Cardiac Shock Wave Therapy for Chronic Refractory Angina Pectoris. A Prospective Placebo-Controlled Randomized Trial

Authors



Jean-Paul Schmid, M.D., Cardiovascular Prevention & Rehabilitation, Swiss Cardiovascular Center, University Hospital (Inselspital), CH-3010 Bern, Switzerland.
Tel.: ++41 31 632 89 72;
Fax: ++41 31 632 89 77;
E-mail: jean-paul.schmid@insel.ch

Summary

Background: Cardiac shock wave therapy (CSWT) delivered to the myocardium increases capillary density and regional myocardial blood flow in animal experiments. In addition, nonenzymatic nitric oxide production and the upregulation of vascular growth factor's mRNA by CSWT have been described. The aim of the study was therefore to test its potential to relieve symptoms in patients with chronic stable angina pectoris. Methods: Twenty-one patients (mean age 68.2 ± 8.3 years, 19 males) with chronic refractory angina pectoris and evidence of inducible myocardial ischemia during MIBI-SPECT imaging, were randomized into a treatment (n = 11) and a placebo arm (n = 10). The region of exercise-induced ischemia was treated with echocardiographic guidance during nine sessions over a period of 3 months. One session of CSWT consisted of 200 shots/spot (9--12 spots/session) with an energy intensity of 0.09 mJ/mm2. In the control group acoustic simulation was performed without energy application. Medication was kept unchanged during the whole treatment period. Results: In the treatment group, symptoms improved in 9/11 patients, and the ischemic threshold, determined by cardiopulmonary exercise stress testing, increased from 80 ± 28 to 95 ± 28 W (P= 0.036). In the placebo arm, only 2/10 patients reported an improvement and the ischemic threshold remained unchanged (98 ± 23 to 107 ± 23 W; P= 0.141). The items “physical functioning” (P= 0.043), “general health perception” (P= 0.046), and “vitality” (P= 0.035) of the SF-36 questionnaire significantly improved in the treatment arm, whereas in the placebo arm, no significant change was noted. Neither arrhythmias, troponin rise nor complications were observed during treatment. Conclusions: This placebo controlled trial shows a significant improvement in symptoms, quality of life parameters and ischemic threshold during exercise in patients with chronic refractory angina pectoris treated with CSWT. Thus, CSWT represents a new option for the treatment of patients with refractory AP.

Introduction

Coronary artery disease (CAD) is the most relevant health problem in Western industrialized nations. Current available management is based on three major options: medical therapy, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). Significant improvement in morbidity and mortality has been reported with these three forms of therapy [1] with a persisting annual incidence of death of 1.8% and nonfatal myocardial infarction of 3.2%[2]. On the other hand, the number of patients with CAD unsuitable for revascularization and persisting symptoms refractory to medical therapy continues to rise. The report from the ESC joint study group on the treatment of refractory angina [3] estimates this patient group to be in the order of 5–10%.

Several new therapeutic interventions have been used in patients with refractory angina pectoris in order to relieve symptoms and to improve quality of life (QOL) with improvement of perfusion (exercise training, enhanced external counterpulsation) [4,5] or modulation of the sympathetic nervous system (spinal cord stimulation) [6]. Newer techniques focused on the stimulation of angiogenesis (transmyocardial laser revascularization [7] or gene and stem cell therapy) [8,9]. More recently, low-energy cardiac shock wave therapy (CSWT) has been postulated to represent an effective and noninvasive therapeutic option for the treatment of refractory angina, based on the observation of Wang et al. that shock wave treatment was able to induce neo-vascularization in a tendon–bone junction of a rabbit model [10]. The mechanisms involved comprise mRNA expression of vascular endothelial growth factor (VEGF) [11], endothelial cell proliferation, and endothelial nitric oxide synthase (eNOS) expression [12]. Furthermore, nonenzymatic nitric oxide production by CSWT of a L-arginine containing solution has been reported [13].

First studies in animal models and humans have shown an improvement of myocardial ischemia and left ventricular remodeling [11,14,15]. The aim of our study was to test the effect of CSWT in a randomized placebo-controlled trial.

Materials and Methods

Twenty-one patients with angiographically proven CAD not suitable for percutaneous or surgical revascularization, chronic refractory angina pectoris, and objective evidence of stress-induced myocardial ischemia on nuclear perfusion imaging studies were included. Chronic refractory angina was defined as persisting symptoms during exertion despite optimal tolerable antiischemic therapy.

Exclusion criteria were an acute coronary syndrome within 3 months, symptoms of unstable angina, breast plastic surgery with silicon implants, uncontrolled heart failure, presence of a left ventricular thrombus, poorly controlled diabetic retinopathy, history of malignant tumor, and participation in other trials.

Patients were randomized into an active treatment (n = 11) or a placebo arm (n = 10). At baseline and 3 months after the end of treatment, a standardized questionnaire (Short-form-36) [16] were administrated, and a cardiopulmonary exercise test (CPX) was performed for determination of maximal exercise capacity and the ischemic threshold.

The characteristics of the study population are summarized in Table 1. All patients were kept on their usual oral medication during the trial period, including nitrates, beta-blockers, potassium channel openers or calcium channel blockers. The study protocol was reviewed and approved by the local Ethical Committee and complied with the Declaration of Helsinki regarding investigations in humans. All patients provided written informed consent.

Table 1. Baseline patient characteristics
 Treatment n = 11Placebo n = 10 P-value
  1. ACE: Angiotensin Converting Enzyme; ARB: Angiotensin Receptor Blocker; CCS: Canadian Cardiovascular Society functional classification of angina.

Age (years)72.6 ± 8.363.4 ± 3.20.014
Gender (M/F)10/19/1ns
CCS class 2 or 3 (n)10/19/1ns
Localisation of ischemia (n)  ns
 Anterior22 
 Lateral1 
 Inferior88 
Vessel disease (n)  ns
 1-vessel01 
 2-vessel14 
 3-vessel105 
Left ventricular ejection fraction (%)54.3 ± 13.359.9 ± 11.2ns
Hospitalization for angina in the last 12 months (n)63ns
History of coronary artery bypass surgery (n)85ns
Medication    
 Betablocker (%)7370ns
 Nitrate (%)3660ns
 Nicorandil (%)4630ns
 Molsidomin (%)1820ns
 Calcium-channel blocker (%)1850ns
  ACE-Inhibitor, ARB (%)9170ns
  Statins (%)9190ns
  Antiplatelet agents (%)100100ns
Cardiovascular risk factors   ns
 Smoking (%)1840 
  Arterial hypertension (%)8270 
  Dyslipidemia (%)9180 
  Diabetes (%)1820 
  Positive family history (%)2720 

Shock Wave Therapy

CSWT was delivered by an electromagnetic shockwave device (Modulith SLC, Storz Medical, Taegerwilen, Switzerland). In the placebo group, CSWT was simulated by reproducing the noise of shock waves from a CD-player without application of shock wave energy. Therefore, the operators were not blinded to the treatment arm.

To delineate the ischemic region for CSWT, previously determined by myocardial perfusion scintigraphy, an in-line echocardiographic probe was used. During a treatment session, the borders of the ischemic region were exposed to CSWT (9–12 treatment spots with 200 shots per spot; energy flux density: 0.09 mJ/mm2). The shock waves were applied during diastole, using an ECG monitoring with R-wave triggering.

The treatment consisted of a total of nine sessions over 3 months on an outpatient basis. The nine sessions were divided in three clusters of three sessions applied in a week, followed by a treatment free interval of 3 weeks to allow an angiogenic response to the CSWT stimulus. Each session lasted about 45 min, dependent on the heart rate of the patient. Troponin-I was determined at baseline and after the third session of each treatment cluster to monitor myocardial damage by CSWT.

Cardiopulmonary Exercise Testing (CPX)

All patients underwent symptom limited CPX at baseline and 3 months after the last session of CSWT. CPX was performed using an upright computer-controlled, rotational speed independent bicycle (Ergometrics 800S, Ergoline® GmbH, Bitz, Germany). Workload was increased by 10 or 15 W/min, using a ramp protocol. Respiratory gas exchange was measured breath-by-breath (Oxycon Alpha®, Jaeger-Toennies, Höchberg, Germany). The ischemic threshold was determined by the point of change (deflection) in the linearity of the oxygen uptake (VO2) curve [17] (Figure 1) and expressed in watt. The exercise test was stopped when typical chest pain occurred and/or significant ST-segment depression (>0.2 mV) developed.

Figure 1.

Representative example of a cardiopulmonary exercise stress test. The graph shows the oxygen uptake curve. One minute of rest is followed by a warm-up period of 3 min, followed by an increase in work load using a 10 or 15 W/min ramp protocol. Dashed lines indicate the slope of O2-uptake with a change in the linearity (arrow), corresponding to a decrease of stroke volume due to myocardial ischemia [17].

Medical Outcomes Study-36 Item Short Form Health Survey (SF-36)

The SF-36 questionnaire was used to assess QOL and symptoms. It is a standardized multidimensional instrument [16], consisting of eight components, representing: "physical function" (extent to which health limits physical activity, such as self-care, walking, climbing stairs); the "role of physical function" (the extent to which physical health interferes with work or other daily activities); "bodily pain" (intensity of pain and effect of pain on normal work, both inside and outside the home); "general health perception" (personal evaluations of current health, health outlook, and resistance to illness); "vitality" (feeling full of energy rather than tired and worn out); "social function" (the extent to which physical health or emotional problems interfere with normal social activities); "role of emotional function" (the extent to which emotional problems interfere with work or daily activities); and "mental health" (including depression, anxiety, behavioral-emotional control, and general affect). The SF-36 scores are converted to a scale between 0 and 100, with a higher score indicating better QOL.

Statistical Analysis

Statistical analysis was performed using the SPSS® for Windows® software (version 15.0.1, SPSS® Inc., Chicago, IL, USA). Mean values ± standard deviation (SD) are reported for all key variables. All comparisons of means were effectuated using nonparametric tests (Wilcoxon and Mann-Whitney-Test). The level of statistic significance was set at a two-tailed P-value <0.05.

Results

Coronary angiography showed a 3-vessel disease in 15, a 2-vessel disease in 5 and a 1-vessel disease in 1 patient. Thirteen patients had previously undergone CABG surgery (Table 1). The patients had a high cardiovascular risk comprising treated arterial hypertension in 76%, dyslipidemia in 85%, diabetes mellitus in 19%, former or current smoking in 29% and a positive family history for coronary heart disease in 24%.

All patients tolerated CSWT well and no patient had to stop treatment prematurely. In 3 patients, the standard energy level had to be reduced slightly due to an unpleasant feeling at the site of shock wave delivery on the chest, but none of the patients had a rise in Troponin-I levels and no arrhythmias occurred.

Nine out of 11 patients in the treatment group reported a decrease in exercise-induced angina (Table 2). In contrast, only 2 out of 10 patients in the placebo group reported a symptomatic improvement.

Table 2. Treatment effects of CSWT judged by the patient
Improvement of symptomsTreatment n = 11Placebo n = 10
Considerably better71
Slightly better21
No change28
Worsening00

SF-36 QOL Questionnaire

There was no significant change in any of the eight items of the SF-36 (Figure 2) in the placebo group but an improvement was noted in 3 of the eight items in the treatment group (physical function, general health perception, and vitality). The other items showed a trend towards improvement, but did not reach statistical significance.

Figure 2.

Outcome data of the Study-36 Item Short Form Health Survey (SF-36) for the control and the treatment group.

Cardiopulmonary Exercise Testing

There was a significant increase in the ischemic threshold in the treatment group (19.4%, P= 0.036; Figure 3), expressed by the workload at which the linearity of the oxygen uptake curve changed. In the placebo treated patients, the ischemic threshold at baseline occurred later than in the treated group, but increased only by 8.4%, which was not statistically significant (P= 0.141). The other baseline and exercise test parameters did not differ between baseline and follow-up or between the groups (Table 3).

Figure 3.

Ischemic threshold determined by the change of slope of the oxygen uptake curve during cardiopulmonary exercise testing before (black bars) and 3 months after treatment (gray bar). Treatment effects are seen only in the treatment group.

Table 3. Parameters of cardiopulmonary exercise testing
 Treatment n = 11Placebo n = 10  
 BaselineFollow-upBaselineFollow-up P-valuea P-valueb
  1. aBaseline: treatment versus placebo group.

  2. bChange baseline – follow-up: treatment versus placebo group.

Heart rate rest (1/Min)71 ± 1171 ± 867 ± 1664 ± 170.4680.705
Heart rate peak (1/Min)120 ± 19120 ± 21114 ± 26117 ± 240.6840.182
SBP rest (mmHg)118 ± 20126 ± 24120 ± 12126 ± 140.7050.904
DBP rest (mmHg)75 ± 874 ± 1174 ± 676 ± 60.6540.724
SBP peak (mmHg)154 ± 29154 ± 29148 ± 48172 ± 170.9730.412
DBP peak (mmHg)78 ± 1075 ± 1182 ± 1282 ± 80.1121.000
Work load peak (W)91.2 ± 29.194.1 ± 35.2112.3 ± 23.1120.3 ± 31.10.1650.353

Discussion

Treatment of refractory angina pectoris is difficult and the fact that no further option for coronary revascularization (PCI or CABG) can be offered to the patients has a big impact on QOL. Different methods have been tested in the past (spinal cord stimulation, laser revascularization, enhanced external counterpulsation, gene and stem cell therapy) with variable success. However, most of these treatment options are invasive or poorly accepted by the patients. A new approach has been introduced by Caspari et al. [18] with the first patients treated with CSWT in January 1998, demonstrating the up regulation of VEGF m-RNA in human umbilical vascular endothelial cells [19]. Nishida et al. [11] applied CSWT for the first time in a model of chronic ischemia in vivo and showed that CSWT effectively increased regional myocardial blood flow and normalized ischemia-induced myocardial dysfunction in pigs. They confirmed the up regulation of mRNA and protein expression of VEGF in the ischemic myocardium and demonstrated an increase in the density of factor VIII-positive capillaries at the treated sites. Uwatoku et al. [14] studied the effects of CSWT in the acute setting in pigs and showed that left ventricular remodeling improved after acute myocardial infarction when CSWT was started in the early phase of the disorder. Fukumoto [15] and Khattab et al. [20] finally confirmed these data in patients with symptomatic end-stage CAD inspite of receiving maximally tolerated medical therapy and no indication for PCI or CABG by showing a reduction in symptoms and nitroglycerin use. This treatment improved myocardial perfusion as assessed by myocardial scintigraphy, which persisted up to 12 months.

A first placebo controlled study by Kikuchi et al. [21] showed the effectiveness of CSWT in 8 patients with a cross-over design. Chest pain symptoms and cardiac function were significantly improved only by CSWT. Our study confirms these data and expands the knowledge on safety and clinical responsiveness of CSWT in patients with angina pectoris.

Mechanism of the Cardiac Shock Wave Therapy

The exact mechanism of stimulation of neoangiogenesis by CSWT is still not well understood. One hypothesis postulates, that shock waves exert their biological effect via mechanical interference on nearby cells and structures at the activated sites [22]. The physical process involved is thought to be the triggering of cavitational bioeffects. These correspond to an activation of preexisting bodies of gas, activated by low-pressure amplitudes, which exert shear stress-like forces on the tissue by the inertial collapse of microbubbles. Findings of earlier studies suggest that local delivery of shock waves stimulate early expression of angiogenesis-related growth factors, including eNOS [12] and VEGF [11]. However, neovascularization of ischemic tissue depends not only on local resident endothelial cell activation and proliferation (angiogenesis) but also on the formation of new vasculature stemming in part from differentiation of bone marrow-derived endothelial precursor cells (vasculogenesis) [23]. In this regard, Aicher et al. [24] were able to show that preconditioning of both, nonischemic and chronic ischemic tissue with low-energy CSWT improves recruitment of circulating endothelial progenitor cells via enhanced expression of chemoattractant factors.

Clinical Implications

This prospective, randomized study shows that CSWT reduces clinical symptoms and objective signs of myocardial ischemia. CSWT therefore emerges as a new noninvasive technique for treatment of refractory angina pectoris in patients with advanced CAD.

The improvements in clinical symptoms and exercise capacity in patients with refractory angina pectoris suggest the use of this method in end stage coronary heart disease, when all other therapeutic options (i.e., PCI and CABG) have failed. The technique is simple, easily applicable and without known side effects. First effects can be seen as early as 6 weeks after treatment initiation and the benefit lasts up to at least 12 months [15]. Due it's noninvasive character it can easily be repeated if symptoms reappear.

Limitations

This study is limited by the small patient number and the fact that operators were not blinded to the treatment status. However, symptom relief was consistent in the treatment arm and relied on patient's declaration and completion of a questionnaire, which were independent from an operator's analysis.

Due to the small number of patients, baseline characteristics were not evenly distributed between the two groups. The age of the treatment group was significantly higher and their ischemic threshold during CPX occurred earlier than in the control group. The size of the study population was too low however to allow for any conclusion regarding the relation between age and severity of ischemic disease on one hand and the success of CSWT on the other. However, in the literature on CSWT reported so far, age does not seem to be a limiting factor of success and very encouraging results have been reported also in patients with an extensive exercise induced ischemic area [15].

The treatment effect was not assessed by the repetition of myocardial szintigraphy after treatment. We focused solely on the measurement of the ischemic threshold by CPX and clinical parameters. The correlation of the functional and clinical parameters with perfusion images would have certainly strengthened the conclusions of this study.

The follow-up (3 months) was short and studies with a longer follow-up are warranted to assess the therapeutic effect in the course of time. Persistance of a good clinical result so far have been reported up to 1 year [15].

Conclusions

The present study shows an improvement in clinical symptomatology and ischemic threshold in patients with severe CAD and refractory angina pectoris. This method appears to be of clinical benefit in this patient population who does not qualify for heart transplantation or other invasive strategies. There was also an improvement in QOL, which is crucial for these patients in view of their situation without further therapeutic options. Larger studies are however needed to confirm the finding of our study and the long-term effects of this method.

Acknowledgement

We thank Dr. Ernest H. Marlinghaus, Storz Medical AG, Switzerland for technical assistance and support.

Conflict of Interest

The authors declare no conflict of interest.

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