Ron Blankstein

Diagnostic and Prognostic Value of Absence of Coronary Artery Calcification

OBJECTIVES In this study, we systematically assessed the diagnostic and prognostic value of absence of coronary artery calcification (CAC) in asymptomatic and symptomatic individuals. BACKGROUND Presence of CAC is a well-established marker of coronary plaque burden and is associated with a higher risk of adverse cardiovascular outcomes. Absence of CAC has been suggested to be associated with a very low risk of significant coronary artery disease, as well as minimal risk of future events. METHODS We searched online databases (e.g., PubMed and MEDLINE) for original research articles published in English between January 1990 and March 2008 examining the diagnostic and prognostic utility of CAC. RESULTS A systematic review of published articles revealed 49 studies that fulfilled our criteria for inclusion. These included 13 studies assessing the relationship of CAC with adverse cardiovascular outcomes in 64,873 asymptomatic patients. In this cohort, 146 of 25,903 patients without CAC (0.56%) had a cardiovascular event during a mean follow-up period of 51 months. In the 7 studies assessing the prognostic value of CAC in a symptomatic population, 1.80% of patients without CAC had a cardiovascular event. Overall, 18 studies demonstrated that the presence of any CAC had a pooled sensitivity and negative predictive value of 98% and 93%, respectively, for detection of significant coronary artery disease on invasive coronary angiography. In 4,870 individuals undergoing myocardial perfusion and CAC testing, in the absence of CAC, only 6% demonstrated any sign of ischemia. Finally, 3 studies demonstrated that absence of CAC had a negative predictive value of 99% for ruling out acute coronary syndrome. CONCLUSIONS On the basis of our review of more than 85,000 patients, we conclude that the absence of CAC is associated with a very low risk of future cardiovascular events, with modest incremental value of other diagnostic tests in this very low-risk group.

Adenosine-induced stress myocardial perfusion imaging using dual-source cardiac computed tomography.

OBJECTIVES This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA). BACKGROUND Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans. METHODS Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers. RESULTS The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 +/- 10.7 years; 82% male; body mass index 30.4 +/- 5 kg/m(2)) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis > or =50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with > or =50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis > or =70%. CONCLUSIONS Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis.

Improved Cardiac Risk Assessment With Noninvasive Measures of Coronary Flow Reserve

Background— Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether noninvasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease carries incremental prognostic significance. Methods and Results— A total of 2783 consecutive patients referred for rest/stress positron emission tomography were followed up for a median of 1.4 years (interquartile range, 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images. Rest and stress myocardial blood flows were calculated with factor analysis and a 2-compartment kinetic model and were used to compute coronary flow reserve (coronary flow reserve equals stress divided by rest myocardial blood flow). The primary end point was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of coronary flow reserve (<1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95% confidence interval, 2.5–12.4; P<0.0001) compared with the highest tertile. Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the c index from 0.82 (95% confidence interval, 0.78–0.86) to 0.84 (95% confidence interval, 0.80–0.87; P=0.02) and in a net reclassification improvement of 0.098 (95% confidence interval, 0.025–0.180). Addition of coronary flow reserve resulted in correct reclassification of 34.8% of intermediate-risk patients (net reclassification improvement=0.487; 95% confidence interval, 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. Conclusion— Noninvasive quantitative assessment of coronary vasodilator function with positron emission tomography is a powerful, independent predictor of cardiac mortality in patients with known or suspected coronary artery disease and provides meaningful incremental risk stratification over clinical and gated myocardial perfusion imaging variables.

Association Between Coronary Vascular Dysfunction and Cardiac Mortality in Patients With and Without Diabetes Mellitus

Background— Diabetes mellitus increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among diabetics compared with nondiabetics. Methods and Results— A total of 2783 consecutive patients (1172 diabetics and 1611 nondiabetics) underwent quantification of coronary flow reserve (CFR; CFR=stress divided by rest myocardial blood flow) by positron emission tomography and were followed up for a median of 1.4 years (quartile 1–3, 0.7–3.2 years). The primary end point was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2- and 4.9-fold increase in the rate of cardiac death for diabetics and nondiabetics, respectively (P=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination for both diabetics and nondiabetics (c index, 0.77–0.79, P=0.04; 0.82–0.85, P=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for nondiabetic patients with known CAD (2.8%/y versus 2.0%/y; P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes mellitus and normal stress perfusion and systolic function (0.3%/y versus 0.5%/y; P=0.65). Conclusions— Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to those of patients with prior CAD, whereas those with preserved CFR have event rates comparable to those of nondiabetics.

Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study.

BACKGROUND The JUPITER trial showed that some patients with LDL-cholesterol concentrations less than 3·37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations of 2 mg/L or more benefit from treatment with rosuvastatin, although absolute rates of cardiovascular events were low. In a population eligible for JUPITER, we established whether coronary artery calcium (CAC) might further stratify risk; additionally we compared hsCRP with CAC for risk prediction across the range of low and high hsCRP values. METHODS 950 participants from the Multi-Ethnic Study of Atheroslcerosis (MESA) met all criteria for JUPITER entry. We compared coronary heart disease and cardiovascular disease event rates and multivariable-adjusted hazard ratios after stratifying by burden of CAC (scores of 0, 1-100, or >100). We calculated 5-year number needed to treat (NNT) by applying the benefit recorded in JUPITER to the event rates within each CAC strata. FINDINGS Median follow-up was 5·8 years (IQR 5·7-5·9). 444 (47%) patients in the MESA JUPITER population had CAC scores of 0 and, in this group, rates of coronary heart disease events were 0·8 per 1000 person-years. 74% of all coronary events were in the 239 (25%) of participants with CAC scores of more than 100 (20·2 per 1000 person-years). For coronary heart disease, the predicted 5-year NNT was 549 for CAC score 0, 94 for scores 1-100, and 24 for scores greater than 100. For cardiovascular disease, the NNT was 124, 54, and 19. In the total study population, presence of CAC was associated with a hazard ratio of 4·29 (95% CI 1·99-9·25) for coronary heart disease, and of 2·57 (1·48-4·48) for cardiovascular disease. hsCRP was not associated with either disease after multivariable adjustment. INTERPRETATION CAC seems to further stratify risk in patients eligible for JUPITER, and could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment. Focusing of treatment on the subset of individuals with measurable atherosclerosis could allow for more appropriate allocation of resources. FUNDING National Institutes of Health-National Heart, Lung, and Blood Institute.

Incremental value of adenosine-induced stress myocardial perfusion imaging with dual-source CT at cardiac CT angiography.

PURPOSE First, to assess the feasibility of a protocol involving stress-induced perfusion evaluated at computed tomography (CT) combined with cardiac CT angiography in a single examination and second, to assess the incremental value of perfusion imaging over cardiac CT angiography in a dual-source technique for the detection of obstructive coronary artery disease (CAD) in a high-risk population. MATERIALS AND METHODS Institutional review board approval and informed patient consent were obtained before patient enrollment in the study. The study was HIPAA compliant. Thirty-five patients at high risk for CAD were prospectively enrolled for evaluation of the feasibility of CT perfusion imaging. All patients underwent retrospectively electrocardiographically gated (helical) adenosine stress CT perfusion imaging followed by prospectively electrocardiographically gated (axial) rest myocardial CT perfusion imaging. Analysis was performed in three steps: (a)Coronary arterial stenoses were scored for severity and reader confidence at cardiac CT angiography, (b)myocardial perfusion defects were identified and scored for severity and reversibility at CT perfusion imaging, and (c)coronary stenosis severity was reclassified according to perfusion findings at combined cardiac CT angiography and CT perfusion imaging. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of cardiac CT angiography before and after CT perfusion analysis were calculated. RESULTS With use of a reference standard of greater than 50% stenosis at invasive angiography, all parameters of diagnostic accuracy increased after CT perfusion analysis: Sensitivity increased from 83% to 91%; specificity, from 71% to 91%; PPV, from 66% to 86%; and NPV, from 87% to 93%. The area under the receiver operating characteristic curve increased significantly, from 0.77 to 0.90 (P < .005). CONCLUSION A combination protocol involving adenosine perfusion CT imaging and cardiac CT angiography in a dual-source technique is feasible, and CT perfusion adds incremental value to cardiac CT angiography in the detection of significant CAD.

Detection of hemodynamically significant coronary artery stenosis: incremental diagnostic value of dynamic CT-based myocardial perfusion imaging.

PURPOSE To determine the feasibility of computed tomography (CT)-based dynamic myocardial perfusion imaging for the detection of hemodynamically significant coronary artery stenosis, as defined with fractional flow reserve (FFR). MATERIALS AND METHODS Institutional review board approval and informed patient consent were obtained before patient enrollment in the study. The study was HIPAA compliant. Subjects who were suspected of having or were known to have coronary artery disease underwent electrocardiographically triggered dynamic stress myocardial perfusion imaging. FFR measurement was performed within all main coronary arteries with a luminal narrowing of 50%-85%. Estimated myocardial blood flow (MBF) was derived from CT images by using a model-based parametric deconvolution method for 16 myocardial segments and was related to hemodynamically significant coronary artery stenosis with an FFR of 0.75 or less in a blinded fashion. Conventional measures of diagnostic accuracy were derived, and discriminatory power analysis was performed by using logistic regression analysis. RESULTS Of 36 enrolled subjects, 33 (mean age, 68.1 years ± 10 [standard deviation]; 25 [76%] men, eight [24%] women) completed the study protocol. An MBF cut point of 75 mL/100 mL/min provided the highest discriminatory power (C statistic, 0.707; P <.001). While the diagnostic accuracy of CT for the detection of anatomically significant coronary artery stenosis (>50%) was high, it was low for the detection of hemodynamically significant stenosis (positive predictive value [PPV] per coronary segment, 49%; 95% confidence interval [CI]: 36%, 60%). With use of estimated MBF to reclassify lesions depicted with CT angiography, 30 of 70 (43%) coronary lesions were graded as not hemodynamically significant, which significantly increased PPV to 78% (95% CI: 61%, 89%; P = .02). The presence of a coronary artery stenosis with a corresponding MBF less than 75 mL/100 mL/min had a high risk for hemodynamic significance (odds ratio, 86.9; 95% CI:17.6, 430.4). CONCLUSION Dynamic CT-based stress myocardial perfusion imaging may allow detection of hemodynamically significant coronary artery stenosis.

Prognostic Value of Nonobstructive and Obstructive Coronary Artery Disease Detected by Coronary Computed Tomography Angiography to Identify Cardiovascular Events

Background—The contribution of plaque extent to predict cardiovascular events among patients with nonobstructive and obstructive coronary artery disease (CAD) is not well defined. Our objective was to evaluate the prognostic value of plaque extent detected by coronary computed tomography angiography. Methods and Results—All consecutive patients without prior CAD referred for coronary computed tomography angiography to evaluate for CAD were included. Examination findings were classified as normal, nonobstructive (<50% stenosis), or obstructive (≥50%). Based on the number of segments with disease, extent of CAD was classified as nonextensive (⩽4 segments) or extensive (>4 segments). The cohort included 3242 patients followed for the primary outcome of cardiovascular death or myocardial infarction for a median of 3.6 (2.1–5.0) years. In a multivariable analysis, the presence of extensive nonobstructive CAD (hazard ratio, 3.1; 95% confidence interval, 1.5–6.4), nonextensive obstructive (hazard ratio, 3.0; 95% confidence interval, 1.3–6.9), and extensive obstructive CAD (hazard ratio, 3.9; 95% confidence interval, 2.2–7.2) were associated with an increased rate of events, whereas nonextensive, nonobstructive CAD was not. The addition of plaque extent to a model that included clinical probability as well as the presence and severity of CAD improved risk prediction. Conclusions—Among patients with nonobstructive CAD, those with extensive plaque experienced a higher rate of cardiovascular death or myocardial infarction, comparable with those who have nonextensive disease. Even among patients with obstructive CAD, greater extent of nonobstructive plaque was associated with higher event rate. Our findings suggest that regardless of whether obstructive or nonobstructive disease is present, the extent of plaque detected by coronary computed tomography angiography enhances risk assessment.

Effects of Sex on Coronary Microvascular Dysfunction and Cardiac Outcomes

Background— Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown. Methods and Results— We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5–2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75–086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049–0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041). Conclusions— CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Female Gender Is an Independent Predictor of Operative Mortality After Coronary Artery Bypass Graft Surgery Contemporary Analysis of 31 Midwestern Hospitals

Background—Women have a higher operative mortality (OM) after coronary artery bypass graft (CABG) surgery than men. Suggested contributing factors have included women’s increased age, advanced disease, comorbidities, and smaller body surface area (BSA). It is unclear whether women’s increased risk factors fully account for this difference or whether female gender within itself is associated with increased OM. We attempted to determine whether, all other factors being equal, there is a significant difference in OM between men and women undergoing CABG. Methods and Results—We retrospectively reviewed a clinical database of 15,440 patients who underwent CABG at 31 Midwestern hospitals in 1999–2000. Each patient record consisted of >400 data elements. Risk-adjusted mortality rates were computed using a predictive equation derived by stepwise logistic regression. Overall, women were older, had a higher incidence of diabetes and valvular disease, and were more likely to be presenting in shock. The OM for the entire population was 2.88% (women 4.24% versus men 2.23%, P<0.0001). Lower BSA was found to be an independent predictor of increased mortality, and a direct inverse relationship between BSA and OM was noted. After adjusting for all comorbidities including BSA, female gender remained an independent predictor of increased mortality (risk-adjusted OM was 3.81% for women and 2.43% for men). Thus, whereas risk adjustment reduced women’s OM from 90% higher than men’s to 22% higher, a significant difference remained. Conclusions—In this contemporary data set from 31 Midwestern hospitals, female gender was an independent predictor of perioperative mortality, even after accounting for all comorbidities, including low BSA.