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Positron Emission Tomography-Measured Abnormal Responses of Myocardial Blood Flow to Sympathetic Stimulation Are Associated With the Risk of Developing Cardiovascular Events
Open accessAbstract
Objectives We sought to assess prospectively whether patients with normal coronary angiograms but with impaired myocardial blood flow (MBF) increases to cold pressor testing (CPT) are at increased risk for cardiovascular events.Background Invasive angiographic assessments of coronary vasomotor function have demonstrated an impairment of endothelium-related coronary flow increases to independently predict future cardiovascular events. It is unknown whether noninvasive positron emission tomography (PET)-measured MBF alterations to sympathetic stimulation with CPT are associated with the risk of developing cardiovascular events.Methods A total of 72 patients (44 men, 28 women, age 58 +/- 8 years) referred for diagnostic cardiac catheterization were studied. Myocardial blood flow was measured in absolute units with (13)N-ammonia using PET, at baseline and during CPT in each patient. Cardiovascular events (cardiovascular death, acute coronary syndrome, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, ischemic stroke, or peripheral revascularization) were assessed as clinical outcome parameters over a mean follow-up period of 66 +/- 8 months. Patients were assigned to three groups: group 1, patients with >/=40% increase in MBF (%DeltaMBF), n = 22; group 2, patients with >0 and <40% increases in MBF, n = 32; and group 3, patients with decreases in MBF (</=0%), n = 18.Results During follow-up, one of the group 1 patients developed a cerebral stroke. In group 2, 15 cardiovascular events occurred in 9 patients and in group 3, 7 patients experienced 9 cardiovascular events (p </= 0.0001, univariate by log-rank test). Impaired MBF increases in group 2 and group 3 were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis (p = 0.033, log-rank test). After adjusting for known coronary risk factors, MBF responses to CPT revealed a nonsignificant trend to be independently associated with a higher incidence for cardiovascular events (p = 0.065, multivariate by Cox regression model).Conclusions Noninvasive PET-measured impaired MBF increases to sympathetic stimulation are associated with the risk of developing cardiovascular events.
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“Nevertheless, because impairment of coronary endothelial function (32) and specifically impaired MBF response as assessed by PET (33) have been shown to be independent predictors of unfavorable cardiovascular outcome, our results may at least raise questions about safety in patients with impaired MFR, such as CAD patients.”
From Caffeine decreases exercise-induced myocardial flow reserve (2006) · cites this paper as [33]
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“Furthermore, there is also an intrinsic variability of the severity of endothelium-dependent vasomotor dysfunction in the individual, despite the presence of a similar risk profile, which has to be taken into consideration.(11,37) Another explanation is that the extent of a diminished global MBF response to CPT, as in…”
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Myocardial Blood Flow Quantification Using Positron-Emission Tomography
Yoshinaga, K., Tomiyama, Y., Suzuki, E., & Tamaki, N. (2013) · Circulation Journal · doi:10.1253/circj.cj-13-0235 · Cited by 24
Alexánderson, E., García-Rojas, L., Jiménez, M., Jácome, R., Calleja, R., García, A. M., Ochoa, J. M., Meave, A., & Alexanderson, G. R. (2010) · Journal of Nuclear Cardiology · doi:10.1007/s12350-010-9273-8 · Cited by 21
Direct 4D Parametric Imaging in Dynamic Myocardial Perfusion PET
Rahmim, A., Tang, J., & Mohy‐ud‐Din, H. (2014) · DOAJ (DOAJ: Directory of Open Access Journals) · Cited by 20
Clinical Utility and Future Applications of PET/CT and PET/CMR in Cardiology
Pan, J. A., & Salerno, M. (2016) · Diagnostics · doi:10.3390/diagnostics6030032 · Cited by 19
Women with Stable Angina Pectoris and No Obstructive Coronary Artery Disease: Closer to a Diagnosis
Michelsen, M. M., Mygind, N. D., Frestad, D., & Prescott, E. (2017) · European Cardiology Review · doi:10.15420/ecr.2016:33:2 · Cited by 18
Coronary Microvascular Dysfunction Years After Cessation of Anabolic Androgenic Steroid Use
Bulut, Y., Rasmussen, J., Brandt, N., Frystyk, J., Thevis, M., Schou, M., Gustafsson, F., Hasbak, P., & Kistorp, C. (2024) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.51013 · Cited by 17
Huang, R., Abdelmoneim, S. S., Nhola, L. F., & Mulvagh, S. L. (2014) · Journal of Diabetes Research · doi:10.1155/2014/243518 · Cited by 17
“Antecedent to and associated with epicardial coronary artery stenosis, T2DM patients develop abnormal microvascular function in systemic circulatory beds, including those of the myocardium [1–4].”
BackgroundAcetylcholine versus cold pressor testing for evaluation of coronary endothelial function
AlBadri, A., Wei, J., Mehta, P. K., Landes, S., Petersen, J. W., Anderson, R. D., Samuels, B. A., Azarbal, B., Handberg, E. M., Li, Q., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172538 · Cited by 17
Xie, H., Guo, L., Velo, A. F., Liu, Z., Liu, Q., Guo, X., Zhou, B., Chen, X., Tsai, Y., Miao, T., et al. (2024) · Medical Image Analysis · doi:10.1016/j.media.2024.103391 · Cited by 15
“Studies have shown that the non-invasive quantification of MBF and MFR offers a predictive measure of cardiovascular diseases [6]–[8].”
Alexánderson, E., Cruz, P., Vargas, A., Meave, A., Ricalde, A., Talayero, J. A., Romero-Ibarra, J. L., Goldson, T. M., Lastra, O. L. V., Medina, G., et al. (2007) · Journal of Nuclear Cardiology · doi:10.1016/j.nuclcard.2007.05.003 · Cited by 15
Quantitative myocardial perfusion imaging with a MR cold pressor test
Ritter, C. O., Kowalski, M. K., Weng, A. M., Beer, M., Hahn, D. W., & Köstler, H. (2011) · Magnetic Resonance in Medicine · doi:10.1002/mrm.22941 · Cited by 14
“18 cc/[g min]) (19,20) and former published rest MR perfusion studies of our group (11,13,15,24,25).”
BackgroundSchindler, T. H., & Schelbert, H. (2007) · Journal of Nuclear Cardiology · doi:10.1016/j.nuclcard.2007.09.009 · Cited by 12
“Their investigation suggests that myocardial perfusion imaging by means of SPECT combined with different forms of vasomotor stress, such as bicycle exercise and pharmacologic vasodilation, may be a unique tool by which to identify early changes in coronary function and morphology, providing important diagnostic and pr…”
MethodSelf-citationChen, A.-D., Wang, H., Fan, B., Xu, Y., Chen, W., & Dai, N. (2017) · British Journal of Radiology · doi:10.1259/bjr.20160702 · Cited by 12
Cardona, A., Seshasai, S. R. K., Davey, J., Arrebola-Moreno, A. L., Ambrosio, G., Kaski, J. C., & Ray, K. K. (2015) · International Journal of Clinical Practice · doi:10.1111/ijcp.12630 · Cited by 11
Coronary vasomotor function assessed by positron emission tomography
Tamaki, N., Yoshinaga, K., & Naya, M. (2009) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-009-1311-x · Cited by 11
Troy, A. M., & Cheng, H. M. (2021) · Physiological Measurement · doi:10.1088/1361-6579/ac18fd · Cited by 12
Homaeinezhad, M. R., Ghaffari, A., Aghaee, M., Toosi, H. N., & Rahmani, R. (2011) · Biomedical Signal Processing and Control · doi:10.1016/j.bspc.2011.05.011 · Cited by 9
“MHOM = new double[ mm]; threads[2] =(HANDLE )_beginthread(PreProcess, 0, ¶m3);”
Kato, S., Kitagawa, K., Yoon, Y. E., Nakajima, H., Nagata, M., Takase, S., Nakamori, S., Ito, M., & Sakuma, H. (2014) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2013.12.015 · Cited by 9
“41 mL/min/g [10, 11, 17, 18, 21, 25].”
MethodLeucker, T. M., Valenta, I., & Schindler, T. H. (2017) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00046 · Cited by 8
“J Am Coll Cardiol (2011) 58(7):749–51.”
Self-citationQuantitative Cardiac Positron Emission Tomography: The Time Is Coming!
Sciagrà, R. (2012) · Scientifica · doi:10.6064/2012/948653 · Cited by 7
“e abnormal MBF and CFR response to CPT has been shown to have prognostic implications [170].”
BackgroundStuijfzand, W. J., Raijmakers, P. G. H. M., Driessen, R. S., Lammertsma, A. A., van Rossum, A. C., Nap, A., Appelman, Y., Lemkes, J. S., van Leeuwen, M. A. H., van Royen, N., et al. (2016) · EuroIntervention · doi:10.4244/eijv12i5a98 · Cited by 7
Horigome, M., Kumazaki, S., Hattori, N., Kasai, H., Horigome, M., Aizawa, K., Izawa, A., Tomita, T., Tsutsui, H., Koyama, J., et al. (2009) · Cardiology · doi:10.1159/000226093 · Cited by 7
“confirmed the repeatability and feasibility of this noninvasive method for the evaluation of endothelial function. They also demonstrated that the increase in MBF during CPT tended to be independently associated with a higher incidence of cardiovascular events [”
MethodEvolving strategies for the treatment of microvascular angina in women
Duvernoy, C. S. (2012) · Expert Review of Cardiovascular Therapy · doi:10.1586/erc.12.55 · Cited by 7
Croteau, É., Renaud, J. M., Archer, C., Klein, R., DaSilva, J. N., Ruddy, T. D., Beanlands, R. S., & deKemp, R. A. (2014) · EJNMMI Research · doi:10.1186/s13550-014-0068-9 · Cited by 7
Guehl, N. J., Pelletier‐Galarneau, M., Wooten, D., Guerrero, J., Kas, A., Normandin, M. D., Fakhri, G. E., & Alpert, N. M. (2020) · Circulation Cardiovascular Imaging · doi:10.1161/circimaging.119.009407 · Cited by 7
Myocardial Perfusion Reserve in Ischemic Heart Disease
Neglia, D., & L’Abbate, A. (2009) · Journal of Nuclear Medicine · doi:10.2967/jnumed.108.056317 · Cited by 7
Cardiac PET/Computed Tomography Applications and Cardiovascular Outcome
Schindler, T. H. (2015) · PET Clinics · doi:10.1016/j.cpet.2015.03.009 · Cited by 6
“Aswas initially noted, a dysfunction of the coronary endothelium in individuals with cardiovascular risk but with normal coronary angiograms, as determined with PET-measured flow responses to sympathetic stimulation with CPT and its MFR, was associated with a higher risk for cardiovascular events compared with those i…”
ResultSelf-citationEsteves, F. P., & Travin, M. I. (2014) · Seminars in Nuclear Medicine · doi:10.1053/j.semnuclmed.2014.06.002 · Cited by 5
Why Quantify Myocardial Perfusion?
Gaemperli, O., & Kaufmann, P. A. (2012) · Current Cardiovascular Imaging Reports · doi:10.1007/s12410-012-9130-z · Cited by 5
“(2005) [110] 72 Cardiovascular risk factors CPT-induced MBF increase with (13)N-NH3 PET Cardiovascular death, ACS, MI, PTCA, CABG, stroke, PTA 66±8 months Yes No”
MethodClinical Application of Myocardial Blood Flow Quantification in CAD Patients
Schindler, T. H., Marashdeh, W. M., & Sólnes, L. B. (2016) · Annals of Nuclear Cardiology · doi:10.17996/anc.02.01.84 · Cited by 5
“W ith the advent of positron emission tomography/computed tomography (PET/CT) assessment of myocardial perfusion in concert with myocardial blood flow (MBF) quantification in ml/g/min a comprehensive and non-invasive characterization from subclinical to clinically-manifest stages of the CAD process has become possible…”
BackgroundSelf-citationBorrazzo, C., Galea, N., Pacilio, M., Altabella, L., Preziosi, E., Carnì, M., Ciolina, F., Vullo, F., Francone, M., Catalano, C., et al. (2017) · Physics in Medicine and Biology · doi:10.1088/1361-6560/aaa2a8 · Cited by 5
Renaud, J. M., Al-Mallah, M. H., Soman, P., deKemp, R. A., Beanlands, R. S., Arumugam, P., Armstrong, I. S., Prior, J. O., Madamanchi, C., Goonewardena, S. N., et al. (2024) · Journal of Nuclear Cardiology · doi:10.1016/j.nuclcard.2024.102023 · Cited by 5
Issues in quantification of cardiac PET studies
de Jong, H. W. A. M., & Lubberink, M. (2006) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-006-0283-3 · Cited by 5
“response to medical or interventional therapy is necessary [16] and, in addition, it may permit early detection of CAD in asymptomatic patients with risk factors [17, 18].”
BackgroundNuclear cardiology needs new “blood”
Saraste, A., Nekolla, S. G., & Schwaiger, M. (2009) · Journal of Nuclear Cardiology · doi:10.1007/s12350-009-9055-3 · Cited by 5
“In the absence of angiographically detectable coronary stenosis, abnormal CFR and response to sympathetic stimulation are markers of early alterations of vascular reactivity.(9,10) They may permit early detection of CAD in individuals with coronary risk factors, such as such as hypertension, smoking, hyperlipidemia, a…”
BackgroundHighlights of the Year in JACC2005
DeMaria, A. N., Ben‐Yehuda, O., Berman, D. S., Feld, G. K., Ginsburg, G. S., Greenberg, B., Lew, W. Y. W., Sahn, D. J., & Tsimikas, S. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.11.020 · Cited by 5
Gibbons, R. J., & Araoz, P. A. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.05.065 · Cited by 5
Metadata
- Authors
- Schindler, T. H., Nitzsche, E. U., Schelbert, H. R., Olschewski, M., Sayre, J., Mix, M., Brink, I., Zhang, X.-L., Kreissl, M., Magosaki, N., Just, H., & Solzbach, U.
- Affiliations
- University of Freiburg (DE)
- University of Basel (CH)
- University of California, Los Angeles (US)
- Corresponding author
- Schindler, Thomas H.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2005-05
- Volume
- 45
- Issue
- 9
- Pages
- 1505-1512
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W2064009926
- Cited by
- 149
- References
- 29
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 14 · 2014: 14 · 2013: 4 · 2012: 10
- FWCI
- 6.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Heart, Lung, and Blood Institute (HL-331777)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Coronary Interventions and Diagnostics
- Keywords
- myocardial blood flow, cold pressor test, sympathetic stimulation, coronary vasomotor function, endothelial dysfunction, cardiovascular events, 13N-ammonia PET, cardiovascular risk prediction, stroke, myocardial ischemia, coronary artery disease prognosis, follow-up outcomes, acute coronary syndrome, myocardial infarction
- MeSH terms
- Ammonia, Blood Flow Velocity, California, Coronary Artery Disease, Coronary Circulation, Female, Germany, Humans, Male, Middle Aged, Myocardial Infarction, Nitrogen Radioisotopes, Prospective Studies, Switzerland, Incidence, Survival Analysis, Coronary Angiography, Radiopharmaceuticals, Positron-Emission Tomography
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