A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease

This study was approved by the Institutional Review Board and Ethics Committee of 1^st Hospital of Kumming Medical University, and all study subjects signed informed consent for participation in the study and all treatments performed. Subjects were patients who were hospitalized at Department of Cardiology of our hospital from December 2008 to December 2009. Patients were eligible to be included in the study if they met any of the following criteria: 1) Coronary angiography (CA) or multi-slice CT coronary angiography (CTCA) suggestive of moderate to severe coronary artery stenosis. 2) Demonstrated cardiac infarction and > 50 % stenosis after radioactive and sonographic examinations. 3) Chest tightness, onset of shortness of breath, and poor exercise tolerance after receiving formal drug treatment (with or without stent or bypass graft). 4) Hospitalized more than 2 times within 1 year due to the aforementioned problems. 5) CCS angina grading higher than grade II, and NYHA functional classification of I-III. 6) More than 1 month after acute myocardial infarction (AMI) and more than 2 weeks after PCI surgery. A history of PCI or CABG was not a contraindication for inclusion. All patients included in the study were “no option” patients and had coronary heart disease and an imaging examination that confirmed the presence of ischemic myocardium. The diagnosis and treatment in all the patients was in accordance with the related domestic and European guidelines developed in 2007[16].

Patients were excluded from the study if they met any of the following criteria. 1) AMI or CABG within the 4 weeks prior to the study. 2) History of heart transplantation. 3) History of metal valve replacement surgery. 4) Intracardiac thrombus. 5) LVEF < 30 % and unstable hemodynamics. 6) Arrhythmia with a rate < 40 bpm or > 120 bpm. 7) Skin ulceration or infection in the treatment area. 8) Severe obstructive lung disease.

Initially, consecutive patients who met the inclusion criteria were randomly divided into the regimen A treatment group and the regimen B treatment group. After three months, the additional group, a control group, was added and subsequent patients were randomly added to the regimen A and B groups and the control group. Patients in the three groups were enrolled by a physician who was familiar with patients’ conditions, and that physician drew lots to divide the patients into the different groups. The experimental grouping was blinded to both the physicians who were responsible for treatment and follow-up and to the patients themselves. The majority of patients with coronary heart disease in this study had severe symptoms so that they had a strong desire to receive CSWT. Therefore, we pre-set a smaller sample size for the control group and the sample size for this group was limited to no more than 15 patients. The control group did not receive CSWT. The treatment protocol of group A followed the recommended protocol developed by Tohoku University of Japan with respect to the shockwave output and the number of shots delivered to each spot and the protocol developed by the University of Essen, Germany[10, 11]. In group A, a sequence of 1 week treatment followed by three weeks rest was repeated 3 times. During each treatment week, CSWT was performed on days 1, 3 and 5, one session each day. The total duration of treatment was 3 months, thus patients received a total of 9 CSWT treatment sessions. In group B, a modified CSWT treatment schedule was adopted. Patients underwent 3 CSWT sessions/week, and the 9 treatment sessions were completed within 1 month. During follow-up, if the patient exhibited no observable lessening of myocardial ischemia, 1–4 treatment courses were repeated.

Dobutamine stress echocardiography (DSE). Patients underwent DSE after vascular lesions were identified by CA and/or CTCA. The use of β-blockers, calcium antagonists, and nitrates were stopped for at least 24 hours before testing. Continuous intravenous infusion of dobutamine (5–10 μg/kg/min) was administered, and if regional wall motion abnormalities (RWMA) could not be induced by low-dose dobutamine the dose was increased to 20–40 μg/kg/min. The wall motion score index (WMSI) was used to assess the state of motion.

Amplitude of regional myocardial motion was the range of motion measured using M-type echocardiography (Figure1A). This allows semiquantification of myocardial motion which can be displayed as a standard M mode image. Viable myocardial segments were defined as the 2 adjacent abnormal segments with improvement in contraction during drug administration (decrease ≥ 1 point)[17, 18]

Tissue Doppler-based strain rate (SR) was used to measure peak systolic (PS) SR under resting and load conditions (Figure1B)[19, 20]. Strain rate measures the rate of deformation of a tissue segment and is measured in S⁻¹. PSSR represents the maximal rate of deformation in systole. Strain is obtained by integrating strain rate over time and represents deformation of a tissue segment over time. Strain is expressed as the percent change from the original dimension. Systolic strain represents the magnitude of deformation between end diastole used as a reference point and end systole. One of authors of this paper carried out the PSSR measurement for all the patients during the entire follow-up period. However, that author did not know the treatment of each patient. Before this study, that author conducted a preliminary study on the feasibility and repeatability of PSSR measurement of all 16 segments of the left ventricle and the results showed no statistically significant difference (P > 0.05). Before CSWT treatment, radionuclide imaging and stress echocardiography were used to locate the ischemic segments in each patient. These segments might be the middle or the apical segment of interventricular septum, or the lateral basal segment. The PSSR was measured in the specific ischemic segments.

In order to assess myocardial perfusion more accurately, identify the target for CSWT, and evaluate the therapeutic effects during follow-up, MPI was performed after vascular lesions were identified. The use of β-blockers, calcium antagonists, and nitrates were stopped at least 24 hours before testing. A two-day method was adopted for dobutamine load and resting technetium (TC-99 m) methoxy isobutyl isonitrile (^99mTc-MIBI) MPI. The patient was asked to consume a high-fat meal after injection of contrast medium on the first day. Intravenous continuous infusion of dobutamine (20–40 μg/kg/min) was performed 40 min after the contrast medium in the biliary tract was excreted and it was required that the target heart rate (220 - age) was reached. Resting scan was performed 40 min after injection of contrast medium on the second day. Target myocardium was located and quantified according to the 17-segment Myocardial Scoring and the 4-grade scoring system recommended by American Society of Nuclear Cardiology[21‐23]. An increase of 1-point or more in MPI compared to baseline under both basic and loaded conditions was considered as the criterion for local myocardial blood flow improvement.

A 20-meter quiet and spacious corridor was designated, and the patients were asked to walk in the corridor at the maximum speed. If the patient experienced fatigue, dizziness, angina, or shortness of breath within 6 min, the test was stopped.

CSWT was performed with the MODULITH SLC SW therapy device (Storz Medical, Switzerland). In brief, after performing a 12-lead ECG, an ultrasound probe was used to locate the target myocardium based on the results of preoperative testing. A water bag was lowered until it touched the chest wall. Shock waves were applied to the ischemic areas, and were triggered by the R-wave of the ECG when the instrument was activated. The shock wave energy was increased up 0.09 mJ/mm² if the patient did not experience discomfort such as chest pain. Point-to-point combination treatment (8 extra shock wave treatments around the ischemic area) with 200 pulses delivered to each point was given. Thus, there were 1800 shock waves administered for each infarcted segment.

The control group did not undergo CSWT. During the 12-month follow-up, periodic telephone inquiries, out-patient follow-up, and hospitalization were used to adjust the drugs and treat emergencies in addition to the regular 3-month, 6-month, and 12-month follow-ups.

In both A and B groups, if acute heart failure, unregulated blood pressure, and frequent chest tightness occurred, the treatment was supplemented by timely drug reinforcement and interventional treatment.

Patients were followed-up at 3, 6, and 12 months after completion of treatment. Physicians who performed the follow-up examinations were not aware as to which treatment the patients received or if they were in the control group. Follow-up examinations included clinical assessment using the CCS grading of angina, NYHA functional classification, Seattle Angina Questionnaire (SAQ)[24], 6MWT, and recording the nitroglycerin dosage (times/week). Morphological assessment included measurements of the left ventricular end-diastolic diameter (LVDd) (two-dimensional long axis view of the left ventricle), left ventricular end-diastolic volume (EDV) (Simpson method), left ventricular end-systolic volume (ESV) (Simpson method), LVEF (Simpson method), regional wall motion under resting and load conditions (M-type measurement), PSSR under resting and load conditions (quantitative analysis using tissue velocity imaging), MPI score under resting and load conditions (semi-quantitative analysis using bulls-eye map).