A high exercise workload of ≥ 10 METS predicts a low risk of significant ischemia and cardiac events in older adults.

BACKGROUND: Patients who achieve ≥ 10 METS during exercise SPECT myocardial perfusion imaging (MPI) have very low rates of significant ischemia and major adverse cardiac events (MACE). It is unknown how many older adults can achieve ≥ 10 METS, and if low risk extends to this subgroup. METHODS AND RESULTS: We examined the workload achieved, prevalence and predictors of ischemia, and MACE (cardiac death, non-fatal MI, late revascularization) in a cohort of 382 patients ≥ 65 years of age who underwent exercise 99mTc SPECT MPI. The cohort was 64.4% male and 36.9% had known coronary artery disease (CAD). All achieved ≥ 85% of maximum age-predicted heart rate. A workload of ≥ 10 METS was achieved in 25.4%; 50.3% attained 7-9 METS, and 24.4% reached < 7 METS. There was a stepwise decrease in prevalence of any ischemia and significant ischemia (≥ 10% of the left ventricle (LV)) as workload increased (P = 0.037). Patients achieving ≥ 10 METS had a 3.1% prevalence of ≥ 10% LV ischemia (1.2% in those without ST depression). Cardiac death and MACE rates in the ≥ 10 METS subgroup were 0.6%/year and 2.6%/year over a median 7.0 years of follow-up. CONCLUSIONS: A substantial proportion of older adults who undergo exercise SPECT MPI can achieve ≥ 10 METS. This subgroup has low rates of significant LV ischemia and MACE. The favorable diagnostic and prognostic implications of achieving a high workload in an older adult population suggest it is feasible, with certain exceptions, to include this subgroup in workload-based strategies of provisional imaging.

High-frequency QRS analysis to supplement ST evaluation in exercise stress electrocardiography: Incremental diagnostic accuracy and net reclassification.

BACKGROUND: Exercise stress electrocardiography (ECG) alone is underutilized in part due to poor diagnostic accuracy. High-frequency QRS analysis (HF-QRS) is a novel tool to supplement ST evaluation during stress ECG. We compared the diagnostic accuracy and net reclassification of HF-QRS analysis compared with ST evaluation for substantial myocardial ischemia by exercise SPECT myocardial perfusion imaging (MPI). METHODS AND RESULTS: Exercise SPECT MPI was performed in 257 consecutive eligible patients (mean age 59 ± 12, 67% male). An ischemic HF-QRS pattern was defined as a ≥ 1 µV absolute reduction and a ≥ 50% relative reduction of the root-mean-square of the 150-250 Hz band signal in ≥ 3 leads. Left ventricular ischemia of ≥ 10% on SPECT MPI was the diagnostic standard for substantial myocardial ischemia. HF-QRS analysis demonstrated incremental diagnostic value to ST evaluation plus clinical risk factors (AUC 0.804 vs 0.749, P < .0001). A HF-QRS + ST -analysis strategy identified 92.3% of subjects with substantial ischemia and no abnormality in 59.9% of the cohort. No cardiac events occurred in patients without substantial ischemia identified by HF-QRS analysis. CONCLUSIONS: In this prospective analysis, exercise stress ECG with HF-QRS analysis identified any and substantial ischemia with high diagnostic accuracy and may allow more than half of referred patients to safely avoid imaging.

TOWARDS THE DEVELOPMENT OF NOVEL THERAPEUTICS FOR PERIPHERAL ARTERY DISEASE.

Atherosclerosis is the leading cause of morbidity and mortality in the Western world. Peripheral artery disease (PAD) has been less studied then coronary artery disease but is nearly as common. PAD impairs blood flow to the leg(s) and causes functional impairment, leg pain, and amputation. The last drug approved for PAD was in 1999. Blood flow to leg proceeds through one major artery and in PAD total occlusions in the course of that vessel are common. Thus, the extent of new blood vessel growth determines a patients' clinical course. Promoting the growth of new blood vessels (therapeutic angiogenesis) was a major goal of therapy. Results from studies using cytokine growth factors have shown disappointing results. Using clinical and preclinical studies, our laboratory has identified several novel therapeutic approaches. One, a modulator of innate immunity, will be reviewed as an approach that has the potential to create new therapies for PAD.

Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk reduction in diabetic patients with coronary artery disease: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes trial demonstrated similar long-term clinical effectiveness of revascularization (REV) and intensive medical (MED) therapy. Comparisons of post-intervention ischemic burden have not been explored but are relevant to treatment decisions. This study examined differences in 1-year stress myocardial perfusion SPECT (MPS) abnormalities by randomized treatment. METHODS: MPS was performed in 1,505 patients at 1-year following randomization. MPS images were analyzed (masked to treatment) by a Nuclear Core Laboratory using a quantitative percent (%) of total, ischemic, and scarred myocardium. Cox proportional hazards models were used to estimate the relationship between MPS variables and trial endpoints. RESULTS: At 1-year, nearly all REV patients underwent the assigned procedure; while 16% of those randomized to MED received coronary REV. Patients randomized to REV exhibited fewer stress perfusion abnormalities than MED patients (P < .001). CABG patients had more frequent ischemic and scarred myocardium encumbering ≥ 5% of the myocardium when compared to those receiving PCI. Patients randomized to MED had more extensive ischemia and the median % of the myocardium with perfusion abnormalities was lower following REV (3% vs 9%, P = .01). A total of 59% of REV patients had no inducible ischemia at 1-year compared to 49% of MED patients (P < .001). Within the CABG stratum, those randomized to MED had the greatest rate of ischemic (P = .032) and scarred (P = .017) perfusion abnormalities. At 1-year, more extensive and severe stress myocardial perfusion abnormalities were associated with higher 5-year rates of death and a combined endpoint of cardiac death or myocardial infarction (MI) rates (11.3%, 8.1%, 6.8%, for ≥ 10%, 5%-9.9%, and 1-4.9% abnormal myocardium at stress, respectively, P < .001). In adjusted models, selected MPS variables were significantly associated with an increased hazard of cardiac death or MI (hazard ratio = 1.11 per 5% increase in abnormal myocardium at stress, P = .004). CONCLUSIONS: Patient management strategies that focus on ischemia resolution can be useful to guide the efficacy of near-term therapeutic approaches. A 1-year post-therapeutic intervention myocardial perfusion scan provides important information regarding prognosis in stable CAD patients with diabetes.

Radionuclide imaging in stage B heart failure.

This article discusses currently available radionuclide techniques in the diagnostic and prognostic evaluation of patients with chronic heart failure, with a focus on stage B/asymptomatic left ventricular dysfunction. Radionuclide imaging is promising for such patients because it can simultaneously determine left ventricular function, evaluate for the presence of obstructive coronary disease, determine the extent of viable myocardium, and evaluate dyssynchronous left ventricular contraction. Radionuclide imaging can thus provide important noninvasive insights into the pathophysiology, prognosis, and management of patients with asymptomatic left ventricular dysfunction as well as more advanced heat failure.

The prevalence and predictive accuracy of quantitatively defined transient ischemic dilation of the left ventricle on otherwise normal SPECT myocardial perfusion imaging studies.

AIM: TID in the setting of otherwise normal MPI has been suggested as a marker of high risk CAD. In this study we estimate the variance of TID in a normal population and the statistical frequency of false positive TID. This will provide an indirect measurement of predictive accuracy (PA) in a mixed referral population. OBJECTIVE: To study the PA of TID in otherwise normal MPI. METHODS: 688 consecutive patients were studied. We defined TID according to the standard method at 2 cut-off values; 1SD and 2SD, and also by a BSA normalized volume difference with gender-specific 2SD limits (NrVD). RESULTS: 457 patients with otherwise normal MPI were analyzed. PA of TID at 1SD was 4% and 26% at 2SD. PA was slightly higher (42%) using the NrVD, however, still too low to be clinically useful as a high-risk marker. PA of TID in patients with perfusion abnormalities was 58% at 1SD, 80% at 2SD and slightly higher (93%) by NrVD. CONCLUSIONS: In the setting of otherwise normal MPI, elevated TIDr has a low prevalence and poor predictive accuracy and should not be considered summarily as a marker of high risk CAD.

Prognosis in patients achieving ≥10 METS on exercise stress testing: was SPECT imaging useful?

BACKGROUND: The benefit of myocardial perfusion imaging (MPI) over exercise ECG stress testing alone is unclear in individuals attaining a workload of ≥10 METS. The purpose of this prospective study is to determine mortality and nonfatal cardiac events in patients at either intermediate pretest risk for CAD or patients with known CAD, achieving ≥10 METS regardless of peak exercise heart rate. The authors previously reported a low prevalence of significant ischemia in this patient cohort. METHODS: Baseline characteristics, ECG stress test findings, and perfusion and function results from quantitative gated (99m)Tc-SPECT MPI were compared by achievement of a maximum age-predicted heart rate ≥85% in 509 consecutive patients who reached ≥10 METS. Events including all-cause and cardiac mortality, non-fatal myocardial infarction (MI), and late revascularization (>4 weeks after MPI) were prospectively collected. RESULTS: Of the 509 patients achieving ≥10 METS, follow-up for mortality was obtained in 463 (91%). Those lost to follow-up were older and had higher rates of tobacco use. The prevalences of CAD risk factors, prior known CAD, and MPI abnormalities were higher for the 68 patients failing to reach 85% of their target heart rate. The rate of ≥10% left-ventricular (LV) ischemia by MPI remained very low irrespective of attained heart rate (0.6% (3/463)). Six (1.2%) had an LVEF < 40%. Death occurred in 12 (2.6%) patients, one of which was classified as cardiac (0.1%/year). The other 11 deaths were related to cancer. Additionally, there were three nonfatal MIs (0.7 %) and one late revascularization (0.2%). Only one of these patients had any ischemia on MPI. No cardiac event patient had exercise ST depression or ≥5% LV ischemia. CONCLUSIONS: Thus, patients at intermediate risk for CAD or known CAD achieving ≥10 METS have a very low prevalence of ≥10% LV ischemia and very low rates of cardiac mortality, nonfatal MI, and late revascularization, irrespective of heart rate achieved. Cardiac events did not correlate with abnormalities on the index MPI study. These results suggest that patients who attain ≥10 METS during exercise stress have an excellent prognosis over an intermediate term of follow-up, regardless of peak exercise heart rate achieved. The added value of MPI to standard exercise ECG testing in this population is questionable.

Long-term outcomes in patients with normal coronary arteries, nonobstructive, or obstructive coronary artery disease on invasive coronary angiography.

BACKGROUND: Normal or near normal coronary arteries (NNCA) or nonobstructive coronary artery disease (CAD) are commonly found on invasive coronary angiography (ICA). HYPOTHESIS: We aimed to determine long-term outcomes by severity of CAD in a contemporary cohort of patients undergoing ICA for evaluation for ischemic heart disease. METHODS: We assessed a consecutive cohort of 925 patients who underwent non-emergent ICA over 24 months. Cardiac death (CD), nonfatal myocardial infarction (NFMI), late revascularization, and medication use were assessed. RESULTS: Follow-up data was available in 850 patients. Of patients without heart failure, at a median of 6.0 years, there was a significant decrease in survival free from CD or NFMI, and from all cardiac events, for those with obstructive CAD compared with patients with NNCAs or nonobstructive CAD (p < .001 for both). No differences between NNCA and nonobstructive CAD patients in rates of CD or NFMI (2.0% vs. 2.1%/year, p = .58) or all cardiac events (2.4% vs. 2.9%/year, p = .84) were observed. CONCLUSION: Long-term follow-up in a contemporary cohort of consecutive patients undergoing non-emergent ICA for detection of CAD showed no difference in annual rates of CD or NFMI, or total cardiac events, in patients with NNCAs versus those with nonobstructive CAD, whereas patients with obstructive CAD had significantly more events. Event rates were low and similar by gender. Use of aspirin, lipid lowering therapy, and beta-blockers increased in all subgroups after ICA. We speculate this may explain the low incidence of subsequent cardiac events, and similar event rates in patients with NNCA and nonobstructive CAD, even in patients presenting with non-ST-elevation MI.

Lead aVR predicts early revascularization but not long-term events in patients referred for stress electrocardiography.

BACKGROUND: Exercise stress electrocardiography (ExECG) is recommended as a first-line tool to assess ischemia, but standard ST-analysis has limited diagnostic accuracy. ST elevation in lead aVR has been associated with left main and LAD disease in the population undergoing coronary angiography but has not been studied in the general population undergoing stress testing for the initial evaluation of CAD without coronary angiography. We sought to determine the predictive value of lead aVR elevation for ischemia, early revascularization, and subsequent cardiac events in consecutive patients undergoing ExECG. METHODS AND RESULTS: The study cohort included 641 subjects referred for ExECG who were dichotomized by presence or absence of aVR elevation ≥1mm and compared for prevalence and predictors of ischemia and a composite of cardiac death, nonfatal myocardial infarction, and late revascularization. The cohort had a median age of 57 and 57% were male. The prevalence of aVR elevation was 11.5%. The prevalence of significant ischemia on patients who received imaging was significantly higher with aVR elevation (14.3% vs 2.3%, p<0.001). Early revascularization occurred in 10.9% with vs 0.2% without aVR elevation, p<0.001. No subjects without aVR elevation or ST-depression underwent early revascularization. However, cardiac event rates were similar over a median 4.0 years of follow-up with and without aVR elevation (2.8% vs. 2.6%, p = 0.80). aVR elevation did not predict long-term cardiac events by Kaplan-Meier survival analysis (p = 0.94) or Cox proportional hazards modeling (p = 0.35). CONCLUSIONS: aVR elevation during ExECG predicts ischemia on imaging and early revascularization but not long-term outcomes and could serve as a useful adjunct to standard ST-analysis and potentially reduce the need for concurrent imaging.

Recent advances and future trends in multimodality cardiac imaging.

The cardiovascular imaging field has experienced marked growth and technical advancement in the past several decades. In the future, multimodality imaging will provide enhanced characterisation of disease states. Myocardial perfusion imaging will become more quantitative, permitting measurement of absolute blood flow and coronary flow reserves during stress states. A greater use of positron emission tomography (PET) can be expected for both assessing blood flow quantitatively and molecular imaging of atherosclerotic plaques and myocardial disease states. SPECT and PET imaging of myocardial metabolism and cardiac neuronal imaging have already shown great promise for identifying high-risk patients with coronary heart disease and nonischaemic cardiomyopathy. Further progress will occur in computed tomography imaging of the heart and coronary arteries and cardiac magnetic resonance imaging including quantitative estimates of coronary blood flow, coronary and peripheral vessel plaque characterisation, and detection of myocardial cellular dysfunction. Fusion imaging, in which two disparate image data sets are merged into one functional image, will become commonplace. Major breakthroughs in CV imaging will depend on discoveries in basic research, further refinement of instrumentation and software for image processing and analysis, and outcomes research demonstrating the worth of imaging technologies in reducing cardiovascular death and morbidity.

Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist.

This study was undertaken to determine whether the myocardial infarct-sparing effect of ATL-146e, a selective adenosine A(2A) receptor agonist, persists without a rebound effect for at least 48 h and to determine the optimal duration of ATL-146e treatment in anesthetized dogs. Reperfusion injury after myocardial infarction (MI) is associated with inflammation lasting 24-48 h that contributes to ongoing myocyte injury. We previously showed that an ATL-146e infusion, starting just before reperfusion, decreased inflammation and infarct size in dogs examined 2 h after MI without increasing coronary blood flow. In the present study, adult dogs underwent 90 min of left anterior descending coronary artery occlusion. Thirty minutes before reperfusion, ATL-146e (0.01 microg x kg(-1) x min(-1); n = 21) or vehicle (n = 12) was intravenously infused and continued for 2.5 h (protocol 1) or 24 h (protocol 2). At 48 h after reperfusion hearts were excised and assessed for histological risk area and infarct size. Infarct size based on triphenyltetrazolium chloride (TTC) staining as a percentage of risk area was significantly smaller in ATL-146e-treated vs. control dogs (16.7 +/- 3.7% vs. 33.3 +/- 6.2%, P < 0.05; protocol 1). ATL-146e reduced neutrophil accumulation into infarcted myocardium of ATL-146e-treated vs. control dogs (30 +/- 7 vs. 88 +/- 16 cells/high-power field, P < 0.002). ATL-146e infusion for 24 h (protocol 2) conferred no significant additional infarct size reduction compared with 2.5 h of infusion. A 2.5-h ATL-146e infusion initiated 30 min before reperfusion results in marked, persistent (48 h) reduction in infarct size as a percentage of risk area in dogs with a reduction in infarct zone neutrophil infiltration. No significant further benefit was seen with a 24-h infusion.

Etiology and pathophysiology of new-onset heart failure: evaluation by myocardial perfusion imaging.

OBJECTIVE: The IMAGING in Heart Failure study was a prospective, multi-national trial designed to explore the role of single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (MPI) as an initial investigative strategy in patients hospitalized with new-onset heart failure. METHODS: We recruited 201 patients (age 65.3 +/- 14.5 years, 43% women) hospitalized with their first episode of heart failure. Rest/stress gated SPECT Tc-99m sestamibi MPI was performed during or within 2 weeks of the index hospitalization, in addition to standard care. RESULTS: SPECT MPI revealed a broad range of ejection fractions with preserved systolic function in 36% of patients. Forty-one percent of patients had normal perfusion. In the remaining patients, perfusion abnormalities were predominantly due to prior myocardial infarction, with extensive ischemia seen only in 6%. Among patients who underwent coronary angiography, SPECT performance characteristics revealed excellent negative predictive value (96%) for extensive coronary artery disease (CAD). In multivariable analyses, the extent of perfusion abnormality and advancing age predicted the presence of extensive CAD. CONCLUSIONS: These preliminary data derived from a non-randomized observational cohort suggest potential diagnostic utility of MPI for ischemic LV dysfunction in new-onset HF, and sets the stage for a prospective randomized study to confirm these findings.