Venkatesh L. Murthy

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.

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.

Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

IMPORTANCE Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear. OBJECTIVE To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD). DESIGN, SETTING, AND PARTICIPANTS Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up. MAIN OUTCOMES AND MEASURES The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated. RESULTS Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P < .001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P = .002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (β = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (β = -0.09; 95% CI, -0.14 to -0.05; P < .001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P = .002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P = .006), respectively, along with a more impaired strain (β = 0.15; 95% CI, 0.08-0.23; P < .001). No association between change in fitness and CAC was found. CONCLUSIONS AND RELEVANCE Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated with myocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis.

Global Coronary Flow Reserve Is Associated With Adverse Cardiovascular Events Independently of Luminal Angiographic Severity and Modifies the Effect of Early Revascularization

Background— Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease (CAD), identifies patients at risk for cardiac death. We sought to determine the association between CFR, angiographic CAD, and cardiovascular outcomes. Methods and Results— Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease were estimated with the use of the CAD prognostic index, and CFR was measured noninvasively by positron emission tomography. A modest inverse correlation was seen between CFR and CAD prognostic index (r=−0.26; P<0.0001). After adjustment for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CAD prognostic index were independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% confidence interval, 1.20–3.40; P=0.008; hazard ratio for 10-U increase in CAD prognostic index, 1.17; 95% confidence interval, 1.01–1.34; P=0.032). Subjects with low CFR experienced rates of events similar to those of subjects with high angiographic scores, and those with low CFR or high CAD prognostic index showed the highest risk of events (P=0.001). There was a significant interaction (P=0.039) between CFR and early revascularization by coronary artery bypass grafting, such that patients with low CFR who underwent coronary artery bypass grafting, but not percutaneous coronary intervention, experienced event rates comparable to those with preserved CFR, independently of revascularization. Conclusions— CFR was associated with outcomes independently of angiographic CAD and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact the outcomes of revascularization.

Preserved Coronary Flow Reserve Effectively Excludes High-Risk Coronary Artery Disease on Angiography

Myocardial perfusion imaging has limited sensitivity for the detection of high-risk coronary artery disease (CAD). We tested the hypothesis that a normal coronary flow reserve (CFR) would be helpful for excluding the presence of high-risk CAD on angiography. Methods: We studied 290 consecutive patients undergoing 82Rb PET within 180 d of invasive coronary angiography. High-risk CAD on angiography was defined as 2-vessel disease (≥70% stenosis), including the proximal left anterior descending artery; 3-vessel disease; or left main CAD (≥50% stenosis). Patients with prior Q wave myocardial infarction, elevated troponin levels between studies, prior coronary artery bypass grafting, a left ventricular ejection fraction of less than 40%, or severe valvular heart disease were excluded. Results: Fifty-five patients (19%) had high-risk CAD on angiography. As expected, the trade-off between the sensitivity and the specificity of the CFR for identifying high-risk CAD varied substantially depending on the cutoff selected. In multivariable analysis, a binary CFR of less than or equal to 1.93 provided incremental diagnostic information for the identification of high-risk CAD beyond the model with the Duke clinical risk score (>25%), percentage of left ventricular ischemia (>10%), transient ischemic dilation index (>1.07), and change in the left ventricular ejection fraction during stress (<2) (P = 0.0009). In patients with normal or slightly to moderately abnormal results on perfusion scans (<10% of left ventricular mass) during stress (n = 136), a preserved CFR (>1.93) excluded high-risk CAD with a high sensitivity (86%) and a high negative predictive value (97%). Conclusion: A normal CFR has a high negative predictive value for excluding high-risk CAD on angiography. Although an abnormal CFR increases the probability of significant obstructive CAD, it cannot reliably distinguish significant epicardial stenosis from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.

Quantification of Myocardial Perfusion Reserve Using Dynamic SPECT Imaging in Humans: A Feasibility Study

Myocardial perfusion imaging (MPI) is well established in the diagnosis and workup of patients with known or suspected coronary artery disease (CAD); however, it can underestimate the extent of obstructive CAD. Quantification of myocardial perfusion reserve with PET can assist in the diagnosis of multivessel CAD. We evaluated the feasibility of dynamic tomographic SPECT imaging and quantification of a retention index to describe global and regional myocardial perfusion reserve using a dedicated solid-state cardiac camera. Methods: Ninety-five consecutive patients (64 men and 31 women; median age, 67 y) underwent dynamic SPECT imaging with 99mTc-sestamibi at rest and at peak vasodilator stress, followed by standard gated MPI. The dynamic images were reconstructed into 60–70 frames, 3–6 s/frame, using ordered-subsets expectation maximization with 4 iterations and 32 subsets. Factor analysis was used to estimate blood-pool time–activity curves, used as input functions in a 2-compartment kinetic model. K1 values (99mTc-sestamibi uptake) were calculated for the stress and rest images, and K2 values (99mTc-sestamibi washout) were set to zero. Myocardial perfusion reserve (MPR) index was calculated as the ratio of the stress and rest K1 values. Standard MPI was evaluated semiquantitatively, and total perfusion deficit (TPD) of at least 5% was defined as abnormal. Results: Global MPR index was higher in patients with normal MPI (n = 51) than in patients with abnormal MPI (1.61 [interquartile range (IQR), 1.33–2.03] vs. 1.27 [IQR, 1.12–1.61], P = 0.0002). By multivariable regression analysis, global MPR index was associated with global stress TPD, age, and smoking. Regional MPR index was associated with the same variables and with regional stress TPD. Sixteen patients undergoing invasive coronary angiography had 20 vessels with stenosis of at least 50%. The MPR index was 1.11 (IQR, 1.01–1.21) versus 1.30 (IQR, 1.12–1.67) in territories supplied by obstructed and nonobstructed arteries, respectively (P = 0.02). MPR index showed a stepwise reduction with increasing extent of obstructive CAD (P = 0.02). Conclusion: Dynamic tomographic imaging and quantification of a retention index describing global and regional perfusion reserve are feasible using a solid-state camera. Preliminary results show that the MPR index is lower in patients with perfusion defects and in regions supplied by obstructed coronary arteries. Further studies are needed to establish the clinical role of this technique as an aid to semiquantitative analysis of MPI.

Quantitative relationship between the extent and morphology of coronary atherosclerotic plaque and downstream myocardial perfusion.

OBJECTIVES The purpose of this study was to quantify the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR). BACKGROUND Although the relationship between coronary stenosis and myocardial perfusion is well established, little is known about the contribution of other anatomic descriptors of atherosclerosis burden to this relationship. METHODS We evaluated the relationship between atherosclerosis plaque burden, morphology, and composition and regional MFR (MFR(regional)) in 73 consecutive patients undergoing Rubidium-82 positron emission tomography and coronary computed tomography angiography for the evaluation of known or suspected coronary artery disease. RESULTS Atherosclerosis was seen in 51 of 73 patients and in 107 of 209 assessable coronary arteries. On a per-vessel basis, the percentage diameter stenosis (p = 0.02) or summed stenosis score (p = 0.002), integrating stenoses in series, was the best predictor of MFR(regional). Importantly, MFR(regional) varied widely within each coronary stenosis category, even in vessels with nonobstructive plaques (n = 169), 38% of which had abnormal MFR(regional) (<2.0). Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFR(global). CONCLUSIONS Computed tomography angiography descriptors of atherosclerosis had only a modest effect on downstream MFR. On a per-patient basis, the extent and severity of atherosclerosis as assessed by the modified Duke CAD index and the number of coronary segments with mixed plaque were associated with decreased MFR.

Coronary Vascular Dysfunction and Prognosis in Patients With Chronic Kidney Disease

OBJECTIVES This study sought to evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease, which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction. BACKGROUND Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction. METHODS We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion positron emission tomography and followed them for a median of 1.28 years (interquartile range: 0.64 to 2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of positron emission tomography images. Rest and stress myocardial blood flow were calculated using factor analysis and a 2-compartment kinetic model; they were also used to compute coronary flow reserve (stress/rest myocardial blood flow). The primary endpoint was cardiac death. RESULTS Overall, 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95% confidence interval [CI]: 1.3 to 3.5, p = 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the C-index from 0.75 to 0.77 (p = 0.05) and in a net reclassification improvement of 0.142 (95% CI: 0.076 to 0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the net reclassification improvement was 0.489 (95% CI: 0.192 to 0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. CONCLUSIONS The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by positron emission tomography, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.