosine patients had an annualized mortality rate event rates that was more than twice that of exercise patients (3.9% vs 1.6%, P < .0001). Differences in mortality persisted among age groups, including those <55 years old. In the exercise cohort, mortality was inversely related to exercise duration, with comparable mortality noted for patients exercising <3 min and those undergoing adenosine testing. Among patients with normal stress SPECT tests, those undergoing adenosine testing manifest a mortality rate that is substantially higher than that observed among adequately exercising patients, but comparable to that observed among very poorly exercising patients. This elevated risk underscores an important challenge for managing patients undergoing pharmacological stress testing

Energy landscapes of functional proteins are inherently risky

Evolutionary pressure for protein function leads to unavoidable sampling of conformational states that are at risk of misfolding and aggregation. The resulting tension between functional requirements and the risk of misfolding and/or aggregation in the evolution of proteins is becoming more and more apparent. One outcome of this tension is sensitivity to mutation, in which only subtle changes in sequence that may be functionally advantageous can tip the delicate balance toward protein aggregation. Similarly, increasing the concentration of aggregation-prone species by reducing the ability to control protein levels or compromising protein folding capacity engenders increased risk of aggregation and disease. In this Perspective, we describe examples that epitomize the tension between protein functional energy landscapes and aggregation risk. Each case illustrates how the energy landscapes for the at-risk proteins are sculpted to enable them to perform their functions and how the risks of aggregation are minimized under cellular conditions using a variety of compensatory mechanisms