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. 2017 Dec 12;136(24):2325-2336.
doi: 10.1161/CIRCULATIONAHA.117.029992. Epub 2017 Sep 1.

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

Ankur Gupta  1 , Viviany R Taqueti  1 , Tim P van de Hoef  2 , Navkaranbir S Bajaj  1 , Paco E Bravo  1 , Venkatesh L Murthy  3 , Michael T Osborne  4 , Sara B Seidelmann  1 , Tomas Vita  1 , Courtney F Bibbo  1 , Meagan Harrington  1 , Jon Hainer  1 , Ornella Rimoldi  5 , Sharmila Dorbala  1 , Deepak L Bhatt  6 , Ron Blankstein  1 , Paolo G Camici  7 , Marcelo F Di Carli  8
Affiliations

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

Ankur Gupta et al. Circulation. .

Abstract

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.

Keywords: coronary artery disease; coronary circulation; myocardial blood flow; myocardial fractional flow reserve; myocardial revascularization; positron emission tomography computed tomography; women.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda.

Dr. Venkatesh L. Murthy discloses the following relationships - stock in General Electric, research support from INVIA Medical Imaging Solutions, speaking/consulting fees from Bracco Diagnostics and Ionetix.

Dr. Paolo G. Camici discloses the following relationships – consultant for Servier, speaking fees from Menarini.

All other authors have no relevant disclosures.

Figures

Figure 1
Figure 1. Scatter Plot of Coronary Flow Reserve and Maximal Myocardial Blood Flow by Cardiovascular Death
Concordant and discordant impairment of coronary flow reserve and maximal myocardial blood flow identifies unique prognostic phenotypes of patients. Coronary Flow Reserve < 2 and maximal Myocardial Blood Flow < 1.8 ml · g-1· min-1 were defined as impaired. CFR, coronary flow reserve; CV, cardiovascular
Figure 2
Figure 2. Independent and Incremental Prognostic Value of Coronary Flow Reserve and Maximal Myocardial Blood Flow
Hazard ratios are expressed per unit decrease in CFR or maximal MBF. aFor assessment of independent prognostic value, CFR or maximal MBF were modeled as continuous variables in separate models. bFor assessment of incremental prognostic value, both CFR and maximal MBF were modeled as continuous variables together in the same model. cAdjusted Cox model includes the following covariates: age, sex, hypertension, diabetes, dyslipidemia, dialysis, body mass index, known coronary artery disease, left ventricular ejection fraction, amount of myocardial scar/ischemia, revascularization post-positron emission tomography scan, rate-pressure-product, type of radiotracer or stress agent. CFR, coronary flow reserve; CI, confidence interval; HR, hazard ratio; MBF, myocardial blood flow
Figure 3
Figure 3. Annualized Cardiovascular Mortality Rates
Figure shows annualized CV mortality for the four groups based on concordant or discordant impairment of CFR and maximal MBF. Figure 3A shows crude annualized CV mortality risk. Figure 3B shows adjusted annualized CV mortality risk after adjustment for age, sex, baseline CV risk factors, left ventricular ejection fraction, amount of myocardial scar and ischemia, revascularization post-positron emission tomography scan, rate-pressure-product, and type of radiotracer or stress agent. CFR, coronary flow reserve; CV, cardiovascular; mMBF, maximal myocardial blood flow
Figure 4
Figure 4. Event Curves for Cardiovascular Mortality
Figure shows event curves for probability of CV mortality over time for the four groups based on concordant or discordant impairment of CFR and maximal MBF. Figure 4A depicts unadjusted event curves, and Figure 4B depicts adjusted event curves after adjustment for age, gender, baseline CV risk factors, left ventricular ejection fraction, amount of myocardial scar and ischemia, revascularization post-positron emission tomography scan, rate-pressure-product, type of radiotracer or stress agent. CFR, coronary flow reserve; CV, cardiovascular; MBF, myocardial blood flow; PET,
Figure 5
Figure 5. Exploratory Sub-Group Analysis for Independent Prognostic Value of Coronary Flow Reserve and Maximal Myocardial Blood Flow
For the assessment of independent prognostic value, CFR or maximal MBF were modeled as continuous variables in separate models. Hazard ratios are expressed per unit decrease in CFR or maximal MBF. Hazard ratios are adjusted for age, sex, hypertension, diabetes, dyslipidemia, dialysis, body mass index, known coronary artery disease, left ventricular ejection fraction, amount of myocardial scar/ischemia, revascularization post-positron emission tomography scan, rate-pressure-product, type of radiotracer or stress agent. A particular variable is excluded from adjustment when it is sub-group of interest. CAD, coronary artery disease; LVEF, left ventricular ejection fraction
Figure 6
Figure 6. Exploratory Sub-Group Analysis for Incremental Prognostic Value of Coronary Flow Reserve and Maximal Myocardial Blood Flow
For the assessment of incremental prognostic value, both CFR and maximal MBF were modeled together as continuous variables in the same model. Hazard ratios are expressed per unit decrease in CFR or maximal MBF. Hazard ratios are adjusted for age, sex, hypertension, diabetes, dyslipidemia, dialysis, body mass index, known coronary artery disease, left ventricular ejection fraction, amount of myocardial scar/ischemia, revascularization post- positron emission tomography scan, rate-pressure-product, type of radiotracer or stress agent. A particular variable is excluded from adjustment when it is sub-group of interest. CAD, coronary artery disease; LVEF, left ventricular ejection fraction
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