Kenneth A. Narahara

Coronary Calcium Does Not Accurately Predict Near-Term Future Coronary Events in High-Risk Adults

BACKGROUND Prognostic risk models have had limited success in predicting coronary events in subjects with multiple risk factors. We and others have proposed an alternative approach using radiographically detectable coronary calcium. We evaluated and compared the predictive value of these 2 approaches for determining coronary event risk in asymptomatic adults with multiple coronary risk factors. In addition, we assessed the predictive value of a risk model that included calcium score and cardiac risk-factor data. METHODS AND RESULTS We recruited 1196 asymptomatic high-coronary-risk subjects who then underwent risk-factor assessment and cardiac electron-beam CT (EBCT) scanning and were followed up for 41 months with a 99% success rate. We applied the Framingham model and our data-derived risk model to determine the 3-year likelihood of a coronary event. The mean age of our cohort was 66 years, and mean 3-year Framingham risk was 3.3+/-3.6%. Sixty-eight percent (818 subjects) had detectable coronary calcium. There were 17 coronary deaths (1.4%) and 29 nonfatal infarctions (2. 4%). The receiver operating characteristic (ROC) curve areas calculated from the Framingham model, our data-derived risk model, and the calcium score were 0.69+/-0.05, 0.68+/-0.05, and 0.64+/-0.05, respectively (P=NS). When calcium score was included as a variable in the data-derived model, the ROC area did not change significantly (0.68+/-0.05 to 0.71+/-0.04; P=NS). CONCLUSIONS Neither risk-factor assessment nor EBCT calcium is an accurate event predictor in high-risk asymptomatic adults. EBCT calcium score does not add significant incremental information to risk factors, and its use in clinical screening is not justified at this time.

Safety and efficacy of carvedilol in severe heart failure

Abstract Background: Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function. Methods and Results: One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol ( P P = .004). Conclusion: The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

Prognostic significance of cardiac cinefluoroscopy for coronary calcific deposits in asymptomatic high risk subjects

OBJECTIVES This research investigated the prognostic significance of radiographically detectable coronary calcific deposits. BACKGROUND Coronary calcific deposits are almost always associated with coronary atherosclerosis. We investigated the association between fluoroscopically determined coronary calcium and coronary heart disease end points at 1 year of follow-up. METHODS This prospective population-based cohort study was conducted in the suburbs of Los Angeles. Fourteen hundred sixty-one asymptomatic adults with an estimated > or = 10% risk of having a coronary heart disease event within 8 years underwent cardiac cinefluoroscopy for assessment of coronary calcium at initiation of the study. Clinical status including angina, documented myocardial infarction, myocardial revascularization and death from coronary heart disease were determined after 1 year. RESULTS The prevalence of calcific deposits was high (47%). A follow-up examination at 1 year was successfully completed in 99.9% of subjects. Six subjects (0.4%) had died from coronary heart disease and 9 (0.6%) had had a nonfatal myocardial infarction. Thirty-seven subjects (2.5%) reported angina pectoris, and 13 (0.9%) had undergone myocardial revascularization. Fifty-three subjects had at least one event during the 1-year period. Radiographically detectable calcium was associated with the presence of at least one of these end points, with a risk ratio of 2.7 (confidence limits 1.4, 4.6). The presence of coronary calcium was an independent predictor of at least one end point when controlling for age, gender and risk factors. However, three deaths due to coronary heart disease and two nonfatal myocardial infarctions occurred in subjects without detectable coronary calcium. CONCLUSIONS The presence of coronary calcific deposits incurs an increased risk of coronary heart disease events in asymptomatic high risk subjects at 1 year. This increased risk is independent of that incurred by standard risk factors.

Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure

Objectives. The aim of this study was to assess the efficacy of flosequinan in chronic heart failure. Background. Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported. Methods. One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction <40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant. Results. After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treate with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died. Conclusions. These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined.

Comparison of thallium-201 and technetium-99m hexakis 2-methoxyisobutyl isonitrile single-photon emission computed tomography for estimating the extent of myocardial ischemia and infarction in coronary artery disease

Single-photon emission computed tomography (SPECT) using thallium-201 (Tl-201) was compared with technetium-99m hexakis 2-methoxyisobutyl isonitrile (Tc-99m MIBI) in 24 patients with coronary artery diseaes. Patients exercised to the same work load as each isotope was studied. Normal and hypoperfused left ventricular mass was determined with an automated method. Estimated total left ventricular mass was similar for both stress/redistribution Tl-201 and stress/rest Tc-99m MIBI images. The mean estimated defect size in the redistribution Tl-201 images was 32 +/- 34.7 vs 33 +/- 38.4 g in the resting Tc-99m MIBI studies (difference not significant). The individual determinations of defect mass were highly correlated (r = 0.93; p less than 0.0001). Estimated defect size in the stress Tl-201 images (52 +/- 46.2 g) was significantly larger than the exercise Tc-99m MIBI estimates of defect mass (42 +/- 39.9 g; p less than 0.05). A linear correlation existed between stress thallium and technetium estimates of defect size (r = 0.85) but 15 of 24 Tc-99m MIBI defects were smaller than the Tl-201 defects. Partial redistribution of Tc-99m MIBI could explain the discordance. Stress Tc-99m MIBI SPECT defect size determined by visual interpretation or by the use of isocount analysis may be smaller than what is seen with stress Tl-201 SPECT.

Comparison of exercise electron beam computed tomography and sestamibi in the evaluation of coronary artery disease.

This blinded, single center study prospectively compares exercise electron beam computed tomography (EBCT) with stress technetium-99m (Tc-99m) sestamibi single-photon emission computed tomography (SPECT) in 33 patients undergoing coronary angiography for evaluation of chest pain. Patients undergoing routine cardiac catheterization for the diagnosis of chest pain were imaged at rest using EBCT. Patients exercised on a semi-supine ergometer, and exercise EBCT was immediately followed by injection of Tc-99m sestamibi for assessment of myocardial ischemia. At peak exercise, Tc-99m SPECT, followed immediately by nonionic contrast material, was injected intravenously to directly compare these 2 imaging techniques. Patients were reimaged with Tc-99m SPECT at rest 24 to 48 hours after stress. Exercise EBCT, which was analyzed using a global ejection fraction measure, had a sensitivity of 81% and a specificity of 76%, compared with angiography. Using the development of a new regional wall motion abnormality as evidence of obstructive coronary artery disease (CAD), EBCT yielded a specificity of 100% and a sensitivity of 88%. Reversible perfusion defects identified by SPECT, as evidence of obstructive CAD, revealed a sensitivity of 75% and a specificity of 71%. The specificity of regional wall motion analysis by EBCT was significantly better than SPECT (p <0.01) in this population. This study demonstrates regional wall motion assessed by EBCT to be as sensitive and more specific than SPECT myocardial perfusion imaging in identifying obstructive CAD as defined by angiography.

Double-blind comparison of once daily betaxolol versus propranolol four times daily in stable angina pectoris

Abstract Betaxolol is a new, highly cardioselective, once-a-day β blocker with a long half-life (mean 16 hours). The antianginal efficacy of 2 doses of betaxolol (20 and 40 mg) given once daily was evaluated and compared with propranolol (40 or 80 mg) 4 times daily. Ninety-two patients completed the 10-week double-blind trial. The resting and exercise heart rate, blood pressure and double product were similar for all treatment arms of the study during placebo treatment. Significant decreases in these measures occurred during active drug treatment when compared with placebo. No significant intergroup differences were noted at rest. Maximal exercise heart rate and double product were significantly lower during treatment with betaxolol 40 mg daily than in the propranolol 40 mg 4 times/day treatment group (p

Simultaneous maximal exercise radionuclide angiography and thallium stress perfusion imaging

Gold-195m is a new ultra-short-lived radionuclide that can be used for cardiac studies. Accurate, reproducible ejection fraction and ventricular wall motion studies can be obtained from first-transit angiography using commercially available imaging and image-processing equipment. The short half-life of gold-195m (30.5 seconds) makes simultaneous dual isotope imaging possible and substantially reduces the radiation exposure from the isotope angiography. The feasibility and possible benefits of performing dual radionuclide studies were evaluated during a single exercise stress test in 24 subjects with known coronary artery disease (CAD) and in 20 normal volunteers. High-quality first-transit angiograms were obtained in all subjects. An 83% sensitivity and 95% specificity for detecting CAD with thallium-201 imaging was noted in this investigation, suggesting that its diagnostic accuracy was not altered by simultaneous dual isotone imaging. When segmental left ventricular (LV) wall motion was compared with thallium-201 perfusion imaging, divergent results were noted in 15 of 44 subjects. An analysis of the ejection fraction (EF) results at rest and stress provided additional information that could be useful in assessing the clinical significance of such differences in segmental wall motion and perfusion. Simultaneous dual isotope imaging appears to be appropriate for situations in which both LV perfusion and function require evaluation. The use of gold-195m allows such information to be obtained from a single exercise test and can thereby reduce the cost and time required for noninvasive evaluations of patients for CAD.

Thallium-201 single-photon emission computed tomographic estimates of left ventricular mass in patients with and without ischemic heart disease

A new automated edge detection program has been developed to estimate left ventricular mass from single-photon emission computed tomographic (SPECT) thallium-201 images of patients. Left ventricular (LV) mass was measured from contrast angiograms in 21 patients and was compared with LV mass estimated from thallium-201 tomographic studies. A comparison of angiographic mass to mass estimated from stress studies yielded an r = 0.97 (SEE = 21.6 gm) and a comparison of angiographic mass to mass determined from the redistribution images yielded r = 0.96 (SEE = 23.0 gm). Values of mass from stress and redistribution studies varied 7.3% +/- 6.7 and 8.8% +/- 9.2, respectively, when compared with values obtained by cineangiography. LV mass derived from the stress and redistribution studies were highly correlated (r = 0.97; SEE = 21.9 gm). Linear regression analysis revealed a slope of 1.06 (stress ventricular mass = 1.06 X redistribution mass - 14.9 gm). Thirteen patients had two thallium-201 SPECT studies performed approximately 1 month apart. Estimated LV mass was highly correlated when the two studies were compared (r = 0.94; SEE = 21.7 gm comparing the two stress studies; and r = 0.93, SEE = 19.4 gm for the two redistribution studies). We conclude that SPECT thallium-201 imaging can define LV mass accurately and reproducibly in normal, ischemic, or infarcted tissue.

The effect of beta blockade on single photon emission computed tomographic (SPECT) thallium-201 images in patients with coronary disease.

We evaluated the effect of beta blockers on thallium-201 (Tl-201) single photon emission computed tomographic (SPECT) imaging in 12 patients with coronary disease using an automated computer algorithm. Maximal exercise heart rate and blood pressure were reduced and exercise time was increased with beta blockers. Estimated stress defect size decreased from 47 +/- 36.3 gm during placebo treatment to 32 +/- 27.1 gm during beta blocker therapy (-32%; p less than 0.01). The placebo treatment redistribution defect was estimated to be 28 +/- 29.8 gm. It fell to 15 +/- 23.3 gm with beta blockade (-46%; p less than 0.005). All patients had a stress Tl-201 defect during placebo treatment and eight had redistribution defects consistent with residual scar. During beta blocker therapy, 2 of 12 patients had normal stress-redistribution studies and only five patients had redistribution defects. Beta blockade can reduce exercise and redistribution Tl-201 SPECT defect size significantly while simultaneously increasing exercise time and reducing angina. Beta blockers may unmask or may eliminate evidence of redistribution. Tl-201 SPECT imaging may be useful in defining the reduction in ischemia produced by cardiac drugs.