- Email: [email protected]
Reporter Gene Imaging Following Percutaneous Delivery in Swine
Journal of the American College of Cardiology © 2008 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 51, No. 5, 2008 ISSN 0735-1097/08/$34.00
CORRESPONDENCE
Research Correspondence
Reporter Gene Imaging Following Percutaneous Delivery in Swine Moving Toward Clinical Applications
To the Editor: Noninvasive monitoring of cardiac gene therapy is critical to fully understand the biology of gene therapy in living subjects. We and others have monitored reporter gene expression in the myocardium of small (1) and large (2) animals (reviewed in reference 3). However, before these strategies are translated to the clinic, it is critical that they be tested using minimally invasive gene delivery approaches similar to those used clinically. We tested the hypothesis that reporter genes can be delivered using a minimally invasive strategy to the myocardium of a swine, and expression can then be imaged using combined positron emission tomography-computed tomography (PET-CT). Stanford’s Animal Care and Use Committee approved all procedures. Six domestic pigs (Pork Power Farms, Turlock, California) were used in the study. With sterile technique, 8-F vascular sheaths placed in the carotid arteries were used for vascular access. Percutaneous endomyocardial delivery systems (Biocardia, Inc., South San Francisco, California) (Fig. 1, left panel), placed into the sheaths, were used for fluoroscopy-guided delivery of genes (1010 plaque-forming units) or vehicle (phosphate-buffered
Figure 1
saline [PBS]) (Fig. 1, right panel) in 3 doses of 0.2 cc each. Central mean arterial pressure (MAP) was measured. Fortyeight hours after gene delivery, animals were dynamically imaged after intravenous administration of 18F-labeled 9-[4-fluoro-3(hydroxymethyl)butyl]guanine (18F-FHBG; tracer) (4) using a clinical combined PET-CT system (Discovery LS, GE Medical Systems, Milwaukee, Wisconsin) for a total scanning time of 180 min. Data are expressed as mean ⫾ SEM. There were no significant differences in weight (control, 37.4 ⫾ 0.4 kg; gene therapy, 36.3 ⫾ 0.7 kg; p ⫽ NS), MAP (control, 107 ⫾ 11 mm Hg; gene therapy, 111 ⫾ 14 mm Hg; p ⫽ NS), or heart rate (control, 90 ⫾ 7 beats/min; gene therapy, 95 ⫾ 9 beats/min; p ⫽ NS) between the 2 groups. There was no morbidity or mortality associated with the procedures. A total of 9.37 ⫾ 1.31 mCi of 18F-FHBG (in 5 ml of PBS) was administered per animal. Figure 2 (top panel, A to D) shows a representative PET-CT scan of the gene therapy group. The CT images (Fig. 2A, top panel) were used for anatomic localization, and 18F-FHBG uptake (Fig. 2B, top panel) was located in the area into which gene
Fluoroscopy-Guided Delivery of Genes
(Left) Percutaneous delivery system consisting of (A) steerable-guiding catheter and (B) helical needle infusion catheter. A steerable catheter provides maximum flexibility, allowing catheter positioning in virtually any area of the left ventricular cavity. The infusion catheter is used first to confirm intramyocardial positioning of the catheter and then for the delivery of therapeutic material. (C) The infusion catheter is “screwed’ inside the myocardium. (Right) Representative image of gene delivery in a swine model. A left ventricular angiogram is performed for delineation of the left ventricular endocardial contour (D). Intramyocardial positioning of the helical catheter is confirmed using contrast media (E), and gene therapy is then delivered.
596
Correspondence
JACC Vol. 51, No. 5, 2008 February 5, 2008:595–8
methods (e.g., intracoronary) may be more useful if the target area is a larger myocardial region or a specific coronary distribution. Adenoviral infection results in strong, albeit relatively shortlived, transgene expression (6). For performing long-term longitudinal monitoring of therapy, other reporter gene strategies will be needed, such as adeno-associated or gutless adenovirus (7,8). PET has nanomolar to picomolar (10⫺12 mol/l) sensitivity and tomographic capabilities, which makes PET the most suitable imaging modality for use in living subjects (compared with magnetic resonance and single photon emission-computed tomography) (9). Based on this study, 3 h after tracer administration appears to be a good time point for assessment of 18F-FHBG uptake in the myocardium. These studies will play a critical role in the monitoring of gene therapy first in pre-clinical large animal models of cardiac disease and then in clinical therapeutic trials. Martin Rodriguez-Porcel, MD Todd J. Brinton, MD Ian Y. Chen, MSE Olivier Gheysens, MD Jennifer Lyons Fumiaki Ikeno, MD Jürgen K. Willmann, MD Lily Wu, MD, PhD Joseph C. Wu, MD, PhD Alan C. Yeung, MD Paul Yock, MD *Sanjiv Sam Gambhir, MD, PhD Figure 2
Representative Positron Emission Tomography (PET) Computed Tomography (CT)
(Top) Image of gene therapy 48 h after percutaneous gene delivery (A to D). (Bottom) Uptake of 18F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (standardized uptake value [SUV]) in (E) control (n ⫽ 2) and (F) gene therapy (n ⫽ 4) groups. *p ⬍ 0.05 compared to region of interest (ROI) (red circle). A ⫽ anterior; B ⫽ bladder; CL ⫽ contralateral; I ⫽ intestines; K ⫽ kidney; L ⫽ left; Li ⫽ liver; LV ⫽ left ventricular; P ⫽ posterior; R ⫽ right.
therapy was delivered (anteroseptum) (Fig. 2C, top panel). Wholebody images (Fig. 2D, top panel) clearly showed the cardiac uptake in chest and abdominal structures. Animals from both groups had comparable 18F-FHBG uptake in paraspinal muscles and the nondelivered myocardial wall (Figs. 2E and 2F). Whereas control animals showed no distinct myocardial tracer uptake, experimental animals had significantly increased (p ⬍ 0.05) 18F-FHBG uptake (Figs. 2E and 2F, respectively). The best myocardial signal/background (left ventricular) ratio was obtained 3 h post-injection (180 min, 4.63 ⫾ 1.4 vs. 90 min, 1.78 ⫾ 0.6; p ⬍ 0.05). Autoradiography and microPET confirmed the increased 18F-FHBG uptake in the anteroseptum of the gene therapy animals. Many different delivery methods have been developed for percutaneous cardiac delivery of gene therapy. The helical needle injection catheter system, used in this study, has the theoretic advantages of endocardial engagement and helical needle-track and has been shown to have good acute delivery success and retention (5). This delivery method has been designed to deliver material (e.g., genes, cells) to a specific and delimited area. Multiple injections or vascular-based delivery
*Stanford University School of Medicine Bio-X Program, Departments of Radiology and Bioengineering The James H. Clark Center 318 Campus Drive, Clark E150 Stanford, California 94305-5427 E-mail: [email protected] doi:10.1016/j.jacc.2007.08.063 Please note: this study was supported by grants NCI SAIRP (to Dr. Gambhir), NHLBI R01 HL078632 (to Dr. Gambhir), NCI ICMIC CA114747 P50 (to Dr. Gambhir), NHLBI R21HL089027 (to Dr. Wu), and the Mayo Clinical Scholarship Program, Mayo Clinic College of Medicine, Rochester, Minnesota (to Dr. Rodriguez-Porcel). The authors thank Olin Palmer and Daniel Rosenman from BioCardia, Inc., for their technical assistance with the catheter delivery system and the Stanford cyclotron team (Dr. Fren Chin and Dr. David Dick) for 18F-FHBG production.
REFERENCES
1. Wu JC, Chen IY, Wang Y, et al. Molecular imaging of the kinetics of vascular endothelial growth factor gene expression in ischemic myocardium. Circulation 2004;110:685–91. 2. Bengel FM, Anton M, Richter T, et al. Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 2003;108:2127–33. 3. Wu JC, Tseng JR, Gambhir SS. Molecular imaging of cardiovascular gene products. J Nucl Cardiol 2004;11:491–505. 4. Yaghoubi S, Barrio JR, Dahlbom M, et al. Human pharmacokinetic and dosimetry studies of [18F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med 2001;42:1225–34. 5. Hou D, Youssef EA, Brinton TJ, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 2005;12 Suppl 9:I150 – 6.
Correspondence
JACC Vol. 51, No. 5, 2008 February 5, 2008:595–8 6. Min JJ, Iyer M, Gambhir SS. Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection. Eur J Nucl Med Mol Imaging 2003;30:1547– 60. 7. Yant SR, Ehrhardt A, Mikkelsen JG, Meuse L, Pham T, Kay MA. Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo. Nat Biotechnol 2002;20:999 –1005.
597
8. Zou L, Zhou H, Pastore L, Yang K. Prolonged transgene expression mediated by a helper-dependent adenoviral vector (hdAd) in the central nervous system. Mol Ther 2000;2:105–13. 9. Bengel FM, Schachinger V, Dimmeler S. Cell-based therapies and imaging in cardiology. Eur J Nucl Med Mol Imaging 2005;32 Suppl 2:S404 –16.
Letters to the Editor
Relationship Between Coronary Microcirculatory Function and Aortic Stiffness in Diabetes I read with great interest the paper by Cortigiani et al. (1). This intriguing study confirmed that coronary flow reserve (CFR) provides independent prognostic information in diabetic and nondiabetic patients with known or suspected coronary artery disease (CAD) and negative dipyridamole stress echocardiography. I feel that a few additional comments are necessary. It is well known that aortic distensibility and CFR as characteristics of coronary microcirculatory function are reduced in diabetes mellitus (DM) (2). Moreover, aortic stiffening may lead to early pulse wave reflection, causing an increase in central systolic blood pressure (BP), a decrease in diastolic BP, and an increase in pulse pressure. The elevation in systolic BP increases myocardial oxygen demand, reduces left ventricular ejection fraction, increases ventricular overload, and induces left ventricular hypertrophy. Because myocardial blood supply depends largely on pressure throughout diastole and the duration of diastole, the contemporary decrease in diastolic BP can compromise coronary perfusion, resulting in subendocardial ischemia (3). Reduction in CFR was found in patients with increased aortic stiffness compared with age-, gender-, and risk factor-matched controls with normal aortic distensibility (4). These findings direct our attention to consider aortic stiffness as an important parameter affecting coronary hemodynamics. The prognostic role of CFR and DM in patients with known or suspected CAD has been confirmed, demonstrating that both variables are independently predictive of cardiovascular survival (5). In recent studies, it has been demonstrated that CFR and indices describing aortic distensibility can be measured simultaneously by echocardiography, helping us better understand their relationship to each other (4,6). To see whether aortic distensibility could add predictive value, patients with and without CAD were examined (7,8). It was found in patients with CAD that aortic distensibility did not offer any added information in predicting cardiovascular survival. The potential complementary prognostic value of aortic distensibility for prediction of cardiovascular mortality over CFR was found in patients without CAD and abnormal CFR, which should be the topic of future research (8). Interestingly, the number of studies evaluating the relationship between CFR and aortic stiffness in DM is limited (2,9,10). Alterations were found in CFR and aortic distensibility indices with correlations in diabetic patients with normal epicardial coronary arteries (2). In diabetic versus nondiabetic patients with
CAD, aortic distensibility was reduced, but CFR was similar (9). Moreover, patients with aortic valve stenosis and type 2 DM had similar CFR and aortic distensibility indices compared with nondiabetic patients with aortic valve stenosis (10). It should be considered that theoretically the echocardiographic evaluation of aortic distensibility simultaneously with CFR measurement is a relatively easy and patient-friendly method. Further investigations are warranted to examine the direct effect of aortic stiffness on coronary perfusion, especially in patients with DM. Furthermore, studies should evaluate the effect of antidiabetic drugs on coronary perfusion and aortic elasticity as well. Finally, studies evaluating the prognostic role of a combination of indices characterizing aortic distensibility and CFR in DM are warranted. *Attila Nemes, MD, PhD, FESC *Second Department of Medicine and Cardiology Center Medical Faculty University of Szeged P.O. Box 427 H-6720 Szeged, Kora´nyi fasor 6 Hungary E-mail: [email protected] doi:10.1016/j.jacc.2007.10.026 REFERENCES
1. Cortigiani L, Rigo F, Gherardi S, et al. Additional prognostic value of coronary flow reserve in diabetic and nondiabetic patients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol 2007;50:1354 – 61. 2. Nemes A, Forster T, Csanady M. Reduced aortic distensibility and coronary flow velocity reserve in diabetes mellitus patients with a negative coronary angiogram. Can J Cardiol 2007;23:445–50. 3. Belz GG. Elastic properties and Windkessel function of the human aorta. Cardiovasc Drugs Ther 1995;9:73– 83. 4. Nemes A, Forster T, Csanady M. Reduction in coronary flow reserve in patients with increased aortic stiffness. Can J Physiol Pharmacol 2007;85:818 –22. 5. Nemes A, Forster T, Geleijnse ML, et al. The additional prognostic power of diabetes mellitus on coronary flow reserve in patients with suspected coronary artery disease. Diabetes Res Clin Pract 2007;78: 126 –31. 6. Nemes A, Forster T, Csanady M. Relationship between coronary flow velocity reserve and aortic stiffness. Am J Physiol Heart Circ Physiol 2006;290:H1311. 7. Nemes A, Geleijnse ML, Soliman OI, ten Cate FJ. Prognostic role of combination of coronary flow reserve with aortic distensibility indices. Eur Heart J 2006;27:2607– 8. 8. Nemes A, Forster T, Geleijnse ML, et al. Prognostic value of coronary flow reserve and aortic distensibility indices in patients with suspected coronary artery disease. Heart Vessels 2008. In press.
Vol. 51, No. 5, 2008 ISSN 0735-1097/08/$34.00
CORRESPONDENCE
Research Correspondence
Reporter Gene Imaging Following Percutaneous Delivery in Swine Moving Toward Clinical Applications
To the Editor: Noninvasive monitoring of cardiac gene therapy is critical to fully understand the biology of gene therapy in living subjects. We and others have monitored reporter gene expression in the myocardium of small (1) and large (2) animals (reviewed in reference 3). However, before these strategies are translated to the clinic, it is critical that they be tested using minimally invasive gene delivery approaches similar to those used clinically. We tested the hypothesis that reporter genes can be delivered using a minimally invasive strategy to the myocardium of a swine, and expression can then be imaged using combined positron emission tomography-computed tomography (PET-CT). Stanford’s Animal Care and Use Committee approved all procedures. Six domestic pigs (Pork Power Farms, Turlock, California) were used in the study. With sterile technique, 8-F vascular sheaths placed in the carotid arteries were used for vascular access. Percutaneous endomyocardial delivery systems (Biocardia, Inc., South San Francisco, California) (Fig. 1, left panel), placed into the sheaths, were used for fluoroscopy-guided delivery of genes (1010 plaque-forming units) or vehicle (phosphate-buffered
Figure 1
saline [PBS]) (Fig. 1, right panel) in 3 doses of 0.2 cc each. Central mean arterial pressure (MAP) was measured. Fortyeight hours after gene delivery, animals were dynamically imaged after intravenous administration of 18F-labeled 9-[4-fluoro-3(hydroxymethyl)butyl]guanine (18F-FHBG; tracer) (4) using a clinical combined PET-CT system (Discovery LS, GE Medical Systems, Milwaukee, Wisconsin) for a total scanning time of 180 min. Data are expressed as mean ⫾ SEM. There were no significant differences in weight (control, 37.4 ⫾ 0.4 kg; gene therapy, 36.3 ⫾ 0.7 kg; p ⫽ NS), MAP (control, 107 ⫾ 11 mm Hg; gene therapy, 111 ⫾ 14 mm Hg; p ⫽ NS), or heart rate (control, 90 ⫾ 7 beats/min; gene therapy, 95 ⫾ 9 beats/min; p ⫽ NS) between the 2 groups. There was no morbidity or mortality associated with the procedures. A total of 9.37 ⫾ 1.31 mCi of 18F-FHBG (in 5 ml of PBS) was administered per animal. Figure 2 (top panel, A to D) shows a representative PET-CT scan of the gene therapy group. The CT images (Fig. 2A, top panel) were used for anatomic localization, and 18F-FHBG uptake (Fig. 2B, top panel) was located in the area into which gene
Fluoroscopy-Guided Delivery of Genes
(Left) Percutaneous delivery system consisting of (A) steerable-guiding catheter and (B) helical needle infusion catheter. A steerable catheter provides maximum flexibility, allowing catheter positioning in virtually any area of the left ventricular cavity. The infusion catheter is used first to confirm intramyocardial positioning of the catheter and then for the delivery of therapeutic material. (C) The infusion catheter is “screwed’ inside the myocardium. (Right) Representative image of gene delivery in a swine model. A left ventricular angiogram is performed for delineation of the left ventricular endocardial contour (D). Intramyocardial positioning of the helical catheter is confirmed using contrast media (E), and gene therapy is then delivered.
596
Correspondence
JACC Vol. 51, No. 5, 2008 February 5, 2008:595–8
methods (e.g., intracoronary) may be more useful if the target area is a larger myocardial region or a specific coronary distribution. Adenoviral infection results in strong, albeit relatively shortlived, transgene expression (6). For performing long-term longitudinal monitoring of therapy, other reporter gene strategies will be needed, such as adeno-associated or gutless adenovirus (7,8). PET has nanomolar to picomolar (10⫺12 mol/l) sensitivity and tomographic capabilities, which makes PET the most suitable imaging modality for use in living subjects (compared with magnetic resonance and single photon emission-computed tomography) (9). Based on this study, 3 h after tracer administration appears to be a good time point for assessment of 18F-FHBG uptake in the myocardium. These studies will play a critical role in the monitoring of gene therapy first in pre-clinical large animal models of cardiac disease and then in clinical therapeutic trials. Martin Rodriguez-Porcel, MD Todd J. Brinton, MD Ian Y. Chen, MSE Olivier Gheysens, MD Jennifer Lyons Fumiaki Ikeno, MD Jürgen K. Willmann, MD Lily Wu, MD, PhD Joseph C. Wu, MD, PhD Alan C. Yeung, MD Paul Yock, MD *Sanjiv Sam Gambhir, MD, PhD Figure 2
Representative Positron Emission Tomography (PET) Computed Tomography (CT)
(Top) Image of gene therapy 48 h after percutaneous gene delivery (A to D). (Bottom) Uptake of 18F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (standardized uptake value [SUV]) in (E) control (n ⫽ 2) and (F) gene therapy (n ⫽ 4) groups. *p ⬍ 0.05 compared to region of interest (ROI) (red circle). A ⫽ anterior; B ⫽ bladder; CL ⫽ contralateral; I ⫽ intestines; K ⫽ kidney; L ⫽ left; Li ⫽ liver; LV ⫽ left ventricular; P ⫽ posterior; R ⫽ right.
therapy was delivered (anteroseptum) (Fig. 2C, top panel). Wholebody images (Fig. 2D, top panel) clearly showed the cardiac uptake in chest and abdominal structures. Animals from both groups had comparable 18F-FHBG uptake in paraspinal muscles and the nondelivered myocardial wall (Figs. 2E and 2F). Whereas control animals showed no distinct myocardial tracer uptake, experimental animals had significantly increased (p ⬍ 0.05) 18F-FHBG uptake (Figs. 2E and 2F, respectively). The best myocardial signal/background (left ventricular) ratio was obtained 3 h post-injection (180 min, 4.63 ⫾ 1.4 vs. 90 min, 1.78 ⫾ 0.6; p ⬍ 0.05). Autoradiography and microPET confirmed the increased 18F-FHBG uptake in the anteroseptum of the gene therapy animals. Many different delivery methods have been developed for percutaneous cardiac delivery of gene therapy. The helical needle injection catheter system, used in this study, has the theoretic advantages of endocardial engagement and helical needle-track and has been shown to have good acute delivery success and retention (5). This delivery method has been designed to deliver material (e.g., genes, cells) to a specific and delimited area. Multiple injections or vascular-based delivery
*Stanford University School of Medicine Bio-X Program, Departments of Radiology and Bioengineering The James H. Clark Center 318 Campus Drive, Clark E150 Stanford, California 94305-5427 E-mail: [email protected] doi:10.1016/j.jacc.2007.08.063 Please note: this study was supported by grants NCI SAIRP (to Dr. Gambhir), NHLBI R01 HL078632 (to Dr. Gambhir), NCI ICMIC CA114747 P50 (to Dr. Gambhir), NHLBI R21HL089027 (to Dr. Wu), and the Mayo Clinical Scholarship Program, Mayo Clinic College of Medicine, Rochester, Minnesota (to Dr. Rodriguez-Porcel). The authors thank Olin Palmer and Daniel Rosenman from BioCardia, Inc., for their technical assistance with the catheter delivery system and the Stanford cyclotron team (Dr. Fren Chin and Dr. David Dick) for 18F-FHBG production.
REFERENCES
1. Wu JC, Chen IY, Wang Y, et al. Molecular imaging of the kinetics of vascular endothelial growth factor gene expression in ischemic myocardium. Circulation 2004;110:685–91. 2. Bengel FM, Anton M, Richter T, et al. Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 2003;108:2127–33. 3. Wu JC, Tseng JR, Gambhir SS. Molecular imaging of cardiovascular gene products. J Nucl Cardiol 2004;11:491–505. 4. Yaghoubi S, Barrio JR, Dahlbom M, et al. Human pharmacokinetic and dosimetry studies of [18F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med 2001;42:1225–34. 5. Hou D, Youssef EA, Brinton TJ, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 2005;12 Suppl 9:I150 – 6.
Correspondence
JACC Vol. 51, No. 5, 2008 February 5, 2008:595–8 6. Min JJ, Iyer M, Gambhir SS. Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection. Eur J Nucl Med Mol Imaging 2003;30:1547– 60. 7. Yant SR, Ehrhardt A, Mikkelsen JG, Meuse L, Pham T, Kay MA. Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo. Nat Biotechnol 2002;20:999 –1005.
597
8. Zou L, Zhou H, Pastore L, Yang K. Prolonged transgene expression mediated by a helper-dependent adenoviral vector (hdAd) in the central nervous system. Mol Ther 2000;2:105–13. 9. Bengel FM, Schachinger V, Dimmeler S. Cell-based therapies and imaging in cardiology. Eur J Nucl Med Mol Imaging 2005;32 Suppl 2:S404 –16.
Letters to the Editor
Relationship Between Coronary Microcirculatory Function and Aortic Stiffness in Diabetes I read with great interest the paper by Cortigiani et al. (1). This intriguing study confirmed that coronary flow reserve (CFR) provides independent prognostic information in diabetic and nondiabetic patients with known or suspected coronary artery disease (CAD) and negative dipyridamole stress echocardiography. I feel that a few additional comments are necessary. It is well known that aortic distensibility and CFR as characteristics of coronary microcirculatory function are reduced in diabetes mellitus (DM) (2). Moreover, aortic stiffening may lead to early pulse wave reflection, causing an increase in central systolic blood pressure (BP), a decrease in diastolic BP, and an increase in pulse pressure. The elevation in systolic BP increases myocardial oxygen demand, reduces left ventricular ejection fraction, increases ventricular overload, and induces left ventricular hypertrophy. Because myocardial blood supply depends largely on pressure throughout diastole and the duration of diastole, the contemporary decrease in diastolic BP can compromise coronary perfusion, resulting in subendocardial ischemia (3). Reduction in CFR was found in patients with increased aortic stiffness compared with age-, gender-, and risk factor-matched controls with normal aortic distensibility (4). These findings direct our attention to consider aortic stiffness as an important parameter affecting coronary hemodynamics. The prognostic role of CFR and DM in patients with known or suspected CAD has been confirmed, demonstrating that both variables are independently predictive of cardiovascular survival (5). In recent studies, it has been demonstrated that CFR and indices describing aortic distensibility can be measured simultaneously by echocardiography, helping us better understand their relationship to each other (4,6). To see whether aortic distensibility could add predictive value, patients with and without CAD were examined (7,8). It was found in patients with CAD that aortic distensibility did not offer any added information in predicting cardiovascular survival. The potential complementary prognostic value of aortic distensibility for prediction of cardiovascular mortality over CFR was found in patients without CAD and abnormal CFR, which should be the topic of future research (8). Interestingly, the number of studies evaluating the relationship between CFR and aortic stiffness in DM is limited (2,9,10). Alterations were found in CFR and aortic distensibility indices with correlations in diabetic patients with normal epicardial coronary arteries (2). In diabetic versus nondiabetic patients with
CAD, aortic distensibility was reduced, but CFR was similar (9). Moreover, patients with aortic valve stenosis and type 2 DM had similar CFR and aortic distensibility indices compared with nondiabetic patients with aortic valve stenosis (10). It should be considered that theoretically the echocardiographic evaluation of aortic distensibility simultaneously with CFR measurement is a relatively easy and patient-friendly method. Further investigations are warranted to examine the direct effect of aortic stiffness on coronary perfusion, especially in patients with DM. Furthermore, studies should evaluate the effect of antidiabetic drugs on coronary perfusion and aortic elasticity as well. Finally, studies evaluating the prognostic role of a combination of indices characterizing aortic distensibility and CFR in DM are warranted. *Attila Nemes, MD, PhD, FESC *Second Department of Medicine and Cardiology Center Medical Faculty University of Szeged P.O. Box 427 H-6720 Szeged, Kora´nyi fasor 6 Hungary E-mail: [email protected] doi:10.1016/j.jacc.2007.10.026 REFERENCES
1. Cortigiani L, Rigo F, Gherardi S, et al. Additional prognostic value of coronary flow reserve in diabetic and nondiabetic patients with negative dipyridamole stress echocardiography by wall motion criteria. J Am Coll Cardiol 2007;50:1354 – 61. 2. Nemes A, Forster T, Csanady M. Reduced aortic distensibility and coronary flow velocity reserve in diabetes mellitus patients with a negative coronary angiogram. Can J Cardiol 2007;23:445–50. 3. Belz GG. Elastic properties and Windkessel function of the human aorta. Cardiovasc Drugs Ther 1995;9:73– 83. 4. Nemes A, Forster T, Csanady M. Reduction in coronary flow reserve in patients with increased aortic stiffness. Can J Physiol Pharmacol 2007;85:818 –22. 5. Nemes A, Forster T, Geleijnse ML, et al. The additional prognostic power of diabetes mellitus on coronary flow reserve in patients with suspected coronary artery disease. Diabetes Res Clin Pract 2007;78: 126 –31. 6. Nemes A, Forster T, Csanady M. Relationship between coronary flow velocity reserve and aortic stiffness. Am J Physiol Heart Circ Physiol 2006;290:H1311. 7. Nemes A, Geleijnse ML, Soliman OI, ten Cate FJ. Prognostic role of combination of coronary flow reserve with aortic distensibility indices. Eur Heart J 2006;27:2607– 8. 8. Nemes A, Forster T, Geleijnse ML, et al. Prognostic value of coronary flow reserve and aortic distensibility indices in patients with suspected coronary artery disease. Heart Vessels 2008. In press.