Maturation of Lesions Induced by Myocardial Cavitation-Enabled Therapy

Abstract

Myocardial contrast echocardiography at enhanced therapeutic parameters may be a novel means of tissue reduction therapy, as for hypertrophic cardiomyopathy. Dahl/SS rats were anesthetized and treated by high amplitude pulsed ultrasound guided by 10 MHz ultrasound images. Contrast microbubbles were infused via the tail vein during intermittent pulse-burst exposure at 4 MPa. A sham group, a low impact group (group A, 5 cycle pulses with Gaussian modulation and 1:4 trigger for 5 min) and a high impact group (group B, 10 cycle pulses with 4 ms square modulation and 1:8 trigger for 10 min) were tested. Higher exposure used in group B yielded more substantial injury than lower exposure in group A. Treated rats in both group A and B had significant increases in wall thickness measured by echocardiography the next day, which returned to normal by the end of 6 weeks. Six weeks after ultrasound exposure, heart tissue samples showed tissue fibrosis in Masson’s trichrome stained histology. Maturation of lesions involved fibrosis replacement, preserving structural tissue integrity. This study showed that myocardial injury noted previously progresses into permanent loss of myocardial tissue that may be sufficient for possible hypertrophic cardiomyopathy therapy. More research is needed to define the treatment parameters required for symptomatic relief for hypertrophic cardiomyopathy.

Multiple ultrasound cavitation-enabled treatments for myocardial reduction

“…The total “macrolesion” can be sufficient for therapy of hypertrophic cardiomyopathy both in terms of heart tissue volume reduction and in akinesis of wall motion and strain. Previous work with Dahl SS rats had demonstrated substantial tissue impact, with minimal impact on heart function after healing for single long (600 s) treatments [ 17 , 18 ]. Adjuvant treatment with methylprednisolone and losartan reduce the initial swelling and aid in reduction of fibrosis.…”

“…All in vivo animal procedures were conducted with the approval and guidance of the University Committee on Use and Care of Animals of the University of Michigan. Normal Dahl SS rats (Charles River, Wilmington, MA, USA) were used for this study for comparison to earlier work [ 14 , 17 ]. For ultrasound treatment, the rats were anesthetized by intraperitoneal injection of ketamine (90 mg kg −1 ) and xylazine (9 ml kg −1 ) and the left thorax was shaved and depilated for ultrasound transmission to the heart.…”

“…A continuous infusion of a microbubble suspension was given during treatment. The suspension was prepared to closely duplicate the ultrasound contrast agent Definity® (Lantheus Medical Imaging, Inc., N. Billerica, MA), as described previously [ 17 , 21 ]. This suspension served as the source of in vivo cavitation nuclei for MCET, and contained 3.7 ± 0.3 (10 9 ) microbubbles per mL of 1.8 ± 0.11 μm diameter.…”

“…Longer-term maturation of the myocardial volumes with MCET microlesions was studied to assess the potential therapeutic effect in normal Dahl-SS rats [ 17 ], and in the SS-16 BN rat model of HCM [ 18 ]. The consomic Dahl SS rat with chromosome 16 from brown Norway rats develops progressive left ventricular (LV) hypertrophy without hypertension [ 19 ].…”

“…The consomic Dahl SS rat with chromosome 16 from brown Norway rats develops progressive left ventricular (LV) hypertrophy without hypertension [ 19 ]. For normal rats, significant inflammatory response to the injury increased the heart wall thickness the day after treatment, as measured by echocardiography [ 17 ]. After 4 weeks, no significant tissue reduction was noted in the treated region with scattered areas of tissue fibrosis.…”