Prognostic value of myocardial flow reserve vs corrected myocardial flow reserve in patients without obstructive coronary artery disease.

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.

Low coronary flow relative to myocardial mass predicts heart failure in symptomatic hypertensive patients with no obstructive coronary artery disease.

AIMS: The transition from hypertension to heart failure (HF) remains poorly understood. We hypothesized that insufficient perfusion to match global metabolic demand, reflected by a low ratio of myocardial blood flow to global myocardial mass, may be a HF risk marker. METHODS AND RESULTS: A retrospective cohort (n = 346) of patients with hypertension who underwent clinical positron emission tomography (PET) myocardial perfusion imaging for chest pain and/or dyspnoea at Brigham and Women's Hospital (Boston, MA, USA) were studied. Patients without obstructive coronary artery disease by history or PET perfusion (summed stress score <3), HF, cardiomyopathy, or ejection fraction (EF) <40% were followed for HF hospitalization (primary outcome), all-cause death, and their composite. Myocardial blood flow, left ventricular (LV) mass, volumes, and EF were obtained from PET, and a 'flow/mass ratio' was determined as hyperaemic myocardial blood flow over LV mass indexed to body surface area. A lower flow/mass ratio was independently associated with larger end-diastolic (ß = -0.44, P < 0.001) and end-systolic volume (ß = -0.48, P < 0.001) and lower EF (ß = 0.33, P < 0.001). A flow/mass ratio below the median was associated with an adjusted hazard ratio of 2.47 [95% confidence interval (CI) 1.24-4.93; P = 0.01] for HF hospitalization, 1.95 (95% CI 1.12-3.41; P = 0.02) for death, and 2.20 (95% CI 1.39-3.49; P < 0.001) for the composite. CONCLUSION: An integrated physiological measure of insufficient myocardial perfusion to match global metabolic demand identifies subclinical hypertensive heart disease and elevated risk of HF and death in symptomatic patients with hypertension but without flow-limiting coronary artery disease.

Coronary vasomotor dysfunction portends worse outcomes in patients with breast cancer.

BACKGROUND: Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer. METHODS: We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death. RESULTS: The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile. CONCLUSIONS: In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer.

Coronary Microvascular Dysfunction, Left Ventricular Remodeling, and Clinical Outcomes in Patients With Chronic Kidney Impairment.

BACKGROUND: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. METHODS: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. RESULTS: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. CONCLUSIONS: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

Coronary vasomotor dysfunction in cancer survivors treated with thoracic irradiation.

BACKGROUND: We sought to test the hypothesis that thoracic radiation therapy (RT) is associated with impaired myocardial flow reserve (MFR), a measure of coronary vasomotor dysfunction. METHODS: We retrospectively studied thirty-five consecutive patients (71% female, mean ± standard deviation (SD) age: 66 ± 11 years) referred clinically for positron emission tomography/computed tomography (PET/CT) myocardial perfusion imaging at a median (interquartile range, IQR) interval of 4.3 (2.1, 9.7) years following RT for a variety of malignancies. Radiation dose-volume histograms were generated for the heart and coronary arteries for each patient. RESULTS: The median (IQR) of mean cardiac radiation doses was 12.0 (1.2, 24.2) Gray. There were significant inverse correlations between mean radiation dose and global MFR (MFRGlobal) and MFR in the left anterior descending artery territory (MFRLAD): Pearson's correlation coefficient = - .37 (P = .03) and - .38 (P = .03), respectively. For every one Gray increase in mean cardiac radiation dose, there was a mean ± standard error decrease of .02 ± .01 in MFRGlobal (P = .04) and MFRLAD (P = .03) after adjustment. CONCLUSIONS: In patients with a history of RT clinically referred for cardiac stress PET, we found an inverse correlation between mean cardiac radiation dose and coronary vasomotor function.

Coronary microvascular dysfunction, left ventricular remodeling, and clinical outcomes in aortic stenosis.

BACKGROUND: We investigated role of coronary microvascular disease (CMD) in maladaptive LV remodeling and prognosis in patients with aortic sclerosis or stenosis and no overt CAD. METHODS: This was a retrospective cohort study of patients with aortic sclerosis or stenosis, normal myocardial perfusion and LV ejection fraction (EF) > 50% (n = 43) and matched controls without AS (n = 43). PET and echocardiograms were performed within 1 year of each other. Myocardial perfusion and myocardial flow reserve (MFR) were quantified using PET imaging. LV structure and function, including global longitudinal strain (GLS), were quantified by transthoracic echocardiography. RESULTS: Global MFR declined with increasing AS severity (P = 0.04). Probability of impaired MFR increased with severity of adverse LV remodeling (OR 1.88, CI 1.03 to 3.41, P =0.04). Reduced MFR associated with impaired GLS (r = - 0.29, P = 0.002) and associated with reduced MACE-free survival at 7.27 years median follow-up. Adjusted annualized rate of MACE was highest in those with impaired GLS and MFR and lowest in those with normal GLS and MFR (30.99% vs 1.86%, P =0.002). CONCLUSION AND RELEVANCE: In patients with AS and no overt CAD, impaired MFR associates with adverse LV remodeling and subclinical LV mechanical dysfunction, and is a marker increased clinical risk.

Feasibility of somatostatin receptor-targeted imaging for detection of myocardial inflammation: A pilot study.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: Thirteen patients, with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG-PET (median time 37 days [IQR 25-55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n = 6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8-7.1] higher in the heart, but only 2.25 times [1.7-3.0; P = .019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggest that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Mass General Brigham YOUNG-MI registry.

AIMS: There are sex differences in presentation, treatment, and outcomes of myocardial infarction (MI) but less is known about these differences in a younger patient population. The objective of this study was to investigate sex differences among individuals who experience their first MI at a young age. METHODS AND RESULTS: Consecutive patients presenting to two large academic medical centres with a Type 1 MI at ≤50 years of age between 2000 and 2016 were included. Cause of death was adjudicated using electronic health records and death certificates. In total, 2097 individuals (404 female, 19%) had an MI (mean age 44 ± 5.1 years, 73% white). Risk factor profiles were similar between men and women, although women were more likely to have diabetes (23.7% vs. 18.9%, P = 0.028). Women were less likely to undergo invasive coronary angiography (93.5% vs. 96.7%, P = 0.003) and coronary revascularization (82.1% vs. 92.6%, P < 0.001). Women were significantly more likely to have MI with non-obstructive coronary disease on angiography (10.2% vs. 4.2%, P < 0.001). They were less likely to be discharged with aspirin (92.2% vs. 95.0%, P = 0.027), beta-blockers (86.6% vs. 90.3%, P = 0.033), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (53.4% vs. 63.7%, P < 0.001), and statins (82.4% vs. 88.4%, P < 0.001). There was no significant difference in in-hospital mortality; however, women who survived to hospital discharge experienced a higher all-cause mortality rate (adjusted HR = 1.63, P = 0.01; median follow-up 11.2 years) with no significant difference in cardiovascular mortality (adjusted HR = 1.14, P = 0.61). CONCLUSIONS: Women who experienced their first MI under the age of 50 were less likely to undergo coronary revascularization or be treated with guideline-directed medical therapies. Women who survived hospitalization experienced similar cardiovascular mortality with significantly higher all-cause mortality than men. A better understanding of the mechanisms underlying these differences is warranted.

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

AIMS: Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment. METHODS AND RESULTS: Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030). CONCLUSION: We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

Network Analysis to Risk Stratify Patients With Exercise Intolerance.

RATIONALE: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. OBJECTIVE: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. METHODS AND RESULTS: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011-2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|>0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P<9.5e-46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pVo2) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements (P<0.01). Compared with a probabilistic model, including 23 independent predictors of pVo2 and pVo2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold (P<0.0001; 95% CI, 2.2-8.1) and 2.8-fold (P=0.0018; 95% CI, 1.5-5.2) increase in hazard for age- and pVo2-adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. CONCLUSIONS: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pVo2 that predict hospitalization in patients with exercise intolerance.

Association between Nonalcoholic Fatty Liver Disease at CT and Coronary Microvascular Dysfunction at Myocardial Perfusion PET/CT.

Background Cardiovascular disease is a major cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). However, the association of NAFLD with coronary microvascular dysfunction is, to our knowledge, unknown. Purpose To determine whether coronary microvascular dysfunction is more prevalent in patients with NAFLD and to determine whether coronary microvascular dysfunction predicts major adverse cardiac events (MACE) independently of NAFLD. Materials and Methods This retrospective study (2006-2014) included patients without evidence of obstructive epicardial coronary artery disease and healthy left ventricular ejection fraction (≥40%) at a clinical rest and stress myocardial perfusion PET/CT. NAFLD was defined by a mean hepatic attenuation of less than 40 HU at CT and coronary microvascular dysfunction as a coronary flow reserve (CFR) of less than 2.0. A composite of all-cause mortality, myocardial infarction, coronary revascularization, and hospitalization because of heart failure comprised MACE (130 of 886 patients; 14.7%). The relation between NAFLD and MACE was assessed by using multivariable Cox regression analysis. Results Among 886 patients (mean age, 62 years ± 12 [standard deviation]; 631 women [mean age, 62 years ± 12 years] and 255 men [mean age, 61 years ± 12]; and ejection fraction, 63% ± 9), 125 patients (14.1%) had NAFLD and 411 patients (46.4%) had coronary microvascular dysfunction. Coronary microvascular dysfunction was more prevalent (64.8% vs 43.4%; P < .001) and CFR was lower (1.9 ± 1.1 vs 2.2 ± 0.7; P < .001) in patients with NAFLD compared with those without NAFLD. NAFLD independently predicted coronary microvascular dysfunction (P = .01). The interaction of NAFLD and male sex predicted MACE (hazard ratio, 1.45; 95% confidence interval: 1.08, 1.69; P = .008) and coronary microvascular dysfunction remained associated with MACE (adjusted hazard ratio, 1.46; 95% confidence interval: 1.02, 2.07; P = .04). Conclusion Coronary microvascular dysfunction was more prevalent in patients with nonalcoholic fatty liver disease and predicted major adverse cardiac events independently of nonalcoholic fatty liver disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh and Lima in this issue.

Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction.

Aims: Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown. Methods and results: Consecutive patients (n = 201) undergoing evaluation for suspected coronary artery disease (CAD) with stress myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up (median 4.1 years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure. Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation (e') velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2, n = 108) demonstrated linearly decreasing e' and increasing E/e' consistent with worsening diastolic function (P for trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired CFR (interaction P = 0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunction (E/e'septal > 15, adjusted OR 2.58, 95%CI 1.22-5.48) and composite cardiovascular outcomes or HFpEF hospitalization alone (adjusted HR 2.47, 95%CI 1.09-5.62). Patients with both impaired CFR and diastolic dysfunction demonstrated >five-fold increased risk of HFpEF hospitalization (P < 0.001). Conclusion: In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.

Diagnostic and prognostic value of myocardial blood flow quantification as non-invasive indicator of cardiac allograft vasculopathy.

Aims: Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results: We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to-severely abnormal PET CAV grading (P < 0.001), respectively. Conclusion: Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events.

Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease.

BACKGROUND: Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. METHODS: Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction >40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. RESULTS: Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD (P<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05-4.02; P=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (P<0.0001, P for interaction=0.04). CONCLUSIONS: Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.

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.

Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage.

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

Marked exercise-induced T-wave heterogeneity in symptomatic diabetic patients with nonflow-limiting coronary artery stenosis.

BACKGROUND: T-wave heterogeneity (TWH) independently predicted cardiovascular mortality in Health Survey 2000 based on 12-lead ECGs recorded at rest. We investigated whether TWH is elevated during exercise tolerance testing (ETT) in symptomatic diabetic patients with nonflow-limiting coronary artery stenosis compared to control subjects without diabetes. METHODS: Cases were all patients (n = 20) with analyzable ECG recordings during both rest and ETT who were enrolled in the Effects of Ranolazine on Coronary Flow Reserve (CFR) in Symptomatic Patients with Diabetes and Suspected or Known Coronary Artery Disease (RAND-CFR) study (NCT01754259); median CFR was 1.44; 80% of cases had CFR <2. Control subjects (n = 9) were nondiabetic patients who had functional flow reserve (FFR) >0.8, a range not associated with inducible ischemia. TWH was analyzed from precordial leads V4 , V5 , and V6 by second central moment analysis, which assesses the interlead splay of T-waves about a mean waveform. RESULTS: During exercise to similar rate-pressure products (p = .31), RAND-CFR patients exhibited a 49% increase in TWH during exercise (rest: 49 ± 5 µV; exercise: 73 ± 8 µV, p = .003). By comparison, in control subjects, TWH was not significantly altered (rest: 52 ± 11 µV; ETT: 38 ± 5 µV, p = .19). ETT-induced ST-segment depression >1 mm (p = .11) and Tpeak -Tend (p = .18) and QTc intervals (p = .80) failed to differentiate cases from controls. CONCLUSIONS: TWH is capable of detecting latent repolarization abnormalities, which are present during ETT in diabetic patients with nonflow-limiting stenosis but not in control subjects. The technique developed in this study permits TWH analysis from archived ECGs and thereby enables mining of extensive databases for retrospective studies and hypothesis testing.

Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non-flow-limiting coronary artery stenosis.

BACKGROUND: Experimental evidence suggests that ranolazine decreases susceptibility to ischemia-induced arrhythmias independent of effects on coronary artery blood flow. OBJECTIVE: In symptomatic diabetic patients with non-flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, we explored whether ranolazine reduces T-wave heterogeneity (TWH), an electrocardiographic (ECG) marker of arrhythmogenic repolarization abnormalities shown to predict sudden cardiac death. METHODS: We studied all 16 patients with analyzable ECG recordings during rest and exercise tolerance testing before and after 4 weeks of ranolazine in the double-blind, crossover, placebo-controlled RAND-CFR trial (NCT01754259). TWH was quantified without knowledge of treatment assignment by second central moment analysis, which assesses the interlead splay of T waves in precordial leads about a mean waveform. Myocardial blood flow (MBF) was measured by positron emission tomography. RESULTS: At baseline, prior to randomization, TWH during rest was 54 ± 7 µV and was not altered following placebo (47 ± 6 µV, p = .47) but was reduced by 28% (to 39 ± 5 µV, p = .002) after ranolazine. Ranolazine did not increase MBF at rest. Exercise increased TWH after placebo by 49% (to 70 ± 8 µV, p = .03). Ranolazine did not reduce TWH during exercise (to 75 ± 16 µV), and there were no differences among the groups (p = .95, ANOVA). TWH was not correlated with MBF at rest before (r2  = .07, p = .36) or after ranolazine (r2  = .23, p = .06). CONCLUSIONS: In symptomatic diabetic patients with non-flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, ranolazine reduced TWH at rest but not during exercise. Reduction in repolarization abnormalities appears to be independent of alterations in MBF.

Prognostic Value of Coronary Flow Reserve in Patients with Dialysis-Dependent ESRD.

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

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.