Effects of intravenous theophylline on exercise-induced myocardial ischemia: II. A concentration-dependent phenomenon

AbstractObjectives. The effects of varying concentrations of theophylline on exercise-induced myocardial ischemia were evaluated in patients with stable coronary artery disease.Background. Theophylline is a competitive antagonist of adenosine and may have potential as an anti-ischemic medication. It is not known whether these effects on myocardial ischemia are concentration dependent.Methods. In a double-blind, randomized, crossover manner, 11 patients received, at 1-week intervals, placebo and each of three theophylline doses by intravenous infusion for 45 min. Graded exercise testing was performed before randomization and immediately after each infusion. Concurrent anti-ischemic medications were withheld for 24 h before each exercise test. Serum theophylline concentrations achieved were 3.9 ± 1.0 mg/liter (low), 8.2 ± 1.8 mg/liter (medium) and 13.2 ± 2.3 mg/liter (high).Results. Compared with placebo, none of the three theophylline infusions produced a significant alteration in rest heart rate, blood pressure, mean frequency or severity of ventricular ectopic activity or noncardiac symptoms. The time to onset of ischemia was progressively increased, with medium and high concentrations achieving statistical significance. Similar patterns were observed for oxygen uptake and the heart rate-systolic blood pressure product at the onset of ischemia. Total exercise duration was significantly prolonged with the medium and high concentrations.Conclusions. It is concluded that administration of varying doses of theophylline before exercise produces a clinically significant and concentration-dependent improvement in the indicators of myocardial ischemia in patients with chronic stable coronary artery disease

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

Triage of patients for attenuation-corrected stress-first Tc-99m SPECT MPI using a simplified clinical pre-test scoring model.

BACKGROUND: Stress-only Tc-99m SPECT MPI saves time and reduces radiation exposure while a normal study has a benign prognosis. However, no guidelines exist as to which patients should undergo stress-first MPI. The purpose of this study was to validate a previously published pre-test prediction scoring model and refine the stress-first triage process further if possible. METHODS: We retrospectively reviewed all patients who underwent an attenuation-corrected Tc-99m SPECT MPI over a 39-month period. Based on 17-segment model semi-quantitative scoring, a successful stress-first MPI was defined as a summed stress attenuation-corrected score ≤ 1. Based on results from multivariate analysis, the previously published prediction score (comprised eight clinical and demographic variables) was compared to triage based on coronary artery disease (CAD) status alone and with the addition of other highly associated variables. Logistic regression and Chi-squared analyses were used to determine the magnitude of variable effect and to compare model results. RESULTS: A total of 2,277 patients were included, and the prediction score successfully stratified patients into low-risk (91.1% successful stress-first), intermediate-risk (79.4%), and high-risk (50.7%) groups. Comparing the use of the prediction score to the use of a history of CAD as the only triage factor, 69.0% of patients would be accurately triaged using the prediction score with a cutoff of 7 (maximized sensitivity and specificity), while 78.6% were correctly triaged with CAD status alone (P \u3c .0001). The addition of variables highly associated with a successful stress-first protocol (congestive heart failure [OR 3.4] and an abnormal resting ECG [OR 2.1]) to CAD status further enhanced triage accuracy to 81% (P \u3c .0001). CONCLUSIONS: While the previously described prediction score effectively identifies patients who can successfully undergo stress-first MPI, it is cumbersome. Triaging based solely on CAD status and with the addition of other key variables is practical and provides improved predictive accuracy for successful stress-first MPI. Utilizing this simplified pre-test scoring model may allow for wider adoption of stress-first imaging protocols which have clear advantages over traditional rest-stress protocols

The clinical value of single photon emission computed tomography myocardial perfusion imaging in cardiac risk stratification of very elderly patients (≥80 years) with suspected coronary artery disease.

BACKGROUND: The role of single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) in cardiac evaluation of the very elderly patients is unclear. We investigated the clinical value of SPECT MPI in very elderly patients (≥80 years) with suspected coronary artery disease (CAD) as well as in comparison to younger patients. METHODS AND RESULTS: A retrospective analysis of prospectively collected data from 8,864 patients [1,093 patients ≥80 years (very elderly), 3,369 patients 65-79 years (elderly), and 4,402 patients 50-64 years (middle-aged)] with suspected CAD who underwent exercise and/or pharmacologic stress testing with SPECT MPI between 1996 and 2005 was performed. Clinical and SPECT MPI characteristics, cardiac event rates, early (≤60 days) cardiac catheterization and revascularization rates of very elderly patients were compared to that of younger patients. Mean follow-up for cardiac events (cardiac death or non-fatal myocardial infarction) was 1.9 ± 0.9 years. Very elderly patients with moderate to severely abnormal SSS had a significantly higher annualized cardiac event rate than those with mildly abnormal or normal study (9.6% vs 3.4% and 2.5% respectively, P \u3c .001). Across all categories of SSS, very elderly patients had a significantly higher cardiac event rate as compared to younger patients (P \u3c .001). Early cardiac catheterization and revascularization referrals in very elderly patients increased as a function of severity of ischemia on SPECT MPI (P \u3c .001), although these referral rates were significantly lower in very elderly patients with mild to moderate and severe ischemia as compared to younger patients (P \u3c .05). CONCLUSIONS: In very elderly patients (≥80 years) with suspected CAD, SPECT MPI has prognostic and incremental value in the noninvasive cardiovascular assessment for risk stratification and may influence medical decisions

Does Risk for Major Adverse Cardiac Events in Patients Undergoing Vasodilator Stress with Adjunctive Exercise Differ from PatientsUndergoing Either Standard Exercise or Vasodilator Stress with Myocardial Perfusion Imaging?

BACKGROUND: In patients with functional limitations, the use of adjunctive exercise with vasodilator stress has advantages over vasodilator stress alone in single photon emission computed tomography myocardial perfusion imaging (MPI) for technical reasons and with regards to more effective cardiac risk stratification. Whether patients who undergo vasodilator with adjunctive exercise stress MPI possess clinical characteristics and cardiac risk that differs from those who undergo standard exercise or vasodilator stress MPI is unknown. METHODS: Prospectively collected data on 19,367 consecutive patients referred for stress MPI to a tertiary care center (9,331 [48%] underwent exercise-only, 3,793 [20%] underwent vasodilator plus exercise, and 6,243 [32%] underwent vasodilator-only) were analyzed. Perfusion data were scored using the ASNC 17-segment with a summed stress score (SSS) \u3c 4 = normal, 4-8 = mildly abnormal, and \u3e 8 = moderate to severely abnormal. Patients were followed a mean of 1.96 ± 0.95 years. Demographics, clinical characteristics, and the occurrence of major adverse cardiac events (cardiac death or nonfatal myocardial infarction) were compared between the three stress modality groups. RESULTS: Comparison of demographics and clinical characteristics revealed significant differences in gender, age, cardiac risk factors, and stress MPI between the three stress modality groups (P \u3c .001). In follow-up, cardiac event-free survival of patients in the vasodilator plus exercise stress group was significantly higher than those in the vasodilator-only group but lower than those in the exercise-only group (P \u3c .001). Annualized cardiac event rates of patients in the vasodilator plus exercise stress group were significantly lower than those in the vasodilator-only group for all three categories of the SSS (P \u3c .001). After multivariable adjustment, with exercise-only as reference category, vasodilator plus exercise and vasodilator-only stress emerged as independent predictors (more likely occurrence) of cardiac death, while vasodilator-only stress emerged as an independent predictor (more likely occurrence) of cardiac death or nonfatal myocardial infarction. With vasodilator-only as the reference category, exercise-only and vasodilator plus exercise stress emerged as independent predictors (less likely occurrence) of cardiac death as well as of cardiac death or nonfatal myocardial infarction. CONCLUSIONS: Patients undergoing vasodilator plus exercise stress MPI possess clinical characteristics and cardiac risk that differs significantly from those undergoing either standard exercise or vasodilator stress MPI and places them in a lower risk category compared to vasodilator stress alone