International Journal of Cardiology 187 (2015) 229–230
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Multimodality imaging of myocardial revascularization using cardiac shock wave therapy☆,☆☆ G. Zuoziene a,d, D. Leibowitz b,⁎, J. Celutkiene a, G. Burneikaite a, L. Ivaskeviciene a, G. Kalinauskas a, V.V. Maneikiene a, D. Palionis c, V. Janusauskas a, N. Valeviciene c, A. Laucevicius a,d a
Vilnius University, Clinic of Cardiac and Vascular Diseases, Vilnius, Lithuania Coronary Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Vilnius University, Center of Radiology and Nuclear Medicine, Vilnius, Lithuania d Center for Innovative Medicine, Vilnius, Lithuania b c
a r t i c l e
i n f o
Article history: Received 17 March 2015 Accepted 19 March 2015 Available online 20 March 2015 Keywords: Myocardial ischemia Revascularization Cardiac imaging
Ischemic heart disease remains a leading cause of morbidity and mortality worldwide. Despite modern therapies, many patients still suffer from refractory angina pectoris (RAP) therefore, alternative non-invasive revascularization methods are under development. One of the methods stimulating angiogenesis is cardiac shock wave therapy (CSWT), a new treatment method offering an alternative to revascularization. Recent studies have demonstrated that the extracorporeal application of low-intensity shockwaves to the myocardium may induce the release of angiogenesis-mediating growth factors such as endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF), as well as induce the recruitment of endothelial progenitor cells [1–4]. This non-invasive treatment method has been used clinically and been shown to improve symptoms and improve perfusion, however, limited data are available on the use of multimodality imaging in patients undergoing this therapy [5–7]. The objective of the current study was to utilize multimodality imaging including cardiac ☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Dr. Leibowitz has received minor consulting fees and travel expenses from Medispec LTD. (Manufacturer of CSWT equipment used). Medispec Ltd. has had no role in the funding or preparation of this manuscript. None of the other authors have any competing interests to report. ⁎ Corresponding author at: Coronary Care Unit, Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem 91240, Israel. E-mail address: [email protected] (D. Leibowitz).
http://dx.doi.org/10.1016/j.ijcard.2015.03.306 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
MRI for the selection of patients and evaluation of dynamic changes of LV function during CSWT therapy. Participation in the study was offered to patients with a diagnosis of Canadian Cardiovascular Society (CCS) classes III–IV angina pectoris. Patients over 18 years of age were enrolled into the study after giving consent. The institutional review board approved the study. The participants had to have documented ischemia on non-invasive imaging and were required to have been on a stable medical regimen for at least 6 weeks. Echocardiographic examination with dobutamine was used to evaluate myocardial viability. Total number of segments with myocardial perfusion defects was assessed using SPECT. Participants underwent repeat dobutamine echocardiography and SPECT imaging following treatment as well. The presence of transient ischemic dilatation (TID) was quantitatively assessed. Participants also underwent assessment of cardiac function (left ventricle volumes, ejection fraction and stroke volume) by MRI before and following CSWT therapy. All the cardiac MRI examinations were performed using a 1.5 T MR scanner (Avanto, Siemens Medical Solutions, Erlangen, Germany). All cMRI evaluations were performed by two experienced observers who were blinded as to whether the MRI was before or after treatment. Coronary angiography was performed in all patients before treatment. Patients with three vessel disease with significant (N70% diameter) stenosis not suitable for revascularization were eligible while patients with LV EF b 40% were excluded from the study. CSWT was performed as previously outlined [5]. In brief, ischemic zones identified by previous noninvasive evaluation, which were targets for CSWT therapy were located by echocardiography. Areas of scarring identified by cMRI were not treated. 100 impulses were applied to one zone with up to 500 total impulses to the patient during a single session. Shockwaves were delivered non-invasively and focused by a special ellipsoid reflector. CSWT treatments during the first week were carried every second day. A three-week treatment-free interval was required after the first week of treatment. During week 5, procedures were carried out every second week (5 zones, 100 impulses for each). The three-week treatment-free interval was again kept and procedures were repeated on week 9 following the same schedule. To evaluate the effect of CSWT all tests including dobutamine echo stress test, echocardiography, cardiac magnetic resonance imaging and
230
G. Zuoziene et al. / International Journal of Cardiology 187 (2015) 229–230
Table 1 Patient demographics and characteristics.
Table 2 Comparison of parameters before and after treatment. Totala (n = 40)
Age Gender (F/M) MI 1 MI 2 MI 3 MI At least 1 aortocoronary bypass surgery 2 aortocoronary bypass surgeries Previous PCI 1 PCI 2 PCI 17 PCI With cardiac pacemaker Diabetes Arterial hypertension Angina pectoris prior to CSWT Class 3 Class 4
67.73 ± 9.45 (44–83) 25%/75% (10/30) 70% (28) 60% (24) 7.5% (3) 2.5% (1) 77.5% (31) 17.5% (7) 45% (18) 30% (12) 12.5% (5) 2.5% (1) 7.5% (3) 22.5% (9) 95% (34) 67.5% (27) 32.5% (13)
MI = myocardial infarction. PCI = percutaneous coronary intervention. CSWT = cardiac shock wave therapy. a Continuous variables: mean ± SD (range); categorical variables: percent (n).
myocardial perfusion radionuclide computer tomography (SPECT) were repeated after six months. The statistical software package SPSS 17.0 (version for Windows) was used for the data analysis. 40 patients with disease in all 3 coronary arteries were enrolled into the study. Clinical characteristics are described in Table 1. CSWT was well tolerated in all subjects. Following treatment with CSWT, a statistically significant difference was detected for the majority of clinical and imaging parameters examined (Table 2). Nitrate consumption decreased by 28.77 tablets, on average, per week (p b 0.001). Changes in ejection fraction of the left ventricle with regards to normal (LV EF 56–78%) values were statistically significant: ejection fraction improved to normal in 10 subjects out of 23, while abnormal values were reported in only 1 patient who had normal values before treatment. In this study we utilized multimodality imaging to demonstrate the efficiency of CSWT for the treatment of refractory angina pectoris. Shockwaves consist of acoustic energy that can be transmitted in a liquid medium and focused with a precision of several millimeters to any intended treatment area inside the body. Oi et al. [8] demonstrated in a model of hind limb ischemia in rabbits that shockwaves induced the development of collateral arteries and increased the capillary density in the treated areas. Aicher et al. [4] showed that CSWT facilitated the recruitment of endothelial progenitor cells and improved blood flow recovery as assessed by laser Doppler imaging in a similar model. Nishida et al. [9] examined the effects of shockwave therapy in a porcine model of chronic myocardial ischemia. They demonstrated improvement in LV systolic function, wall thickening fraction, and regional myocardial blood flow. In addition, they also found a significant increase in markers of neovascularization such as VEGF, the VEGF receptor Flt-1, as well as significant growth of capillaries in the ischemic myocardium of the treatment group. The same group showed that early CSWT can improve LV remodeling after acute myocardial infarction and increase the capillary density in the border zone of the ischemic area. Small nonrandomized, nonblinded studies as well as a placebo-controlled study have demonstrated the clinical benefits of shockwave therapy in patients with refractory angina [5,10]. Our trial extends these findings to a larger study group and demonstrates improvement in LV EF by MRI using this therapy. No previous published data about the usage of cMRI for CSWT evaluation was available from other sources when writing this paper.
Nitrates tablets × per week WMSI at rest WMSI max. LV EF LV EDV LV ESV LV SV TID Systolic ABP Diastolic ABP Mean ABP
n
Before treatment
After treatment
p value
40 39 39 37 37 37 37 38 40 40 40
33.6 ± 10.3 1.52 ± 0.45 1.5 ± 0.42 51.42 ± 11.75 138.38 ± 57.64 71.14 ± 50.84 69.19 ± 23.24 1.14 ± 0.11 134.75 ± 16.33 81.63 ± 8.73 99.33 ± 10.41
4.83 ± 4.32 1.4 ± 0.39 1.34 ± 0.39 56.59 ± 12.04 148.37 ± 65.04 72.19 ± 58.19 76.68 ± 22.22 1.07 ± 0.11 130.88 ± 14.76 80 ± 7.51 96.96 ± 8.75
b0.001 b0.001 b0.001 b0.001 0.334 0.555 0.040 b0.001 0.021 0.062 0.012
WMSI = wall motion score index. LV EDV = left ventricular end-diastolic function. LV ESV = left ventricular end-systolic function. LV SV = left ventricular stroke volume. LV EF = left ventricular ejection fraction. TID = transient ischemic dilatation. ABP = arterial blood pressure.
In summary, after CSWT treatment nitrate use was significantly reduced and LV EF as assessed by cardiac MRI significantly improved. WMSI assessed by echocardiography was reduced, and myocardial perfusion by radionuclide computer tomography imaging improved. The use of cardiac MRI to assess changes following CSWT was established for the first time. Larger and preferably blinded studies using comprehensive cardiac imaging are necessary to further evaluate the efficacy of this non-invasive therapy.
Conflict of interest Dr. Leibowitz has received minor consulting fees and travel expenses from Medispec LTD. (Manufacturer of CSWT equipment used). Medispec Ltd. has had no role in the funding or preparation of this manuscript. None of the other authors have any competing interests to report.
References [1] G. Gotte, E. Amelio, S. Russo, E. Marlinghaus, G. Musci, H. Suzuki, Short-time nonenzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock waves treatment, FEBS Lett. 520 (2002) 153–155. [2] S. Mariotto, E. Cavalieri, E. Amelio, A.R. Ciampa, A.C. de Prati, E. Marlinghaus, et al., Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production, Nitric Oxide 12 (2005) 89–96. [3] A.R. Ciampa, A.C. de Prati, E. Amelio, E. Cavalieri, T. Persichini, M. Colasanti, et al., Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves, FEBS Lett. 579 (2005) 6839–6845. [4] A. Aicher, C. Heeschen, K. Sasaki, C. Urbich, A.H. Zeiher, S. Dimmeler, Low-energy shock wave for enhancing recruitment of endothelial progenitor cells, Circulation 114 (2006) 2823–2830. [5] D. Leibowitz, A.T. Weiss, D. Rott, R. Durst, C. Lotan, The efficacy of cardiac shock wave therapy in the treatment of refractory angina: a pilot prospective, randomized, double-blind trial, Int. J. Cardiol. 167 (6) (2013 Sep 10) 3033–3034. [6] K. Ito, Y. Fukumoto, H. Shimokawa, Extracorporeal shock wave therapy as a new and non-invasive angiogenic therapy, Tohoku J. Exp. Med. 219 (2009) 1–9. [7] G. Zuozienė, A. Laucevičius, D. Leibowitz, Extracorporeal shockwave myocardial revascularization improves clinical symptoms and left ventricular function in patients with refractory angina, Coron. Artery Dis. 23 (1) (2012) 62–67. [8] K. Oi, Y. Fukumoto, K. Ito, T. Uwatoku, K. Abe, T. Hizume, et al., Extracorporeal shock wave therapy ameliorates hind limb ischemia in rabbits, Tohoku J. Exp. Med. 214 (2008) 151–158. [9] T. Nishida, H. Shimokawa, K. Oi, H. Tatewaki, T. Uwatoku, K. Abe, et al., Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo, Circulation 110 (2004) 3055–3061. [10] A.A. Khattab, B. Broderson, D. Schuermann-Kuchenbrandt, H. Beurich, R. Tolg, V. Geist, et al., Extracorporeal cardiac shock wave therapy: first experience in everyday practice for the treatment of chronic refractory angina pectoris, Int. J. Cardiol. 121 (2007) 84–85.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Multimodality imaging of myocardial revascularization using cardiac shock wave therapy☆,☆☆ G. Zuoziene a,d, D. Leibowitz b,⁎, J. Celutkiene a, G. Burneikaite a, L. Ivaskeviciene a, G. Kalinauskas a, V.V. Maneikiene a, D. Palionis c, V. Janusauskas a, N. Valeviciene c, A. Laucevicius a,d a
Vilnius University, Clinic of Cardiac and Vascular Diseases, Vilnius, Lithuania Coronary Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Vilnius University, Center of Radiology and Nuclear Medicine, Vilnius, Lithuania d Center for Innovative Medicine, Vilnius, Lithuania b c
a r t i c l e
i n f o
Article history: Received 17 March 2015 Accepted 19 March 2015 Available online 20 March 2015 Keywords: Myocardial ischemia Revascularization Cardiac imaging
Ischemic heart disease remains a leading cause of morbidity and mortality worldwide. Despite modern therapies, many patients still suffer from refractory angina pectoris (RAP) therefore, alternative non-invasive revascularization methods are under development. One of the methods stimulating angiogenesis is cardiac shock wave therapy (CSWT), a new treatment method offering an alternative to revascularization. Recent studies have demonstrated that the extracorporeal application of low-intensity shockwaves to the myocardium may induce the release of angiogenesis-mediating growth factors such as endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF), as well as induce the recruitment of endothelial progenitor cells [1–4]. This non-invasive treatment method has been used clinically and been shown to improve symptoms and improve perfusion, however, limited data are available on the use of multimodality imaging in patients undergoing this therapy [5–7]. The objective of the current study was to utilize multimodality imaging including cardiac ☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Dr. Leibowitz has received minor consulting fees and travel expenses from Medispec LTD. (Manufacturer of CSWT equipment used). Medispec Ltd. has had no role in the funding or preparation of this manuscript. None of the other authors have any competing interests to report. ⁎ Corresponding author at: Coronary Care Unit, Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem 91240, Israel. E-mail address: [email protected] (D. Leibowitz).
http://dx.doi.org/10.1016/j.ijcard.2015.03.306 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
MRI for the selection of patients and evaluation of dynamic changes of LV function during CSWT therapy. Participation in the study was offered to patients with a diagnosis of Canadian Cardiovascular Society (CCS) classes III–IV angina pectoris. Patients over 18 years of age were enrolled into the study after giving consent. The institutional review board approved the study. The participants had to have documented ischemia on non-invasive imaging and were required to have been on a stable medical regimen for at least 6 weeks. Echocardiographic examination with dobutamine was used to evaluate myocardial viability. Total number of segments with myocardial perfusion defects was assessed using SPECT. Participants underwent repeat dobutamine echocardiography and SPECT imaging following treatment as well. The presence of transient ischemic dilatation (TID) was quantitatively assessed. Participants also underwent assessment of cardiac function (left ventricle volumes, ejection fraction and stroke volume) by MRI before and following CSWT therapy. All the cardiac MRI examinations were performed using a 1.5 T MR scanner (Avanto, Siemens Medical Solutions, Erlangen, Germany). All cMRI evaluations were performed by two experienced observers who were blinded as to whether the MRI was before or after treatment. Coronary angiography was performed in all patients before treatment. Patients with three vessel disease with significant (N70% diameter) stenosis not suitable for revascularization were eligible while patients with LV EF b 40% were excluded from the study. CSWT was performed as previously outlined [5]. In brief, ischemic zones identified by previous noninvasive evaluation, which were targets for CSWT therapy were located by echocardiography. Areas of scarring identified by cMRI were not treated. 100 impulses were applied to one zone with up to 500 total impulses to the patient during a single session. Shockwaves were delivered non-invasively and focused by a special ellipsoid reflector. CSWT treatments during the first week were carried every second day. A three-week treatment-free interval was required after the first week of treatment. During week 5, procedures were carried out every second week (5 zones, 100 impulses for each). The three-week treatment-free interval was again kept and procedures were repeated on week 9 following the same schedule. To evaluate the effect of CSWT all tests including dobutamine echo stress test, echocardiography, cardiac magnetic resonance imaging and
230
G. Zuoziene et al. / International Journal of Cardiology 187 (2015) 229–230
Table 1 Patient demographics and characteristics.
Table 2 Comparison of parameters before and after treatment. Totala (n = 40)
Age Gender (F/M) MI 1 MI 2 MI 3 MI At least 1 aortocoronary bypass surgery 2 aortocoronary bypass surgeries Previous PCI 1 PCI 2 PCI 17 PCI With cardiac pacemaker Diabetes Arterial hypertension Angina pectoris prior to CSWT Class 3 Class 4
67.73 ± 9.45 (44–83) 25%/75% (10/30) 70% (28) 60% (24) 7.5% (3) 2.5% (1) 77.5% (31) 17.5% (7) 45% (18) 30% (12) 12.5% (5) 2.5% (1) 7.5% (3) 22.5% (9) 95% (34) 67.5% (27) 32.5% (13)
MI = myocardial infarction. PCI = percutaneous coronary intervention. CSWT = cardiac shock wave therapy. a Continuous variables: mean ± SD (range); categorical variables: percent (n).
myocardial perfusion radionuclide computer tomography (SPECT) were repeated after six months. The statistical software package SPSS 17.0 (version for Windows) was used for the data analysis. 40 patients with disease in all 3 coronary arteries were enrolled into the study. Clinical characteristics are described in Table 1. CSWT was well tolerated in all subjects. Following treatment with CSWT, a statistically significant difference was detected for the majority of clinical and imaging parameters examined (Table 2). Nitrate consumption decreased by 28.77 tablets, on average, per week (p b 0.001). Changes in ejection fraction of the left ventricle with regards to normal (LV EF 56–78%) values were statistically significant: ejection fraction improved to normal in 10 subjects out of 23, while abnormal values were reported in only 1 patient who had normal values before treatment. In this study we utilized multimodality imaging to demonstrate the efficiency of CSWT for the treatment of refractory angina pectoris. Shockwaves consist of acoustic energy that can be transmitted in a liquid medium and focused with a precision of several millimeters to any intended treatment area inside the body. Oi et al. [8] demonstrated in a model of hind limb ischemia in rabbits that shockwaves induced the development of collateral arteries and increased the capillary density in the treated areas. Aicher et al. [4] showed that CSWT facilitated the recruitment of endothelial progenitor cells and improved blood flow recovery as assessed by laser Doppler imaging in a similar model. Nishida et al. [9] examined the effects of shockwave therapy in a porcine model of chronic myocardial ischemia. They demonstrated improvement in LV systolic function, wall thickening fraction, and regional myocardial blood flow. In addition, they also found a significant increase in markers of neovascularization such as VEGF, the VEGF receptor Flt-1, as well as significant growth of capillaries in the ischemic myocardium of the treatment group. The same group showed that early CSWT can improve LV remodeling after acute myocardial infarction and increase the capillary density in the border zone of the ischemic area. Small nonrandomized, nonblinded studies as well as a placebo-controlled study have demonstrated the clinical benefits of shockwave therapy in patients with refractory angina [5,10]. Our trial extends these findings to a larger study group and demonstrates improvement in LV EF by MRI using this therapy. No previous published data about the usage of cMRI for CSWT evaluation was available from other sources when writing this paper.
Nitrates tablets × per week WMSI at rest WMSI max. LV EF LV EDV LV ESV LV SV TID Systolic ABP Diastolic ABP Mean ABP
n
Before treatment
After treatment
p value
40 39 39 37 37 37 37 38 40 40 40
33.6 ± 10.3 1.52 ± 0.45 1.5 ± 0.42 51.42 ± 11.75 138.38 ± 57.64 71.14 ± 50.84 69.19 ± 23.24 1.14 ± 0.11 134.75 ± 16.33 81.63 ± 8.73 99.33 ± 10.41
4.83 ± 4.32 1.4 ± 0.39 1.34 ± 0.39 56.59 ± 12.04 148.37 ± 65.04 72.19 ± 58.19 76.68 ± 22.22 1.07 ± 0.11 130.88 ± 14.76 80 ± 7.51 96.96 ± 8.75
b0.001 b0.001 b0.001 b0.001 0.334 0.555 0.040 b0.001 0.021 0.062 0.012
WMSI = wall motion score index. LV EDV = left ventricular end-diastolic function. LV ESV = left ventricular end-systolic function. LV SV = left ventricular stroke volume. LV EF = left ventricular ejection fraction. TID = transient ischemic dilatation. ABP = arterial blood pressure.
In summary, after CSWT treatment nitrate use was significantly reduced and LV EF as assessed by cardiac MRI significantly improved. WMSI assessed by echocardiography was reduced, and myocardial perfusion by radionuclide computer tomography imaging improved. The use of cardiac MRI to assess changes following CSWT was established for the first time. Larger and preferably blinded studies using comprehensive cardiac imaging are necessary to further evaluate the efficacy of this non-invasive therapy.
Conflict of interest Dr. Leibowitz has received minor consulting fees and travel expenses from Medispec LTD. (Manufacturer of CSWT equipment used). Medispec Ltd. has had no role in the funding or preparation of this manuscript. None of the other authors have any competing interests to report.
References [1] G. Gotte, E. Amelio, S. Russo, E. Marlinghaus, G. Musci, H. Suzuki, Short-time nonenzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock waves treatment, FEBS Lett. 520 (2002) 153–155. [2] S. Mariotto, E. Cavalieri, E. Amelio, A.R. Ciampa, A.C. de Prati, E. Marlinghaus, et al., Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production, Nitric Oxide 12 (2005) 89–96. [3] A.R. Ciampa, A.C. de Prati, E. Amelio, E. Cavalieri, T. Persichini, M. Colasanti, et al., Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves, FEBS Lett. 579 (2005) 6839–6845. [4] A. Aicher, C. Heeschen, K. Sasaki, C. Urbich, A.H. Zeiher, S. Dimmeler, Low-energy shock wave for enhancing recruitment of endothelial progenitor cells, Circulation 114 (2006) 2823–2830. [5] D. Leibowitz, A.T. Weiss, D. Rott, R. Durst, C. Lotan, The efficacy of cardiac shock wave therapy in the treatment of refractory angina: a pilot prospective, randomized, double-blind trial, Int. J. Cardiol. 167 (6) (2013 Sep 10) 3033–3034. [6] K. Ito, Y. Fukumoto, H. Shimokawa, Extracorporeal shock wave therapy as a new and non-invasive angiogenic therapy, Tohoku J. Exp. Med. 219 (2009) 1–9. [7] G. Zuozienė, A. Laucevičius, D. Leibowitz, Extracorporeal shockwave myocardial revascularization improves clinical symptoms and left ventricular function in patients with refractory angina, Coron. Artery Dis. 23 (1) (2012) 62–67. [8] K. Oi, Y. Fukumoto, K. Ito, T. Uwatoku, K. Abe, T. Hizume, et al., Extracorporeal shock wave therapy ameliorates hind limb ischemia in rabbits, Tohoku J. Exp. Med. 214 (2008) 151–158. [9] T. Nishida, H. Shimokawa, K. Oi, H. Tatewaki, T. Uwatoku, K. Abe, et al., Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo, Circulation 110 (2004) 3055–3061. [10] A.A. Khattab, B. Broderson, D. Schuermann-Kuchenbrandt, H. Beurich, R. Tolg, V. Geist, et al., Extracorporeal cardiac shock wave therapy: first experience in everyday practice for the treatment of chronic refractory angina pectoris, Int. J. Cardiol. 121 (2007) 84–85.
