Rationale:
Tissue inflammation and subsequent fibrosis contribute to ventricle remodelling after ischemic injury, and have emerged as viable therapeutic targets. Comparatively little is understood about the dynamics of inflammation and fibrosis in non-ischemic heart failure, which is challenging to interrogate longitudinally.
Objective:
To investigate the interplay between ventricle loading conditions, tissue inflammation, and progressive fibrosis using non-invasive multimodality molecular imaging to characterize these processes in pressure overload heart failure.
Methods and Results:
We evaluated cardiac inflammation using positron emission tomography radiotracer 68Ga-pentixafor which binds to chemokine CXC-motif receptor 4 (CXCR4). Over the first 7d after transverse aortic constriction (TAC), CXCR4 imaging identified diffuse elevated myocardial inflammation throughout the left ventricle (+34%, p<0.001), returning to sham levels over 6 weeks after surgery. This transient signal colocalized to local enrichment of CD68 macrophages, as confirmed by autoradiography and immunostaining. Magnetic resonance imaging demonstrated a parallel prolongation of myocardial T1 relaxation time in TAC mice, persisting from 8d to 6 weeks after surgery (+22%, p=0.003). The persistent imaging signal correlated to increased tissue fibrosis on histology. Molecular imaging at 1 week after surgery correlated independently with the change in ventricle geometry over the subsequent 3 weeks (CXCR4, rpartial=0.670, p=0.024; T1, rpartial=0.689, p=0.019). Alleviation of ventricle pressure by mechanical unloading restored not only cardiac function and geometry, but also attenuated global inflammation and normalized T1 relaxation time. This finding demonstrates the capacity to monitor therapeutic intervention by serial molecular imaging.
Conclusions:
Inflammation and fibrosis are implicated in the early response to pressure overload, and may be sensitively monitored by multimodality imaging. Such multimodality molecular imaging approaches may guide novel therapeutic approaches in non-ischemic heart failure.
Growth of molecular imaging bears potential to transform nuclear cardiology from a primarily diagnostic method to a precision medicine tool. Molecular targets amenable for imaging and therapeutic intervention are particularly promising to facilitate risk stratification, patient selection and exquisite guidance of novel therapies, and interrogation of systems-based interorgan communication. Non-invasive visualization of pathobiology provides valuable insights into the progression of disease and response to treatment. Specifically, inflammation, fibrosis, and neurohormonal signaling, central to the progression of cardiovascular disease and emerging therapeutic strategies, have been investigated by molecular imaging. As the number of radioligands grows, careful investigation of the binding properties and added-value of imaging should be prioritized to identify high-potential probes and facilitate translation to clinical applications. In this review, we discuss the current state of molecular imaging in cardiovascular medicine, and the challenges and opportunities ahead for cardiovascular molecular imaging to navigate the path from diagnosis to prognosis to personalized medicine.
Experimental craniotomies are a common surgical procedure in neuroscience. Because inadequate analgesia appears to be a problem in animal-based research, we conducted this review and collected information on management of craniotomy-associated pain in laboratory mice and rats. A comprehensive search and screening resulted in the identification of 2235 studies, published in 2009 and 2019, describing craniotomy in mice and/or rats. While key features were extracted from all studies, detailed information was extracted from a random subset of 100 studies/year. Reporting of perioperative analgesia increased from 2009 to 2019. However, the majority of studies from both years did not report pharmacologic pain management. Moreover, reporting of multimodal treatments remained at a low level, and monotherapeutic approaches were more common. Among drug groups, reporting of pre- and postoperative administration of non-steroidal anti-inflammatory drugs, opioids, and local anesthetics in 2019 exceeded that of 2009. In summary, these results suggest that inadequate analgesia and oligoanalgesia are persistent issues associated with experimental intracranial surgery. This underscores the need for intensified training of those working with laboratory rodents subjected to craniotomies.Systematic review registrationhttps://osf.io/7d4qe.
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