Integrated myocardial flow reserve (iMFR) assessment: optimized PET blood flow quantification for diagnosis of coronary artery disease.

PURPOSE: Distinguishing obstructive epicardial coronary artery disease (CAD) from microvascular dysfunction and diffuse atherosclerosis would be of immense benefit clinically. However, quantitative measures of absolute myocardial blood flow (MBF) integrate the effects of focal epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. In this study, MFR and relative perfusion quantification were combined to create integrated MFR (iMFR) which was evaluated using data from a large clinical registry and an international multi-center trial and validated against invasive coronary angiography (ICA). METHODS: This study included 1,044 clinical patients referred for 82Rb rest/stress positron emission tomography myocardial perfusion imaging and ICA, along with 231 patients from the Flurpiridaz 301 trial (clinicaltrials.gov NCT01347710). MFR and relative perfusion quantification were combined to create an iMFR map. The incremental value of iMFR was evaluated for diagnosis of obstructive stenosis, adjusted for patient demographics and pre-test probability of CAD. Models for high-risk anatomy (left main or three-vessel disease) were also constructed. RESULTS: iMFR parameters of focally impaired perfusion resulted in best fitting diagnostic models. Receiver-operating characteristic analysis showed a slight improvement compared to standard quantitative perfusion approaches (AUC 0.824 vs. 0.809). Focally impaired perfusion was also associated with high-risk CAD anatomy (OR 1.40 for extent, and OR 2.40 for decreasing mean MFR). Diffusely impaired perfusion was associated with lower likelihood of obstructive CAD, and, in the absence of transient ischemic dilation (TID), with lower likelihood of high-risk CAD anatomy. CONCLUSIONS: Focally impaired perfusion extent derived from iMFR assessment is a powerful incremental predictor of obstructive CAD while diffusely impaired perfusion extent can help rule out obstructive and high-risk CAD in the absence of TID.

Integrated myocardial flow reserve (iMFR) assessment: diffuse atherosclerosis and microvascular dysfunction are more strongly associated with mortality than focally impaired perfusion.

BACKGROUND AND AIMS: Although treatment of ischemia-causing epicardial stenoses may improve symptoms of ischemia, current evidence does not suggest that revascularization improves survival. Conventional myocardial ischemia imaging does not uniquely identify diffuse atherosclerosis, microvascular dysfunction, or nonobstructive epicardial stenoses. We sought to evaluate the prognostic value of integrated myocardial flow reserve (iMFR), a novel noninvasive approach to distinguish the perfusion impact of focal atherosclerosis from diffuse coronary disease. METHODS: This study analyzed a large single-center registry of consecutive patients clinically referred for rest-stress myocardial perfusion positron emission tomography. Cox proportional hazards modeling was used to assess the association of two previously reported and two novel perfusion measures with mortality risk: global stress myocardial blood flow (MBF); global myocardial flow reserve (MFR); and two metrics derived from iMFR analysis: the extents of focal and diffusely impaired perfusion. RESULTS: In total, 6867 patients were included with a median follow-up of 3.4 years [1st-3rd quartiles, 1.9-5.0] and 1444 deaths (21%). Although all evaluated perfusion measures were independently associated with death, diffusely impaired perfusion extent (hazard ratio 2.65, 95%C.I. [2.37-2.97]) and global MFR (HR 2.29, 95%C.I. [2.08-2.52]) were consistently stronger predictors than stress MBF (HR 1.62, 95%C.I. [1.46-1.79]). Focally impaired perfusion extent (HR 1.09, 95%C.I. [1.03-1.16]) was only moderately related to mortality. Diffusely impaired perfusion extent remained a significant independent predictor of death when combined with global MFR (p < 0.0001), providing improved risk stratification (overall net reclassification improvement 0.246, 95%C.I. [0.183-0.310]). CONCLUSIONS: The extent of diffusely impaired perfusion is a strong independent and additive marker of mortality risk beyond traditional risk factors, standard perfusion imaging, and global MFR, while focally impaired perfusion is only moderately related to mortality.

The Impact of Social Determinants of Health and Lifestyle on the Association of Lipoprotein(a) with Myocardial Infarction and Stroke.

Background: In European cohorts, a higher Mediterranean diet or Life's Simple 7 (LS7) score abolished or attenuated the risk associated with increasing Lipoprotein(a) [Lp(a)] on cardiovascular outcomes. This is unstudied in US cohorts. The impact of social determinants of health (SDOH) on the association of Lp(a) with cardiovascular outcomes remains unstudied. We sought to test if a SDOH score and LS7 score impacts the association of Lp(a) with myocardial infarction (MI) or stroke. Methods: Observational Cohort of US Adults from the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. We performed sequential multivariable Cox proportional hazard analysis, first adjusting for age, gender, non-HDL-C, race and ethnicity, then added SDOH and LS7 scores sequentially. The primary outcomes were time until first fatal or nonfatal MI or stroke. Results: ARIC (n=15,072; median Lp(a)=17.3 mg/dL) had 16.2 years average follow up. MESA (n=6,822; median Lp(a)=18.3 mg/dL had 12.3 years average follow-up. In multivariable analyses adjusted for age, gender, race and ethnicity, and non-HDL-C, Lp(a) was associated (HR, p-value) with MI in ARIC (1.10, <0.001) and MESA (1.09, <0.001), and stroke in ARIC (1.08, <0.001) but not MESA (0.97, 0.50). With SDOH and LS7 added to the model associations remained similar (association of Lp(a) with MI in ARIC 1.09, <0.001 and in MESA 1.10, 0.001, with stroke in ARIC 1.06, <0.003 and in MESA 0.96, 0.39). In models with all covariates, each additional SDOH correlated positively with MI (ARIC 1.13, <0.001; MESA 1.11, <0.001) and stroke (ARIC 1.17, <0.001; HR 1.07, p=0.11) and each additional LS7 score point correlated negatively with MI (ARIC 0.81, <0.001; MESA 0.84, <0.001) and stroke (ARIC 0.82, <0.001; MESA 0.84, <0.001). Conclusions and Relevance: SDOH and lifestyle factors were predictors for MI and stroke that did not impact the association between Lp(a) and cardiovascular events. Our findings support that Lp(a) is an independent risk factor for MI and possibly stroke.

Utility of serum ketone levels for assessment of myocardial glucose suppression for 18F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis.

BACKGROUND: 18F-FDG PET/CT is used to diagnose cardiac sarcoidosis and endocarditis. It requires myocardial glucose utilization (MGU) suppression to avoid false positives, which occur in up to 20% of patients. Serum beta-hydroxybutyrate (BHB) levels may help identify incomplete suppression of MGU. We determined the optimal timing and diagnostic thresholds to identify incomplete suppression of MGU. METHODS AND RESULTS: We retrospectively identified 114 patients referred for 18F-FDG PET/CT for endocarditis, wherein myocardial uptake outside of paravalvular regions is not related to pathology and can be confidently ascribed as being due to inadequate suppression of MGU. Patients followed a high-fat, low-carbohydrate diet and received heparin. Serum BHB, insulin, glucose and hemoglobin A1c were measured. Maximum standardized uptake value (SUVmax) of left ventricle (LV) and mean SUV (SUVmean) in LV blood pool (LVBP) was measured. Logistic regression and area under the receiver-operating characteristic analyses were used to quantify the relationship between biomarkers and MGU suppression. A threshold of BHB ≥ 0.35 mmol·L-1 to detect suppression resulted in sensitivity of 88% and specificity of 61%. A threshold of BHB ≥ 0.95 mmol·L-1 resulted in sensitivity of 45% and specificity of 100%. AUC was 0.87. BHB measured ~ 4 hours prior to 18F-FDG injection performed similarly to or better than later timepoints. CONCLUSIONS: Serum BHB levels are useful for assessing suppression of MGU and could simplify interpretation of 18F-FDG PET/CT inflammation studies.

Cost-effectiveness of Contemporary Statin Use Guidelines With or Without Coronary Artery Calcium Assessment in African American Individuals.

Importance: Clinical and economic consequences of statin treatment guidelines supplemented by targeted coronary artery calcium (CAC) assessment have not been evaluated in African American individuals, who are at increased risk for atherosclerotic cardiovascular disease and less likely than non-African American individuals to receive statin therapy. Objective: To evaluate the cost-effectiveness of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline without a recommendation for CAC assessment vs the 2018 ACC/AHA guideline recommendation for use of a non-0 CAC score measured on one occasion to target generic-formulation, moderate-intensity statin treatment in African American individuals at risk for atherosclerotic cardiovascular disease. Design, Setting, and Participants: A microsimulation model was designed to estimate life expectancy, quality of life, costs, and health outcomes over a lifetime horizon. African American-specific data from 472 participants in the Jackson Heart Study (JHS) at intermediate risk for atherosclerotic cardiovascular disease and other US population-specific data on individuals from published sources were used. Data analysis was conducted from November 11, 2018, to November 1, 2019. Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: In a model-based economic evaluation informed in part by follow-up data, the analysis was focused on 472 individuals in the JHS at intermediate risk for atherosclerotic cardiovascular disease; mean (SD) age was 63 (6.7) years. The sample included 243 women (51.5%) and 229 men (48.5%). Of these, 178 of 304 participants (58.6%) who underwent CAC assessment had a non-0 CAC score. In the base-case scenario, implementation of 2013 ACC/AHA guidelines without CAC assessment provided a greater quality-adjusted life expectancy (0.0027 QALY) at a higher cost ($428.97) compared with the 2018 ACC/AHA guideline strategy with CAC assessment, yielding an incremental cost-effectiveness ratio of $158 325/QALY, which is considered to represent low-value care by the ACC/AHA definition. The 2018 ACC/AHA guideline strategy with CAC assessment provided greater quality-adjusted life expectancy at a lower cost compared with the 2013 ACC/AHA guidelines without CAC assessment when there was a strong patient preference to avoid use of daily medication therapy. In probability sensitivity analyses, the 2018 ACC/AHA guideline strategy with CAC assessment was cost-effective compared with the 2013 ACC/AHA guidelines without CAC assessment in 76% of simulations at a willingness-to-pay value of $100 000/QALY when there was a preference to lose 2 weeks of perfect health to avoid 1 decade of daily therapy. Conclusions and Relevance: A CAC assessment-guided strategy for statin therapy appears to be cost-effective compared with initiating statin therapy in all African American individuals at intermediate risk for atherosclerotic cardiovascular disease and may provide greater quality-adjusted life expectancy at a lower cost than a non-CAC assessment-guided strategy when there is a strong patient preference to avoid the need for daily medication. Coronary artery calcium testing may play a role in shared decision-making regarding statin use.

Multiparametric assessment of left atrial remodeling using 18F-FDG PET/CT cardiac imaging: A pilot study.

BACKGROUND: Left atrial (LA) remodeling is associated with structural, electric, and metabolic LA changes. Integrated evaluation of these features in vivo is lacking. METHODS: Patients undergoing 18F-fluorodeoxyglucose (FDG) PET-CT during a hyperinsulinemic-euglycemic clamp were classified into sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PerAF). The LA was semiautomatically segmented, and global FDG uptake was quantified using standardized uptake values (SUVmax and SUVmean) in gated, attenuation-corrected images and normalized to LA blood pool activity. Regression was used to relate FDG data to AF burden and critical patient factors. Continuous variables were compared using t-tests or Mann-Whitney tests. RESULTS: 117 patients were included (76% men, age 66.4 ± 11.0, ejection fraction (EF) 25[22-35]%) including those with SR (n = 48), PAF (n = 55), and PerAF (n = 14). Patients with any AF had increased SUVmean (2.3[1.5-2.4] vs 2.0[1.5-2.5], P = 0.006), SUVmax (4.4[2.8-6.7] vs 3.2[2.3-4.3], P < 0.001), uptake coefficient of variation (CoV) 0.28[0.22-0.40] vs 0.25[0.2-0.33], P < 0.001), and hypometabolic scar (32%[14%-53%] vs 16.5%[0%-38.5%], P = 0.01). AF burden correlated with increased SUVmean, SUVmax, CoV, and scar independent of age, gender, EF, or LA size (P < 0.03 for all). CONCLUSIONS: LA structure and metabolism can be assessed using FDG PET/CT. Greater AF burden correlates with the increased LA metabolism and scar.

Metabolites Associated with Vigor to Frailty Among Community-Dwelling Older Black Men.

Black versus white older Americans are more likely to experience frailty, a condition associated with adverse health outcomes. To reduce racial disparities in health, a complete understanding of the pathophysiology of frailty is needed. Metabolomics may further our understanding by characterizing differences in the body during a vigorous versus frail state. We sought to identify metabolites and biological pathways associated with vigor to frailty among 287 black men ages 70-81 from the Health, Aging, and Body Composition study. Using liquid chromatography-mass spectrometry, 350 metabolites were measured in overnight-fasting plasma. The Scale of Aging Vigor in Epidemiology (SAVE) measured vigor to frailty based on weight change, strength, energy, gait speed, and physical activity. Thirty-seven metabolites correlated with SAVE scores (p < 0.05), while adjusting for age and site. Fourteen metabolites remained significant after multiple comparisons adjustment (false discovery rate < 0.30). Lower values of tryptophan, methionine, tyrosine, asparagine, C14:0 sphingomyelin, and 1-methylnicotinamide, and higher values of glucoronate, N-carbamoyl-beta-alanine, isocitrate, creatinine, C4-OH carnitine, cystathionine, hydroxyphenylacetate, and putrescine were associated with frailer SAVE scores. Pathway analyses identified nitrogen metabolism, aminoacyl-tRNA biosynthesis, and the citric acid cycle. Future studies need to confirm these SAVE-associated metabolites and pathways that may indicate novel mechanisms involved in the frailty syndrome.

The utility of 82Rb PET for myocardial viability assessment: Comparison with perfusion-metabolism 82Rb-18F-FDG PET.

BACKGROUND: 82Rb kinetics may distinguish scar from viable but dysfunctional (hibernating) myocardium. We sought to define the relationship between 82Rb kinetics and myocardial viability compared with conventional 82Rb and 18F-fluorodeoxyglucose (FDG) perfusion-metabolism PET imaging. METHODS: Consecutive patients (N = 120) referred for evaluation of myocardial viability prior to revascularization and normal volunteers (N = 37) were reviewed. Dynamic 82Rb 3D PET data were acquired at rest. 18F-FDG 3D PET data were acquired after metabolic preparation using a standardized hyperinsulinemic-euglycemic clamp. 82Rb kinetic parameters K1, k2, and partition coefficient (KP) were estimated by compartmental modeling RESULTS: Segmental 82Rb k2 and KP differed significantly between scarred and hibernating segments identified by Rb-FDG perfusion-metabolism (k2, 0.42 ± 0.25 vs. 0.22 ± 0.09 min-1; P < .0001; KP, 1.33 ± 0.62 vs. 2.25 ± 0.98 ml/g; P < .0001). As compared to Rb-FDG analysis, segmental Rb KP had a c-index, sensitivity and specificity of 0.809, 76% and 84%, respectively, for distinguishing hibernating and scarred segments. Segmental k2 performed similarly, but with lower specificity (75%, P < .001) CONCLUSIONS: In this pilot study, 82Rb kinetic parameters k2 and KP, which are readily estimated using a compartmental model commonly used for myocardial blood flow, reliably differentiated hibernating myocardium and scar. Further study is necessary to evaluate their clinical utility for predicting benefit after revascularization.

Assessment of dyssynchrony by gated myocardial perfusion imaging does not improve patient management.

Clinical trials have demonstrated improved outcomes with cardiac resynchronization therapy in patients with heart failure and electrical evidence of dyssynchrony. There has been intense effort at developing imaging markers of dyssynchrony with the aim of improved risk stratification. However, these efforts have not been fruitful to date. This article discusses mechanisms of cardiac dyssynchrony, reviews clinical data supporting resynchronization therapy, and addresses the lack of convincing evidence to support the use of noninvasive imaging measures of dyssynchrony in improving patient management.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease.

BACKGROUND: It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. METHODS: MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. RESULTS: A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CONCLUSIONS: CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Ideal Cardiovascular Health, Cardiovascular Remodeling, and Heart Failure in Blacks: The Jackson Heart Study.

BACKGROUND: The lifetime risk of heart failure (HF) is higher in the black population than in other racial groups in the United States. METHODS AND RESULTS: We measured the Life's Simple 7 ideal cardiovascular health metrics in 4195 blacks in the JHS (Jackson Heart Study; 2000-2004). We evaluated the association of Simple 7 metrics with incident HF and left ventricular structure and function by cardiac magnetic resonance (n=1188). Mean age at baseline was 54.4 years (65% women). Relative to 0 to 2 Simple 7 factors, blacks with 3 factors had 47% lower incident HF risk (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.73; P<0.0001); and those with ≥4 factors had 61% lower HF risk (HR, 0.39; 95% CI, 0.24-0.64; P=0.0002). Higher blood pressure (HR, 2.32; 95% CI, 1.28-4.20; P=0.005), physical inactivity (HR, 1.65; 95% CI, 1.07-2.55; P=0.02), smoking (HR, 2.04; 95% CI, 1.43-2.91; P<0.0001), and impaired glucose control (HR, 1.76; 95% CI, 1.34-2.29; P<0.0001) were associated with incident HF. The age-/sex-adjusted population attributable risk for these Simple 7 metrics combined was 37.1%. Achievement of ideal blood pressure, ideal body mass index, ideal glucose control, and nonsmoking was associated with less likelihood of adverse cardiac remodeling by cardiac magnetic resonance. CONCLUSIONS: Cardiovascular risk factors in midlife (specifically elevated blood pressure, physical inactivity, smoking, and poor glucose control) are associated with incident HF in blacks and represent targets for intensified HF prevention.

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.