Reduced Local Perfusion After Shock Wave Treatment of Rotator Cuff Tendinopathy

Ultrasound in Med. & Biol., Vol. 37, No. 3, pp. 417–425, 2011 Copyright Ó 2011 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter

doi:10.1016/j.ultrasmedbio.2010.11.019

d

Original Contribution REDUCED LOCAL PERFUSION AFTER SHOCK WAVE TREATMENT OF ROTATOR CUFF TENDINOPATHY O,* VITO PESCE,* ANGELA NOTARNICOLA,* LORENZO MORETTI,* SILVIO TAFURI,z MARIA FORCIGNAN
yx and BIAGIO MORETTI*

* Department of Clinical Methodology and Surgical Techniques, Orthopedics Section, Faculty of Medicine and Surgery of University of Bari, General Hospital, Bari, Italy; y Course of Motor and Sports Sciences, Faculty of Medicine and Surgery of University of Bari, General Hospital, Bari, Italy; z Hygiene Section, Department of Biomedical Sciences and Human Oncology, Faculty of Medicine and Surgery of University of Bari, General Hospital, Bari, Italy; and x SITOD, Italian Society of Shock Waves Therapy, Naples, Italy (Received 6 August 2010; revised 10 October 2010; in final form 30 November 2010)

Abstract—A marked neovascularity has been demonstrated in tendinopathies, due to the inflammatorydegenerative process. The aim of this study was to assess the effect of extracorporeal shock wave therapy (ESWT) on tissue perfusion in the treatment of tendinopathy. An observational clinical study was made of 30 patients undergoing ESWT for tendinopathy of the rotator cuff. A clinical improvement was obtained in 65.6% of patients at 2 and 6 months. This was associated with a statistically significant reduction in the oxygen tissue saturation, measured by oxymetry that was apparent already during treatment, as well as at subsequent followup visits. The reduced perfusion achieved with ESWT supports the hypothesis that this treatment can regulate the inflammatory process and offset increased vascularization, restoring physiologic tendon conditions. (E-mail: [email protected]) Ó 2011 World Federation for Ultrasound in Medicine & Biology. Key Words: Shock waves, Neovascularity, Tendinopathy, Oxymetry.

INTRODUCTION

2009). In view of this finding, Alfredson and Ohberg (2005) suggested treating tendinosis by sclerosing procedures, reporting a significant regression of the clinical and anatomopathologic picture after such treatment. There is currently great interest in the literature in the use of extracorporeal shock wave therapy (ESWT) to treat tendinosis, and in ascertaining the mechanism of action of this treatment bearing in mind the good results reported, featuring success rates ranging from 50% to 70% (Rebuzzi et al. 2008). ESWT was first applied in a patient in 1980 to disintegrate kidney stones (Chaussy et al. 1980). The method has since been extended to the treatment of musculoskeletal diseases like calcific tendinosis, to induce lithotripsy of the calcified metaplasia (Loew et al. 1995). Shockwaves are defined as transient pressure oscillations that propagate in three dimensions and typically bring about a clear increase in pressure within few nanoseconds (Hundt 1974). There are very rapidly rising positive pressure impulses from 5 to 120 MPa in around 5 ns, followed by a decrease to negative pressure values of –20 MPa (Staudenraus 1995). When a shock wave bombards a tissue, we must consider the presence of two effects: the stress-related phenomenon induced by the ultra-short rise time around

The treatment of tendinopathy is still a challenge because the etiopathogenic mechanism triggering this painful disorder is still not entirely clear, although an inflammatory, degenerative pathogenic model has been proposed (Cook et al. 2009). In fact, considerable volume of research has shown that in tendinopathy conditions there are high concentrations of substance P, interleukin 1, metalloproteinases and vascular endothelial growth factor (VEGF) (Fan et al. 1993; Sakai et al. 2001; Voloshin et al. 2005). The neovascularization process thus induced, characterized by the formation of a rich vascular microcirculation in the tendon tissue, is thought to provoke irritation of the surrounding nerve tissue, triggering local painful reaction (Alfredson et al. 2003a). Some authors have recently demonstrated the prevalence of angiogenesis in the shoulder affected by rotator cuff tendinosis compared with the contralateral unaffected shoulder (Lewis et al. Address correspondence to: Angela Notarnicola, Department of Clinical Methodology and Surgical Techniques, Orthopedics Section, Faculty of Medicine and Surgery of University of Bari, General Hospital, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail: [email protected] 417

418

Ultrasound in Medicine and Biology

5 ns and the cavitation bubbles produced at the interface between the solid and the surrounding liquid. These two physical effects work synergically to produce shock wave (SW) action. In urology lithotripsy, the former stress effect of SW, is important to disintegrate the kidney stones but the successive cavitation effect is able to produce fine passable fragments, which are most critical for clinical success. The cavitation is widely documented in soft tissue to result in vessel rupture and angiogenesis. In vitro studies of human umbilical venous endothelial cells treated with energy density flux (EDF) , 0.09 mJ/mm2, corresponding to just 10% of the energy used for renal lithotripsy, have demonstrated an increased expression of VEGF and its receptor Flt-1 (Nishida et al. 2004), causing migration and proliferation of the endothelial cells in situ (a neoangiogenic effect). In osteoblast cultures, the formation of capillary vessels has been observed (a vasculogenic effect) due to the recruitment of bone marrow-derived endothelial progenitor cells (Wang et al. 2004). Moreover, in skin tissue a stimulated secretion of angiogenic factors have been observed (a paracrine effect) (Huemer et al. 2005). This neovascularization effect is, therefore, useful in the treatment of refractory ulcers and wounds, skin flaps (Huemer et al. 2005), osteonecrosis (Ma et al. 2007), delayed fracture consolidation (Wang 2003) and myocardial ischemia (Nishida et al. 2004). However, in calcific tendinosis apart from disaggregating the calcifications, immediate analgesic and anti-inflammatory effects were obtained, as well as long-term (1–4 months) regenerative stimuli (Wang et al. 2003). This efficacy has been mainly correlated to an increased synthesis of nitric oxide, an important mediator of anti-inflammatory, angiogenic and vasodilation actions (Mariotto et al. 2005). To exploit the anti-inflammatory and regenerative effects of this treatment, it has since been applied to treat noncalcific tendinopathies, such as rotator cuff tendinosis, epicondylitis, plantar fascitis, Achilles and knee-cap tendinopathy. Experimental research studies of tendinosis have demonstrated a SW neoangiogenic effect (Wang et al. 2002, 2003) that raises some doubts about how the success is obtained, in the sense that if neovascularization is responsible for the pathogenic mechanism and painful reaction, why should ESWT, which induces a local neoangiogenic reaction, be able to relieve the clinical picture? Would it not seem more reasonable that neoangiogenic stimuli should further aggravate the condition? We designed an observational clinical study of patients affected by unilateral tendinosis of the rotator cuff undergoing ESWT, monitoring the tissue oxymetry values during the treatment cycle and follow-up. In fact, in this clinical model, oxymetry can indirectly reveal

Volume 37, Number 3, 2011

even modest increases in the local microcirculation that are not detectable by power-Doppler (Voelckel et al. 1998). Indeed, in a previous preliminary experience, we had monitored patients undergoing ESWT by power-Doppler but were unable to demonstrate evident differences either during treatment or at follow-up. Power-Doppler can assess high velocity flows, especially in the large vessels, but is less efficient in the study of low velocity flows in the microcirculation and the relative regional perfusion (Newman et al. 1994; Eriksson et al. 1991). As Erikson and colleagues (1991) point out, Doppler examinations are designed to assess the mean or maximal velocity in a vessel rather than ‘‘inflow’’ to a tissue. For this reason, therefore, we adopted oxymetry as the assessment method since it may be more sensitive to alterations in the microcirculation (Fassiadis et al. 2006; Spencer et al. 2007). MATERIALS AND METHODS The study was conducted at the Operative Units of Orthopedics and Traumatology of Bari University Hospital from February to September 2009. Having obtained prior approval from the local ethics committee, 30 patients were recruited for the study after giving written informed consent to participate. Inclusion criteria were: (1) a clinical and ultrasound (US) diagnosis of unilateral noncalcific tendinosis of the supraspinal shoulder tendon; (2) age between 45 and 75 years; (3) a clinical history of tendinosis lasting at least 6 months and not more than 18 months; (4) US findings of thickening and nonhomogeneity of the supraspinatus (SS) tendon insertion using a linear 7.5 Hz probe (MyLab 50, Esaote, Italy) (the conventional US reports include the following findings: shape, normal or spindle; echogenicity: homogeneous or nonhomogeneous) (Zanetti et al. 2003); and (5) indications for ESWT. Exclusion criteria included: (1) previous trauma or instability of the shoulder; (2) US findings of thinning or lesions of the supraspinatus tendon insertion; (3) comorbidities (diabetes mellitus, renal failure, collagen disorders, rheumatic disease, etc); (4) the administration of cortisone infiltrating therapy in the previous 6 months; (5) previous shoulder surgery; and (6) contraindications for ESWT (cancer or infections of the affected field, clotting diseases, a history of epilepsy, the presence of a pacemaker, pregnancy, anticoagulation therapy). The study included 30 patients, 17 males and 13 females, mean age 62.37 years (range, 45–78; SD 5 9.2), with a clinical history of intense pain in one shoulder lasting a mean of 9.43 months (range, 7–14; SD 5 1.9). Patients were clinically assessed with the visual analog scale (VAS) pain scale (0 5 no pain and 10 5 the worst possible pain) and constant score (,115 an ‘‘excellent’’

ESWT on tissue perfusion in the treatment of tendinopathy d A. NOTARNICOLA et al.

clinical picture, 11–20 5 ‘‘good’’, 21–30 5 ‘‘fair’’, 31–100 5 ‘‘poor’’), as well as US (three possible situations: nonhomogeneity and thickening of the supraspinatus tendon, improvements of the nonhomogeneity and thickening compared with the previous assessment, resolution) at the time of enrolment and at follow-up (FU) at 2 and 6 months after the last of the three SW treatment administrations (Table 1). Before each session, and at each FU, we recorded the tissue oxymetry values of the symptomatic and contralateral shoulders, using the cerebral and somatic/peripheral oxymeter INVOS 5100C (Somanetics Corporation, Troy, MI, USA). This device is approved by the Food and Drug Administration (FDA) for use to monitor adult and pediatric patients, newborns and premature infants, when their clinical conditions pose a risk of brain or body hypoperfusion or ischemia, as in cardiosurgery, vascular surgery, cardiac catheterization procedures, postoperative intensive care, and neonatal and pediatric intensive care. The system exploits the principle of near-infrared spectroscopy (NIRS) and is equipped with the SomaSensor and NIRSensor (Somanetics Corporation) LED phototherapy device that emits a light source with a wavelength of 650 nm to 1100 nm and a dual photosensor that records different hemoglobin absorption levels according to the degree of oxygenation. This bloodless, noninvasive technique provides information on the oxygen tissue saturation levels (cerebral or somatic) and indirect data on regional perfusion. We positioned the sensor under US-guidance at the level of the supraspinal insertion of the humerus with the shoulder in extra-rotation and adduction. ESWT was administered with a Minilith SL1 (Storz, Swiss) electromagnetic generator equipped with in-line US-guidance, during three sessions, at 3–4 day intervals, emitting 2000 impulses with an energy flux density (EFD) ranging from 0.04 to 0.07 mJ/mm2. The three dimensions of focal volume that characterized this shock wave are 5.5 mm, 5.5 mm and 35.3 mm and the section is 95 mm. When minimal energy is generated, DIGEST (2000) calculated that at –6 dB of the focal area, the positive energy and the total energy are respectively 1.23 mJ and 2.59 mJ. At 5 MPa, they are 1.77 mJ and 4.03 mJ and, at 5 mm from the focal area, they are 0.91 mJ and 1.91 mJ. No local anesthesia was needed, in accordance with the ISMST guidelines (Tiele 2009). ESWT, clinical monitoring and oxymetry using the NIRS system were all performed by the same operator, a physiatrist at our Unit, and US monitoring was always done by the same radiologist at the Radiology Operative Unit of our University Hospital, using a linear 7.5 MHz probe (MyLab 50). Statistical analysis Continuous variables are expressed as means, standard deviation (SD) and range. Categorical variables

419

are shown as proportions. The Kruskal-Wallis test for independent samples was used to compare continuous variables. A value of p , 0.05 was taken as statistically significant. The VAS, constant score and percent oxymetry values were compared with those recorded at enrolment; we also studied the oxymetric differences between the values for the affected and the healthy shoulder. A linear regression model was designed to calculate the coefficient of linear determination for the valuation of the correlation between the values of the pain scale (VAS) and the values of oxygen tissue saturation in the pathologic shoulder. Data processing was done with Epi-Info 6.00 software (public domain softwareCDC Atlanta, GA; WHO, Geneva, Switzerland). RESULTS At entry to the study, patients had a mean VAS score of 8.3 (range, 6–10, SD 5 1.1), a mean constant score of 46.9 (range, 35–60, SD 5 7.3) and these conditions were classified as ‘‘poor’’. In all cases, US showed a thickened, nonhomogeneous supraspinal tendon. The mean tissue oxymetry value was 80.1% (range, 67–89, SD 5 6.9) at the affected shoulder vs. 45.7% (range, 40–52, SD 5 3.6) at the contralateral normal shoulder, this difference being statistically significant (p , 0.0001) (Table 2). At the second ESWT session, the oxymetry value at the affected shoulder (mean 62.7%, range, 45–79, SD 5 9.4%) had significantly declined (p , 0.0001) while the values were unchanged in the contralateral shoulder (mean 45.8%, range, 40–51, SD 5 2.9; p . 0.05). At the third session, the oxymetry values had dropped still further (mean 57.4%, range, 42–80, SD 5 12.2), again statistically significantly compared with the baseline values of the same shoulder (p , 0.001). We did not find any significant changes in the unaffected shoulder (mean 45.7%, range, 41–54 SD 5 3.2) compared with its own value at the baseline (p . 0.05). At the 2-month FU, the VAS (4.2, range, 1–8, SD 5 2.2) (p , 0.001) and constant scores (23, range, 7–50, SD 5 14.2) had significantly reduced (p , 0.001) and the conditions were classified as ‘‘excellent’’ in eight patients (26.66%), ‘‘good’’ in eight (26.66%), ‘‘fair’’ in four (13.33%), while the remaining 10 patients (33.33%) were still in ‘‘poor’’ conditions. US revealed complete resolution of the condition in six patients (20%), an improvement in 17 (56.66%) vs. persistence in 6 (20%). The oxymetry values were significantly lower in the affected shoulder (53.2%, range, 40–76, SD 5 12) (p , 0.001), with no particular changes in the contralateral joint (44.9%, range, 40–49, SD 5 2.4) (p . 0.05). At the 6-month FU, the improved conditions persisted, VAS (2.9, range, 1–7, SD 5 2.2) (p , 0.001) and constant scores (20.3, range, 8–50 SD 5 15.4)

420

Ultrasound in Medicine and Biology

Volume 37, Number 3, 2011

Table 1. Age, gender, pain scores (VAS), constant score and US tendon valuation of the patients in the study at the fist session of SW treatment and after 2 and 6 months At 1st session of SW

Patient

Age

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 mean SD

45 56 73 67 65 48 65 64 57 48 68 76 78 70 64 65 76 54 58 78 63 54 58 71 65 64 64 48 55 54 62 9.3

m f f f m m f m m f f m f m m f f m m f f f m m m f m m m m

After 2 months

After 6 months

Time from the beginning tendinopathy (months)

VAS

Constant score

US exam

VAS

Constant score

US exam

VAS

Constant score

US exam

12 7 8 9 11 14 12 10 9 8 7 8 9 10 12 13 14 10 8 8 9 7 8 9 8 8 9 8 9 9 9.4 2

8 9 10 8 7 8 8 9 7 6 8 9 10 8 9 8 10 8 7 8 8 9 10 10 7 6 8 9 8 8 8.3 1.1

51 45 50 39 42 55 45 56 54 52 39 45 49 58 41 39 35 36 42 45 35 50 60 45 50 40 60 55 50 45 46.9 7.3

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 0

4 5 4 5 3 4 2 3 3 2 2 4 2 1 3 1 4 3 2 3 2 7 8 8 6 6 7 8 7 7 4.2 2.2

14 16 18 22 32 24 29 25 10 14 10 8 8 10 7 10 8 14 12 11 13 35 40 40 40 36 50 50 45 40 23 14.2

2 1 2 2 2 2 2 2 2 1 1 2 1 1 2 1 2 2 2 2 2 2 3 2 3 2 3 3 3 3 2 0.6

3 3 2 2 2 1 1 2 2 1 1 2 1 1 1 1 2 1 1 1 2 5 7 7 5 5 6 7 6 6 2.9 2.2

10 12 10 10 25 8 8 21 10 11 8 8 8 8 8 10 8 12 12 11 12 40 35 35 40 35 50 50 50 45 20.3 15.4

1 1 2 2 2 2 2 2 2 1 1 2 1 1 2 1 1 2 2 2 2 2 3 2 3 2 2 3 3 3 1.9 0.7

At US examination: 3 5 nonhomogeneity and thickening of the supraspinatus tendon; 2 5 improvement; 15 resolution. VAS 5 visual analog scale; US 5 ultrasound; SW 5 shock waves.

(p , 0.001) yielding the following classification of the patient sample: 12 patients (40%) ‘‘excellent’’, seven (23.33%) ‘‘good’’, one (3.33%) ‘‘fair’’ and the remaining nine (30%) still in ‘‘poor’’ conditions. US demonstrated complete resolution of the initial picture in eight patients (26.66%), an improvement in 17 (56.66%) and persistence in five (16.67%). There was a statistically significant reduction in the oxymetry values in the affected shoulder compared with baseline (mean 51.5%, range, 40–72, SD 5 11.2) (p , 0.001), and a nonsignificant decline in the healthy shoulder (mean 43.4%, range, 40–48; SD 5 2.9) (p 5 0.06) (Figs. 1 and 2). We found a correlation between the values of VAS and oxygen tissue saturation in the pathologic shoulder (r2 5 0.165; p , 0.0001; Fig. 3). There was a statistically significant difference at ultrasound findings for values of oxymetry of the pathologic shoulder in patients with resolution (mean 5 45.4; SD 5 6.1), improvement

(mean 5 50; SD 5 9.9) and nonhomogeneity and thickening of the supraspinatus tendon (mean 5 76.9; SD 5 8.4; H 5 59.4; p , 0.0001). DISCUSSION In this work, we found that 2 months after SW treatment for shoulder tendinopathy, there was a clinical improvement in 65.6% of patients. It was associated to the US change and to a significant reduction in the perfusion valued by oxygen tissue saturation. This condition was persistent at the revaluation at the sixth month. We marked a discrepancy between six patients with an unchanged US images and 10 poor clinical conditions at the second month and between five patients with an unchanged US images and nine poor clinical conditions at the sixth month. These results are in agreement with those found by other authors on the lack of correlation

ESWT on tissue perfusion in the treatment of tendinopathy d A. NOTARNICOLA et al.

421

Table 2. Oxygen saturation (52%) of both shoulders of the patients during the study at each one of three SW sessions and at the follow-ups after 2 and 6 months 1st session of SW

2nd session of SW

3rd session of SW

After 2 months

After 6 months

Patient

O2% pathologic shoulder

O2% healthy shoulder

O2% pathologic shoulder

O2 % healthy shoulder

O2 % pathologic shoulder

O2% healthy shoulder

O2% pathologic shoulder

O2% healthy shoulder

O2% pathologic shoulder

O2% healthy shoulder

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 mean SD

71 85 84 75 83 72 77 83 67 88 85 87 68 85 88 89 78 79 76 69 78 88 87 79 68 76 86 79 87 85 80.1 6.9

45 40 43 41 47 50 42 46 50 52 40 47 42 50 45 50 43 41 42 45 48 46 43 50 43 47 50 43 50 49 45.7 3.6

55 72 60 55 66 65 60 65 48 69 65 62 45 59 47 55 60 50 60 52 54 70 75 77 65 70 79 74 71 75 62.7 9.4

44 50 45 42 50 46 43 50 51 48 42 48 40 45 46 45 47 43 43 44 48 42 46 48 44 43 51 44 48 47 45.8 2.9

50 73 65 50 55 50 52 50 43 55 50 47 42 47 50 45 50 45 45 50 49 72 75 74 67 68 72 72 78 80 57.4 12.2

46 43 42 43 42 50 45 45 49 46 44 44 41 45 42 45 45 44 46 45 47 43 45 49 54 45 54 44 49 48 45.7 3.2

48 60 60 45 50 45 46 45 42 49 40 46 40 44 43 41 48 44 42 45 47 69 76 69 62 65 70 69 70 76 53.2 12

45 46 46 45 40 43 41 43 49 47 41 45 44 46 42 43 45 46 42 45 45 44 45 48 49 44 49 46 47 47 44.9 2.4

47 55 52 48 45 40 42 43 42 47 42 44 40 44 42 40 47 43 42 46 48 68 72 72 59 63 71 65 65 70 51.5 11.2

42 44 42 42 40 42 44 41 43 46 40 48 40 40 40 40 45 40 40 45 45 43 47 46 48 45 43 42 48 50 43.4 2.9

between the parameters of subjective and clinical functional evaluation and diagnostic examinations, and may be explained by a the different, subjective perception of the resolution of the patients’ symtomatology (Benazzo et al. 2008; Agletti et al. 2004). In no patient, the oxygen saturation decreases but pain condition remains poor or oxygen saturation remains unchanged but pain condition improves. In fact we found a correlation between pain scores and oxygen saturation. We also identified a relationship between tendon thicknesses deduced by ultrasound and oxygen saturation. The histologic picture of tendinopathies is defined as ‘‘angiofibroblastic tendinosis’’ (Nirschl 1990) on the basis of power-Doppler US that invariably reveals vascular hyperplasia (Zanetti et al. 2003; Rees et al. 2006) and biopsy, which show an increased microcirculation density, associated with the proliferation of endothelial cells, smooth muscle cells and perivascular inflammatory cells as well as fibroblasts and nociceptive fibers (Lian et al. 2007; Scott et al. 2008a, 2008b). Many immunohistochemical studies have also demonstrated high glutamine levels (a potent pain modulator in

the central nervous system) and receptors on the nerve fibers surrounding the tendon in patients with painful tendinopathies (Alfredson et al. 2001, 2003a, 2003b). These findings indicate that in tendon disorders the nociceptive nerve fibers are accompanied by the formation of new vessels. This hypothesis is supported by the success obtained with sclerosing treatment of neovessels in tendinosis (Ohberg et al. 2002, 2003; Tasto et al. 2005). The term tendinosis is used to refer to a thickened, slightly nonhomogeneous tendon (Ashman et al. 2001). Tenocyte hyperplasia, prominent neovascularization with endothelial hyperplasia, loss of longitudinal collagenous architecture and microtears with collagen fiber separation have been found in histologic specimens in patients with patellar tendinosis (Yu et al. 1995). Similar abnormalities with alterations in fiber structure, focal variations in cellularity and neovascularization have also been histologically demonstrated in thickened, nonhomogeneous Achilles tendons (Rolf et al. 1997). Movin and colleagues (1997) found neovascularization in 26 of 40 tendon specimens obtained during

422

Ultrasound in Medicine and Biology

90 80

****

70

*

60

*

*

*

50 40 30 20

pain s houlder

10

c ontr o- later al s houlder

0 pre-SW

2nd s es s ion

3rd s es s ion

2nd month

6th month

comparison with pain shoulder before SW =* p<0.05 comparison with controlateral shoulder before SW= ** p<0.05

Fig. 1. Graph shows the mean percentage tissue saturation oxymetry values of the affected shoulder (blue line) and contralateral shoulder (pink line) during ESWT sessions and at 2- and 6-month follow-up.

semiquantitative histologic analysis of painful Achilles tendons. A 55% prevalence of neovascularization has been reported in such patients (Zanetti et al. 2003). Recent clinical and experimental research has indicated a possible pathogenic role of angiogenesis in inducing and maintaining tendinosis (Pufe et al. 2005; Rees et al. 2006). VEGF, a potent angiogenic cytokine, plays a main role in pathologic soft tissue processes by regulating the response to hypoxia and inflammation (Yamazaki et al. 2006). In fact, VEGF expression is increased in response to mechanical loads and trauma, promoting the proliferation, migration and survival of endothelial cells and modulating the permeability of the capillaries in response to local edema (Abraham et al. 2002). Some authors (Lewis et al. 2009; Newman et al. 1994) have demonstrated a greater perfusion in painful

Volume 37, Number 3, 2011

shoulder tendinosis, with pictures ranging from a moderate neovascularization (where the presence of neovessel formation is undetectable at power-Doppler) to increases exceeding 50% of the extension of the vessels in the tendon tissue. It has been hypothesized, on the basis of results in experimental studies, that shock waves applied to the tendon tissue increase VEGF synthesis, inducing new vessel formation (Wang et al. 2002, 2003), increased transforming growth factor-b1 and insulin-like growth factor-I expression and fibroblasts (Chen et al. 2004), stimulating the tenocyte metabolism and extracellular matrix deposits (Bosch et al. 2007), as well as inhibiting the synthesis of interleukin-1 and metalloproteinases, thus, limiting the inflammatory process (Han et al. 2009). Overall, this action could restore the tissue metabolic balance in which the cell proliferation stimuli and recovery of the extracellular matrix condition and are, in turn, modulated by the local vascular response. This depends on the clinical phase of the disease: in the overtly inflammatory phase, there is a restrictive effect and, in the cold phase, a neoangiogenic effect, with a largely degenerative action, preventing the possible evolution to a tendon lesion (Riley et al. 1994). We can support that when the pathologic process is characterized by a prevalence of flogosis (phlogosis), as in the tendinitis and bursitis, the SW wash out the inflammatory mediators, turning off the associated angiogenesis process (Mariotto et al. 2009). In ischemic conditions, however, as tendinosis in the critical area of bone insertion, skin ulcers, delayed union and complex regional pain syndrome (Wang et al. 2003; Moretti et al. 2009; Bara et al. 2000; Notarnicola et al. 2010), when the tissue is damaged by a reduced blood perfusion, the

Fig. 2. US image of the rotator cuff tendon in a patient. The arrow indicates the thickness of the supraspinal tendon. (a) Image at baseline, showing thickening and nonhomogeneity of the tendon. (b) Image at 2 months after ESWT, showing a normal thickness and homogeneity of the supraspinal insertion.

ESWT on tissue perfusion in the treatment of tendinopathy d A. NOTARNICOLA et al.

Fig. 3. Graph shows the correlation between the VAS value and the percentage of oxymetry in pathologic shoulder in the patients of the study.

SW (shock waves) should be able to induce a revascularisation stimulus. We suppose ESWT resets angiogenesis, flogosis and degeneration processes to normal healthy functioning. In this scenario, we carried out this clinical study to verify the effects of ESWT, applied to treat tendinosis, on regional perfusion. Regional oxymetry using the NIRS system (Fassiadis et al. 2006; Spencer et al. 2007) can identify local hyperemia with reliability comparable to that of power-Doppler, providing an indirect measure of tissue O2 saturation and the tissue O2 utilization index (Towse et al. 2005; Muellner et al. 1999; France et al. 2006; van Lieshout et al. 2001). Moreover, it has the advantage of being able to detect perfusion in vessels with a diameter ,0.2 mm, that is the limit of sensitivity of power-Doppler (Voelckel et al. 1998). Owing to the lack of data in literature on the reference range of saturation for normal tendon tissue, we used the contralateral shoulder values as reference physiologic oxymetry values. This demonstrated that the shoulder affected by supraspinal tendinosis had statistically higher perfusion values, due to the ongoing neoangiogenic and inflammatory processes, as already reported in previous experiences with echo-power-Doppler. These values were reduced already by the second ESWT session and gradually returned to values similar to those in the contralateral shoulder over the subsequent follow-up visits. When the SW are applied on tendon, they induce membrane hyperpolarization, activation of the Ras proteins, nonenzymatic synthesis of nitric oxide and the creation of stress fibers and cellular gaps. This can modulate the expression of cytokines and matrix metalloproteinases, inducing an anti-inflammatory effect (Ciampa et al. 2005; Mariotto et al. 2005; Gotte et al. 2002; Mariotto et al. 2009; Seidl et al. 1994; Stojadinovic et al. 2008). The progressive resolution of the inflammation process then limits and reduces the primary local angiogenic response and, thus, modulates the disease process and

423

restores the metabolic and functional balance of the various tendon structures. In view of our results, we hypothesized that in an inflamed tendon (even in a degenerative process) where the angiogenic process is active, ESWT induces an integrated anti-inflammatory and regenerative action on the different tissue components. However, before this work, none supported the hypothesis that SW could reduce the angiogenesis induced by pathologic degeneration in the tendon. Until nowadays it was hypotesized that cavitation effect should be able only to induce vessel rupture and angiogenesis. Han and colleagues demonstrated that ESWT cause a decrease of the expression of high levels of inflammatory mediators as matrix metalloproteinases (MMPs) and interleukins (ILs) in human tendinopathy-affected tenocytes (2009). Other researchers verified that ESW bring on a mitogenic response of tendons (Chen et al. 2004) and that they stimulate tenocyte proliferation and collagen synthesis, mediated by early up-regulation of proliferating cell nuclear antigen (PCNA) and transforming growth factor-b1 (TGF-b1) gene expression, endogenous nitric oxide (NO) release and synthesis and TGF-beta1 protein and then collagen synthesis (Chao et al. 2008). Previous works also verified that SW causes a transient stimulation of metabolism in tendinous structures accelerating the initiation of the healing process in injured tendons (Bosch et al. 2007). An interesting field of research should be the valuation of the possible induction of endogenous angiogenesis inhibitors after a SW tendon treatment, justifying results of our clinical valuation. The discordance we observed in our work of the effects of ESWT between the clinical result, which demonstrated a suppression of local perfusion, and what was previously observed in experimental studies, which showed neoangiogenic stimuli, could be justified by the difference between experimental models and the clinical picture. In fact, in experimental studies, the effects of ESWT were studied in a tendon tissue model with physiologic histocellular characteristics, or in which the pathologic process had been induced only a few hours or days before (Bosch et al. 2007; Chao et al. 2008). Moreover, the tissue samples were frequently animal tissues (Bosch et al. 2007) and only in a few cases were human tenocytes studied (Han et al. 2009). The many studies probing the effects of ESWT to treat tendinosis have demonstrated in vitro and in animal models that multiple enzymatic pathways underlying anti-inflammatory and regenerative actions are activated. In view of our findings, we can state that ESWT used to treat tendinosis acts mainly by modulating the inflammatory process, restoring the balance of the tendon structure in toto, limiting the neoangiogenic process and inducing

424

Ultrasound in Medicine and Biology

a trophic metabolic response in the different tissue components. A notable point is the finding of a reduced perfusion of the microcirculation, measured on quantitative parameters, in the injured tendon after ESWT. Instead, a weak point of this study is the fact that it is not possible to ascertain, by oxymetric monitoring alone, whether this reduced perfusion is caused by vasoconstriction or by inhibiting neoangiogenesis. The phenomenon could be further be studied by integrating other assessment methods, such as laser Doppler flowmetry that can evaluate the endothelial function at the microcirculation level, as well as histologic and immunohistochemical examinations. REFERENCES Abraham D, Taghavi S, Riml P, Paulus P, Hofmann M, Baumann C, Kocher A, Klepetko W, Aharinejad S. VEGF-A and -C but not -B mediate increased vascular permeability in preserved lung grafts. Transplantation 2002;73:1703–1706. Aglietti P, Giron F, Buzzi R, Biddau F, Sasso F. Anterior cruciate ligament reconstruction: One-patellar tendon-bone compared with double semitendinosus and gracilis tendon grafts. A prospective, randomized clinical trial. J Bone Joint Surg Am 2004;86-A:2143–2155. Alfredson H, Forsgren S, Thorsen K, Fahlstr€om M, Johansson H, Lorentzon R. Glutamate NMDAR1 receptors localised to nerves in human Achilles tendons. Implications for treatment? Knee Surg Sports Traumatol Arthrosc 2001;9:123–126. Alfredson H, Lorentzon M, B€ackman S, B€ackman A, Lerner UH. cDNAarrays and real-time quantitative PCR techniques in the investigation of chronic Achilles tendinosis. J Orthop Res 2003a;21:970–975. Alfredson H, Ohberg L, Forsgren S. Is vasculo-neural ingrowth the cause of pain in chronic Achilles tendinosis? An investigation using ultrasonography and colour Doppler, immunohistochemistry, and diagnostic injections. Knee Surg Sports Traumatol Arthrosc 2003b;11:334–338. v. Alfredson H, Ohberg L. Neovascularisation in chronic painful patellar tendinosis–promising results after sclerosing neovessels outside the tendon challenge the need for surgery. Knee Surg Sports Traumatol Arthrosc 2005;13:74–80. Ashman CJ, Klecker RJ, Yu JS. Forefoot pain involving the metatarsal region: Differential diagnosis with MR imaging. RadioGraphics 2001;21:1425–1440. Bara T, Synder M, Studniarek M. The application of shock waves in the treatment of delayed bone union and pseudoarthrosis in long bones. Ortop Traumatol Rehabil 2000;2:54–57. Bosch G, Lin YL, van Schie HT, van De Lest CH, Barneveld A, van Weeren PR. Effect of extracorporeal shock wave therapy on the biochemical composition and metabolic activity of tenocytes in normal tendinous structures in ponies. Equine Vet J 2007;39: 226–231. Benazzo F, Zanon G, Pederzini L, Modonesi F, Cardile C, Falez F, Ciolli L, La Cava F, Giannini S, Buda R, Setti S, Caruso G, Massari L. Effects of biophysical stimulation in patients undergoing arthroscopic reconstruction of anterior cruciate ligament: Prospective, randomized and double blind study. Knee Surg Sports Traumatol Arthrosc 2008;16:595–601. Chao YH, Tsuang YH, Sun JS, Chen LT, Chiang YF, Wang CC, Chen MH. Effects of shock waves on tenocyte proliferation and extracellular matrix metabolism. Ultrasound Med Biol 2008;34: 841–852. Chaussy C, Brendel W, Schmiedt E. Extracorporeally induced destruction of kidney stones by shock waves. Lancet 1980;2:1265–1268. Chen YJ, Wang CJ, Yang KD, Kuo YR, Huang HC, Huang YT, Sun YC, Wang FS. Extracorporeal shock waves promote healing of

Volume 37, Number 3, 2011 collagenase-induced Achilles tendinitis and increase TGF-beta1 and IGF-I expression. J Orthop Res 2004;22:854–861. Ciampa AR, de Prati AC, Amelio E, Cavalieri E, Persichini T, Colasanti M, Musci G, Marlinghaus E, Suzuki H, Mariotto S. Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves. Cook JL, Purdam CR. Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy. Br J Sports Med 2009;43409–43416. DIGEST. Archives of the physical-technical advisory council of the DIGEST. 2000. Eriksson R, Persson HW, Dymling SO, Lindstr€om K. Evaluation of Doppler ultrasound for blood perfusion measurements. Ultrasound Med Biol 1991;17:445–452. Fan TP, Hu DE, Guard S, Gresham GA, Watling KJ. Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists. Br J Pharmacol 1993;110:43–49. Fassiadis N, Zayed H, Rashid H, Green DW. Invos cerebral oximeter compared with the transcranial Doppler for monitoring adequacy of cerebral perfusion in patients undergoing carotid endarterectomy. Int Angiol 2006;25:401–406. France CR, France JL, Patterson SM. Blood pressure and cerebral oxygenation responses to skeletal muscle tension: A comparison of two physical maneuvers to prevent vasovagal reactions. Clin Physiol Funct Imaging 2006;26:21–25. Gotte G, Amelio E, Russo S, Marlinghaus E, Musci G, Suzuki H. Shorttime non-enzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock waves treatment. FEBS Lett 2002;520:153–155. Han SH, Lee JW, Guyton GP, Parks BG, Courneya JP, Schon LC. J. Effect of extracorporeal shock wave therapy on cultured tenocytes. Foot Ankle Int 2009;30:93–98. Huemer GM, Meirer R, Gurunluoglu R, Kamelger FS, Dunst KM, Wanner S, Piza-Katzer H. Comparison of the effectiveness of gene therapy with transforming growth factor-beta or extracorporal shock wave therapy to reduce ischemic necrosis in an epigastric skin flap model in rats. Wound Repair Regen 2005;13:262–268. Hundt E. Die Physik, Bibliographisches Institut Mannheim. Dudenverlag 1974;S360. Lewis JS, Raza SA, Pilcher J, Heron C, Poloniecki JD. The prevalence of neovascularity in patients clinically diagnosed with rotator cuff tendinopathy. BMC Musculoskelet Disord 2009;10:163. Lian Ø, Scott A, Engebretsen L, Bahr R, Duronio V, Khan K. Excessive apoptosis in patellar tendinopathy in athletes. Am J Sports Med 2007;35:605–611. Loew M, Jurgowski W, Mau HC, Thomsen M. Treatment of calcifying tendinitis of rotator cuff by extracorporeal shock waves: A preliminary report. J Shoulder Elbow Surg 1995;4:101–106. Ma HZ, Zeng BF, Li XL. Upregulation of VEGF in subchondral bone of necrotic femoral heads in rabbits with use of extracorporeal shock waves. Calcif Tissue Int 2007;81:124–131. Mariotto S, Cavalieri E, Amelio E, Ciampa AR, de Prati AC, Marlinghaus E, Russo S, Suzuki H. Extracorporeal shock waves: From lithotripsy to anti-inflammatory action by NO production. Nitric Oxide 2005;12:89–96. Mariotto S, de Prati AC, Cavalieri E, Amelio E, Marlinghaus E, Suzuki H. Extracorporeal shock wave therapy in inflammatory diseases: Molecular mechanism that triggers anti-inflammatory action. Curr Med Chem 2009;16:2366–2372. Moretti B, Notarnicola A, Garofalo R, Moretti L, Patella S, Marlinghaus E, Patella V. Shock waves in the treatment of stress fractures. Ultrasound Med Biol 2009;35:1042–1049. Movin T, Gad A, Reinholt FP, Rolf C. Tendon pathology in longstanding achillodynia: Biopsy findings in 40 patients. Acta Orthop Scand 1997;68:170–175. Muellner T, Nikolic A, Schramm W, Vecsei V. New instrument that uses near-infrared spectroscopy for the monitoring of human muscle oxygenation. J Trauma 1999;46:1082–1084. Newman JS, Adler RS, Bude RO, Rubin JM. Detection of soft-tissue hyperemia: Value of power Doppler sonography. AJR Am J Roentgenol 1994;163:385–389.

ESWT on tissue perfusion in the treatment of tendinopathy d A. NOTARNICOLA et al. Nirschl RP. Patterns of failed healing in tendon injury. In: Leadbetter W, Buckwalter J, Gordon S, (eds). Sports-induced inflammation: Clinical and basic science concepts. Park Ridge, IL: American Academy of Orthopaedic Surgeons; 1990. p. 577–585. Nishida T, Shimokawa H, Oi K, Tatewaki H, Uwatoku T, Abe K, Matsumoto Y, Kajihara N, Eto M, Matsuda T, Yasui H, Takeshita A, Sunagawa K. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 2004;110:3055–3061. Notarnicola A, Moretti L, Tafuri S, Panella A, Filipponi M, Casalino A, Panella M, Moretti B. Shockwave therapy in the management of complex regional pain syndrome in medial femoral condyle of the knee. Ultrasound Med Biol 2010;36:874–879. Ohberg L, Alfredson H. Ultrasound guided sclerosis of neovessels in painful chronic Achilles tendinosis: Pilot study of a new treatment. Br J Sports Med 2002;36:173–175. Ohberg L, Alfredson H. Sclerosing therapy in chronic Achilles tendon insertional pain-Results of a pilot study. Knee Surg Sports Traumatol Arthrosc 2003;11:339–343. Pufe T, Petersen WJ, Mentlein R, Tillmann BN. The role of vasculature and angiogenesis for the pathogenesis of degenerative tendons disease. Scand J Med Sci Sports 2005;15:211–222. Rebuzzi E, Coletti N, Schiavetti S, Giusto F. Arthroscopy surgery versus shock wave therapy for chronic calcifying tendinitis of the shoulder. J Orthop Traumatol 2008;9:179–185. Rees JD, Wilson AM, Wolman RL. Current concepts in the management of tendon disorders. Rheumatology (Oxford) 2006;45: 508–521. Riley GP, Harrall RL, Constant CR, Chard MD, Cawston TE, Hazleman BL. Tendon degeneration and chronic shoulder pain: Changes in the collagen composition of the human rotator cuff tendons in rotator cuff tendinitis. Ann Rheum Dis 1994;53:359–366. Rolf C, Movin T. Etiology, histopathology, and outcome of surgery in achillodynia. Foot Ankle Int 1997;18:565–569. Sakai H, Fujita K, Sakai Y, Mizuno K. Immunolocalization of cytokines and growth factors in subacromial bursa of rotator cuff tear patients. Kobe J Med Sci 2001;47:25–34. Scott A, Lian Ø, Bahr R, Hart DA, Duronio V, Khan KM. Increased mast cell numbers in human patellar tendinosis: Correlation with symptom duration and vascular hyperplasia. Br J Sports Med 2008a;42:753–757. Scott A, Lian Ø, Roberts CR, Cook JL, Handley CJ, Bahr R, Samiric T, Ilic MZ, Parkinson J, Hart DA, Duronio V, Khan KM. Increased versican content is associated with tendinosis pathology in the patellar tendon of athletes with jumper’s knee. Scand J Med Sci Sports 2008b;18:427–435. Seidl M, Steinbach P, W€orle K, Hofst€adter F. Induction of stress fibres and intercellular gaps in human vascular endothelium by shockwaves. Ultrasonics 1994;32:397–400.

425

Spencer CT, Bryant RM, Byrne B, Heal E, Margossian R, Cade WT. Pediatric congenital and acquired heart disease: What else is new? Abstract 2769: Impaired skeletal muscle oxygen utilization contributes to exercise intolerance in Barth Syndrome. Circulation 2007;116:II–615. Staudenraus J. In vivo Strasswllenmessung. In Chaussy (Hrsg). Die Stosswelle in Forschung und Kinik. Attempto Verlag 1995; S21–S26. Stojadinovic A, Elster EA, Anam K, Tadaki D, Amare M, Zins S, Davis TA. Angiogenic response to extracorporeal shock wave treatment in murine skin isografts. Angiogenesis 2008;11:369–380. Tasto JP, Cummings J, Medlock V, Hardesty R, Amiel D. Microtenotomy using a radiofrequency probe to treat lateral epicondylitis. Arthroscopy 2005;21:851–860. Tiele R. New guidelines for ESWT. Newsletter ISMST 2009;5:20. Towse TF, Slade JM, Meyer RA. Effect of physical activity on MRI-measured blood oxygen level-dependent transients in skeletal muscle after brief contractions. J Appl Physiol 2005;99:715–722. van Lieshout JJ, Pott F, Madsen PL, van Goudoever J, Secher NH. Muscle tensing during standing: Effects on cerebral tissue oxygenation and cerebral artery blood velocity. Stroke 2001;32:1546–11551. Voloshin I, Gelinas J, Maloney MD, O’Keefe RJ, Bigliani LU, Blaine TA. Proinflammatory cytokines and metalloproteases are expressed in the subacromial bursa in patients with rotator cuff disease. Arthroscopy 2005;21:1076. Voelckel S, Bodner G, Voelckel W, Stadlwieser C, De Koekkoek P, Springer P. Doppler ultrasound determination of vascular resistance in arteriovenous shunts of the finger tip. Ultraschall Med 1998;19: 181–186. Wang CJ, Huang HY, Pai CH. Shock wave-enhanced neovascularization at the tendon-bone junction: An experiment in dogs. J Foot Ankle Surg 2002;41:16–22. Wang CJ. An overview of shock wave therapy in musculoskeletal disorders. Chang Gung Med J 2003;26:220–232. Wang CJ, Wang FS, Yang KD, Weng LH, Hsu CC, Huang CS, Yang LC. Shock wave therapy induces neovascularization at the tendon-bone junction. A study in rabbits. J Orthop Res 2003;21:984–989. Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, Huang HC, Yang YJ, Yang KD. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1a and VEGF-A expression in shock wave-stimulated osteoblasts. J Biol Chem 2004;279:10331–10337. Yamazaki Y, Morita T. Molecular and functional diversity of vascular endothelial growth factors. Mol Divers 2006;10:515–527. Yu JS, Popp JE, Kaeding CC, Lucas J. Correlation of MR imaging and pathologic findings in athletes undergoing surgery for chronic patellar tendinitis. AJR Am J Roentgenol 1995;165:115–118. Zanetti M, Metzdorf A, Kundert HP, Zollinger H, Vienne P, Seifert B, Hodler J. Achilles tendons: Clinical relevance of neovascularization diagnosed with power Doppler US. Radiology 2003;227:556–560.