Are we getting closer to a new non-invasive anti-heart attack therapy?

Nowadays there is still a great need to improve non-invasive techniques to restore proper circulation after a heart attack. Low frequency vibrations have previously been observed to help clear blood clots in catheter systems and also to stimulate the coronary circulation if delivered to the heart in the diastolic phase. In a presented article, scientists from Ahof Biophysical Systems and In-Vitro Labs (Canada) also showed that low-frequency percussion vibrations (50 Hz) promote the dissolution of clots in vessels imitating coronary vessels, located under the meat barrier imitating the chest. Vibration was tested in combination with heparin or heparin and streptokinase (anticoagulants) to approach the clinical scenario of heart attack therapy.

• The vibrations in combination with heparin+streptokinase decreased the clot mass by 51%, while heparin+streptokinase without vibrations was responsible just for the 3% mass decrease.
• Fully clot-blocked channels were unblocked along the entire length of the clot in all 16 vibrated samples. Fully open channels were observed after 15 or 20 minutes of vibration with heparin and after 5 or 10 minutes with  heparin+streptokinase. This process did not take place in the control samples (without vibrations).
• Only 1 out of 16 clots became fragmented under the influence of vibration, which could model the risk of embolism in the course of vessels.

Prepared on the basis of:

Diastolic timed Vibro-Percussion at 50 Hz delivered across a chest wall sized meat barrier enhances clot dissolution and remotely administered Streptokinase effectiveness in an in-vitro model of acute coronary thrombosis. Hoffmann A, Gill H. Thromb J. 2012 Nov 12;10(1):23.

Study population

Blood clots were examined. They were delivered from a healthy male (46 y.o.) or female (50 y.o.), the authors of the study. There were 2 vibration groups and 2 control groups among the clots. The first vibration group consisted of 8 clots placed in heparinized saline (HS), the second – 8 clots placed in HS with the addition of streptokinase (HS+SK). The vibration groups were subjected to vibrations. In the control groups clots were similarly placed in HS (n = 8) or HS+SK (n = 8), but were not treated with vibration.

Test procedure

The clot fragment was appropriately prepared and measured (weight, size) and placed in a 4 mm diameter duct imitating a large epicardial coronary artery. The tube was filled with HS (1000 units of heparin in an attached 500 ml bag with 0.9% NaCl) and fluid movement was induced to simulate cardiac activity (120/ 80 mm Hg, ~ 60 bpm). In the longitudinal axis of the duct, the clot blocked fluidity fully on several centimeters distance. Heparin was added to prevent the formation of secondary clots after primary disintegration, and also to imitate the conditions of anticoagulation therapy, the standard clinical scenario in myocardial infarction therapy. The same system was tested additionally with the addition of SK to enhance the activity of heparin. SK was administered separately (~15,000 IU/ 100 µm, in a volume of 0.5 ml) approximately 2 cm before the clot – mimicking intravenous or systemic administration of this thrombolytic agent. 4 cm thick Salami meat was placed on the tube with the clot (to mimic the typical distance separating the human chest wall from the anterior surface of the heart).

Before and after the administration of 20-minute vibrations (or no vibrations), the whole system with the clot was photographed in detail, paying attention to the condition of the clot, its morphology or fragmentation. Five parameters describing the degree of clot disintegration in relation to the initial state were subjected to statistical evaluation, such as: clot weight (the result was expressed in %), formation of open channels along the long axis of the clot (yes or no), achievement of clot mobility or fragmentation (yes or no).

Use of vibration in the study

The allocation of the clot to the vibration group or control group (without vibration) was performed randomly. The HS solution pulsed rhythmically from ~80 to ~120 mm Hg, imitating the work of the arteries. The vibrations were given intermittently for 20 minutes – they were turned on and off very quickly at 1-second intervals (metronome), so that they were active only in the diastolic timed phase. The vibration was provided by the Acuvibe HT 1280 massage device generating vibrations with a frequency of 50 Hz and an amplitude of 4 mm. The vibrations parameters used were well tolerated by both women and men in the preliminary studies. The vibration frequency was chosen based on previous reports on the positive effect of 50 Hz percussion vibrations on the heart rate and coronary circulation. Moreover, the selected value is within the frequency range used in vibrating catheters, such as the Trellis 8 Peripheral Infusion System (Bacchus Medical), where up to 3500 rpm is applied, i.e. the rotation causing mechanical oscillation of the catheter tubes at a frequency of about 58 Hz.

Results

Pulsating HS, without SK

The vibrations influenced clot solubility in the HS. After 20 min of clot incubation in pulsating HS, in the control group (without vibrations) a minimal decrease in the mass of clots was observed (by 1.8 ± 1.2 %), while the mass of clots subjected to vibrations decreased by 23.0 ± 5.0 %. The difference between the vibrating group and the control group was statistically significant (p <0.00000085).

The vibrations influenced the development of fully open clot channels in the HS. The initial clots completely blocked the flow of fluid. After 20 min of incubation in pulsating HS, in the control group (no vibration) no open channels were formed in any of the 8 clots, while in the vibration group all clots developed fully open channels (p < 0.0002). Clots opening was usually achieved within 15 or 20 minutes of intervention.

In the vibration group two clots became mobile and 1 – fragmented. In the control group, none of the clots become mobile or fragmented. The comparison of the two groups did not show statistical significance in mobility or fragmentation.

Pulsating HS+SK

Vibrations + SK influenced clot solubility. After 20 min of clot incubation in pulsating HS+SK, in the control group (without vibrations) a minimal decrease in the mass of clots was observed (by 3.0 ± 1.5 %), while in the group subjected to vibrations the mass of clots decreased by 51.0 ± 4.6 %. The difference between the vibration group and the control group was statistically significant (p < 0.00000098).

Vibrations + SK influenced the development of fully open clot channels. The initial clots completely blocked the fluid flow. After 20 min of clot incubation in pulsating HS+SK, in the control group (without vibration) no open channels were formed in any clot, while in the vibration group all clots developed fully open channels (p <0, 0002). Clot opening was usually achieved in the first 5 or 10 minutes of intervention.

In the control group none clot mobility or fragmentation was observed, while in the vibration group mobility was achieved in 1 out of 8 clots and no fragmentation was noted (0 out of 8). The differences between the vibration and the control group were not statistically significant (p = 1.0 in both cases).

Comment

In the treatment of myocardial infarction, invasive techniques such as ballooning and stenting often provide the best results, but this is not always possible at the right time and place. However, the immediate and complete restoration of normal blood flow in the occluded artery is the main determinant of possible clinical success. Therefore, an alternative non-invasive thrombolytic therapy is used, although this therapy brings a relatively low frequency of complete reperfusion and is associated with the risk of hemorrhage. Taking into account previous reports on the positive effect of vibration on the dissolution of clots and the stimulation of the coronary circulation, the aim of this study was to test in a simple model the effect of percussion vibrations on clotted coronary-like vessels placed under the meat barrier imitating the chest.

The presented experiment proved that percussion vibrations (50 Hz, ~4.0 mm) administered in the diastolic phase, acting through the meat barrier on a blood clot in a system imitating a fragment of the human coronary system, disintegrate the clot. This effect is enhanced by the addition of a thrombolytic agent. It was noticed that in all vibrated clot samples (enriched and not enriched by SK addition) open channels were formed, but this did not happen in any of the controls (without vibrations). The process of creating these channels was intensified by SK. Although in the pulsating HS the clot masses decreased not very spectacularly under the influence of vibration (by 21 % more than in the control group), after adding SK, as much as 48 % decrease in the clot mass was achieved in the vibration group compared to the control group. It is likely that a combination of the triggers for unobstructed corridor formation worked here. The turbulent flow caused by the vibrations could disclose a larger clot area for SK.

The authors cite a number of limitations that characterize their research, including oversimplification of the chest model through which the vibrations were applied to the also oversimplified coronary artery model. This experimental design explains the preliminary nature of this research – if no positive effect of vibration could be detected on clot disintegration in a simple model, it would probably not encourage further, more complex and costly clinical research. The authors note that Koiwa et al. observed the penetration of percussion vibrations with similar parameters (and even with a smaller amplitude of 2 mm) from the human chest to the heart about 20 years earlier.

In addition, since the larger vascular system has not been studied here, it is not known whether the observed clot disintegration would affect the risk of secondary occlusions. The detachment of a fragment of the clot and the formation of a secondary thrombus in the course of the blood vessels could be a dangerous consequence/ side effect of “vibrinolytic” (vibration + fibrinolytic) therapy. However, the authors point out that such a scenario is unlikely, as they found only 1 fragmentation in 16 clots exposed to vibration, despite a significant reduction in the mass of all of them. In addition, statistical tests showed that the differences in the occurrence of fragmentation between the control and vibration groups were not significant. Nevertheless, it should be emphasized that the induction of turbulent blood flow by vibration, which works so well in interaction with thrombolytic agents in disintegration/ dissolution of the clot, carries indeed a potential risk of clot fragmentation and requires further research. {However it should also be noted that the currently used standard thrombolytic therapy (administration of anticoagulants) also carries the risk of secondary blood clots; editorial note.}

Future research should also focus on more accurate and complete models, as well as on further testing of various vibration parameters. The selection of the frequency used in the discussed work was supported by a number of publications and was thoroughly discussed by the authors. There appear to be vibration parameters, such as frequency, by which a blood clot in the natural system can resonate appropriately to achieve effective and safe disintegration without fragmentation. Moreover, it should be noted that fragmentation of the clot occurred only in 1 case and in the HS + vibration group. No fragmentation was observed in the HS+SK + vibration group, so the use of an appropriate thrombolytic agent in the proposed experimental “vibrinolytic therapy” should also be considered. Perhaps the one more “aggressive”, which – due to interaction with the turbulent flow induced by vibrations – could be administered in a lower dose, reducing the risk of common complications of current non-invasive thrombolytic therapy – the risk of haemorrhage.

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