Whole-body periodic acceleration (WBPA) has been developed as a passive exercise device capable of improving endothelial function by applying pulsatile shear stress to vascular endothelium. We hypothesized that treatment with WBPA improves exercise capacity, myocardial ischemia, and left ventricular (LV) function because of increased coronary and peripheral vasodilatory reserves in patients with angina. Twenty-six patients with angina who were not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting were randomly assigned to remain sedentary (sedentary group) or undergo 20 sessions of WBPA with the motion platform for 4 weeks (WBPA group) in addition to conventional medical treatment. WBPA was applied at 2 to 3 Hz and approximately ±2.2 m/s 2 for 45 minutes. We repeated the symptom-limited treadmill exercise test and adenosine sestamibi myocardial scintigraphy. In the WBPA group, the exercise time until 0.1-mV ST-segment depression increased by 53% (p <0.01) and the double product at 0.1-mV ST-segment depression by 23% (p <0.001). Severity score of myocardial scintigraphy during adenosine infusion decreased from 20 ± 10 to 14 ± 8 (p <0.001) and severity score at rest also decreased from 13 ± 10 to 8 ± 10 (p <0.01). On scintigraphic images at rest, LV end-diastolic volume index decreased by 18% (p <0.01) with an augmentation of LV ejection fraction from 50 ± 16% to 55 ± 16% (p <0.01). In contrast, all studied parameters remained unchanged in the sedentary group. In conclusion, treatment with WBPA for patients with angina ameliorates exercise capacity, myocardial ischemia, and LV function.
Recently, Sackner et al invented whole-body periodic acceleration (WBPA), a new therapeutic device capable of improving endothelial function by applying pulsatile shear stress to vascular endothelium, presumably owing to the production and release of vasoactive substances such as nitric oxide. Heparin possesses several functions aside from an anticoagulant effect. Heparin potentiates and accelerates coronary collateral growth resulting from interaction with angiogenic growth factors. Heparin also increases the bioavailability of nitric oxide by liberating vessel-immobilized myeloperoxidase. We designed the present study to test the impact of repeated WBPA therapy with heparin pretreatment on exercise capacity, myocardial ischemia, and left ventricular (LV) function in patients with angina pectoris and mild LV dysfunction.
Methods
We investigated 26 patients (19 men, 7 women) 45 to 86 years of age (mean 68 ± 10) with chronic effort angina and mild LV dysfunction with an ejection fraction (EF) <55% (mean 51 ± 10). All had angiographically proved significant coronary narrowing (≥75%) involving ≥1 major coronary artery and developed ≥0.1-mV ST-segment depression during treadmill exercise testing. None had acute exacerbation of symptoms in the preceding 6 months. Patients were randomized to remain sedentary (sedentary group, n = 13) or undergo heparin WBPA therapy (WBPA group, n = 13). All patients underwent conventional medical therapy throughout the study. WBPA was applied with a gurney-like motion platform device (Acceleration Therapeutics AT101; Non-Invasive Monitoring Systems, North Bay Village, Florida) at a frequency of 2 to 3 Hz and approximately ±2.2 m/s 2 for 45 minutes. A single intravenous dose of heparin (5,000 IU) was given 10 to 20 minute before each WBPA. The procedure was repeated 20 times over 4 weeks. Primary end points of the present study were improvements in exercise capacity, myocardial ischemia, and LV size and function. The study protocol complied with the Declaration of Helsinki and was approved by the ethics committee of Kitano Hospital (Osaka, Japan), and all patients gave written informed consent for the study.
Before performing the baseline exercise test, all patients performed preliminary treadmill exercise several times to habituate themselves to the test. All antianginal medications were withdrawn ≥2 days before the study. Sublingual nitroglycerin was allowed for angina symptom relief. Symptom-limited graded treadmill exercise testing was performed with a standard Bruce protocol in a fasting state, and a post-treatment treadmill exercise test was repeated at the same time of day as the baseline test. A 12-lead electrocardiogram was recorded at rest and 1-minute intervals until onset of limiting chest pain, leg fatigue or ≥0.2-mV ST-segment depression. Blood pressure was measured with a sphygmomanometer during each minute of exercise and recovery. Time to 0.1-mV ST-segment depression was defined as the elapsed time from initiation of exercise to the occurrence of horizontal or downsloping 0.1-mV ST-segment depression measured at 80 ms after the J point. In this study, heart rate and systolic blood pressure at onset of 0.1-mV ST-segment depression were measured to determine the ischemic threshold. All exercise tests and ST-segment evaluations were performed by investigators blinded to results of coronary angiograms and treatment status.
Adenosine myocardial perfusion single-photon emission computed tomography was performed as described previously. Adenosine was infused at 140 μg/kg/min for 5 minutes. At the end of the second minute, technetium-99m sestamibi (25 to 40 mCi) was injected, and myocardial perfusion single-photon emission computed tomographic acquisition was started approximately 60 minutes later. We used software developed at Cedars-Sinai Medical Center, called quantitative gated single-photon emission computed tomography, capable of providing simultaneous assessment of LV perfusion, global function (systolic and diastolic), and regional wall thickening and motion. Visual interpretation of myocardial perfusion single-photon emission computed tomographic images was based on short-axis and vertical long-axis tomograms divided into 17 segments. Each segment was scored by 2 expert observers blinded to treatment group using a 5-point scoring system (0 = normal; 1 = mildly abnormal; 2 = moderately abnormal; 3 = severely abnormal; and 4 = absence of segmental uptake). Subsequently, summed stress and rest scores were calculated by summing respective segmental scores. Maximal score was therefore 68 (17 segments × score 4). When visual scoring was different between the 2 observers, they assessed again the myocardial perfusion images and reached a consensus. Quantitative measurements of LVEF using gated perfusion single-photon emission computed tomography were usually volume-based rather than count-based methods. In particular, the time-volume curve derived from 16-frame gating allowed the end-diastolic volume (EDV) and end-systolic volume (ESV) of the LV cavity to be identified, from which the LVEF was calculated as follows: LVEF (%) = (LVEDV − LVESV)/LVEDV × 100.
Data are expressed as mean ± SD. Two-way analysis of variance using Bonferroni method was carried out to investigate differences in the treadmill exercise test and adenosine myocardial perfusion scintigraphy. Statistical significance was designated at a p value <0.05.
Results
All 26 patients completed the protocol without any complications or adverse effects. No hemorrhagic tendency was noted in any patient treated with heparin. Weekly urinalysis and stool occult blood tests showed negative results.
Baseline characteristics of study patients are listed in Table 1 . There were no significant differences in age, gender, risk factors, and disease complications between the 2 groups. Distribution of the ischemia-related artery was similar in the 2 groups. Number of involved vessels was also comparable between the 2 groups. Similarly, there were no significant differences in medication between the 2 groups.
| Variable | Sedentary Group ⁎ (n = 13) | WBPA Group † (n = 13) |
|---|---|---|
| Age (years) | 66 ± 10 | 69 ± 10 |
| Men/women | 10/3 | 9/4 |
| Hypertension | 10 (77%) | 10 (77%) |
| Diabetes mellitus | 7 (54%) | 7 (54%) |
| Hypercholesterolemia | 10 (77%) | 8 (62%) |
| Cigarette smoker | 6 (46%) | 4 (31%) |
| Body mass index (kg/m 2 ) | 22.6 ± 3.4 | 23.5 ± 3.1 |
| Renal failure | 5 (38%) | 5 (38%) |
| Number of involved coronary arteries | 2.3 ± 0.8 | 2.5 ± 0.7 |
| Ischemia-related coronary artery | ||
| Right | 4 (31%) | 3 (23%) |
| Left anterior descending | 7 (54%) | 8 (62%) |
| Left circumflex | 2 (15%) | 2 (15%) |
| Healed myocardial infarction | 5 (38%) | 7 (54%) |
| Previous percutaneous coronary intervention | 6 (46%) | 6 (46%) |
| Previous coronary artery bypass grafting | 5 (38%) | 5 (38%) |
| Arteriosclerosis obliterans | 1 (8%) | 4 (31%) |
| Previous cerebral infarction | 3 (23%) | 0 (0%) |
| Canadian Cardiovascular Society classification of effort angina | ||
| Class II | 11 (85%) | 10 (77%) |
| Class III | 2 (15%) | 3 (23%) |
| Class IV | 0 (0%) | 0 (0%) |
| Medication | ||
| Aspirin | 13 (100%) | 13 (100%) |
| Angiotensin-converting enzyme inhibitor | 3 (23%) | 1 (8%) |
| Angiotensin II receptor blocker | 6 (46%) | 7 (54%) |
| β Blocker | 8 (62%) | 10 (77%) |
| Calcium channel blocker | 5 (38%) | 6 (46%) |
| Statin | 10 (77%) | 6 (46%) |
| Pioglitazone | 0 (0%) | 1 (8%) |
| Diuretic | 5 (38%) | 6 (46%) |
⁎ Patients with conventional medical therapy alone.
† Patients with whole-body periodic acceleration therapy with heparin pretreatment plus conventional medical therapy.
Exercise time and hemodynamic parameters at rest and at 0.1-mV ST-segment depression during the treadmill exercise test are presented in Table 2 . There were no significant differences in hemodynamic parameters at rest at baseline and after treatment between the 2 groups. In the sedentary group, exercise time to 0.1-mV ST-segment depression remained unchanged before and after conventional treatment. In contrast, in the WBPA group, WBPA with heparin pretreatment significantly increased exercise time to 0.1-mV ST-segment depression. In the sedentary group, the double product at 0.1-mV ST-segment depression remained unchanged before and after conventional treatment. In contrast, in the WBPA group it was significantly (p <0.001) increased.
| Variable | Sedentary Group ⁎ | WBPA Group † | ||
|---|---|---|---|---|
| Baseline | After Treatment | Baseline | After Treatment | |
| Exercise time (seconds) | 269 ± 186 | 244 ± 159 | 261 ± 123 | 400 ± 164 ‡ § |
| Heart rate (beats/min) | ||||
| At rest | 70 ± 8 | 69 ± 9 | 68 ± 6 | 68 ± 8 |
| Ischemia | 111 ± 15 | 107 ± 17 | 112 ± 10 | 115 ± 9 |
| Systolic blood pressure (mm Hg) | ||||
| At rest | 122 ± 12 | 125 ± 11 | 121 ± 12 | 119 ± 12 |
| Ischemia | 138 ± 19 | 134 ± 21 | 136 ± 24 | 163 ± 29 ‡ § |
| Rate–pressure product × 10 −2 (mm Hg × beats/min) | ||||
| At rest | 86 ± 15 | 86 ± 14 | 82 ± 10 | 81 ± 10 |
| Ischemia | 154 ± 37 | 145 ± 41 | 154 ± 35 | 189 ± 39 ‡ § |
⁎ Patients with conventional medical therapy alone.
† Patients with whole-body periodic acceleration therapy with heparin pretreatment plus conventional medical therapy.
‡ p <0.01 versus baseline values.
Figure 1 shows 2 representative patients from each group. In 1 patient from the sedentary group, in the LV short-axis and horizontal long-axis views, posterolateral hypoperfusion or defect and LV size remained unchanged as determined by stress and at-rest imaging after conventional treatment ( Figure 1 ). In 1 patient from the WBPA group, in the LV short-axis and horizontal long-axis views, posterolateral hypoperfusion or defect clearly decreased as determined by stress and at-rest imaging after heparin WBPA treatment. In addition, LV size remarkably decreased as determined by stress and at-rest imaging after treatment ( Figure 1 ). At baseline, the summed stress and rest scores of adenosine myocardial perfusion scintigrams were comparable between the 2 groups. Summed stress and rest scores remained unchanged in the sedentary group. In contrast, in the WBPA group after treatment with heparin WBPA therapy, summed stress and rest scores significantly decreased ( Figure 2 ). Changes in global LV parameters (EDV index, ESV index, EF) are presented in Figure 3 . At baseline, LVEDV index, LVESV index, and LVEF were similar between the 2 groups. In the sedentary group, all global LV parameters remained unchanged after conventional treatment ( Figure 3 ). In the WBPA group, we found significantly smaller LVEDV and LVESV indexes after treatment. In addition, LVEF significantly increased ( Figure 3 ).
