Matthijs Blankesteijn

Structural and Functional Adaptations of the Heart After Coronary Artery Ligation in the Mouse

In Western societies heart failure is becoming a pandemic disease for which the current treatment is still symptomatic rather than curative36. Developing an effective therapy for heart failure is a challenging assignment for many research groups. Mouse models are increasingly used in this research quest, because modification of the genome is relatively easier than in any other mammal. However, due to the small size of the mouse, many techniques had to be scaled down and refined. In the past 5 years, this process has been largely concluded. Various tools, including non-invasive echocardiography4,26,28,31,34,38,39,49and magnetic resonance imaging37,45are available now to examine in mouse models the molecular mechanisms underlying heart failure or to test the efficacy of novel interventions.

Urocortin 3 Gene Transfer Increases Function of the Failing Murine Heart

Peptide infusions of peptides the corticotropin releasing factor family, including urocortin 2, stresscopin, and urocortin 3 (UCn3), have favorable acute effects in clinical heart failure (HF), but their short half-lives make them unsuitable for chronic therapy. This study asked whether UCn3 gene transfer, which provides sustained elevation of plasma UCn3 levels, increases the function of the failing heart. HF was induced by transmural left ventricular (LV) cryoinjury in mice. LV function was assessed 3 weeks later by echocardiography. Those with ejection fractions (EF) <40% received intravenous saline or intravenous adeno-associated virus type-8 encoding murine UCn3 (AAV8.mUCn3; 1.9 × 1013 genome copies/kg). Five weeks after randomization, repeat echocardiography, assessment of LV function (+dP/dt, -dP/dt), and quantification of Ca2+ transients and sarcomere shortening in isolated cardiac myocytes were conducted, and assessment of LV Ca2+ handling and stress proteins was performed. Three weeks after myocardial infarction, prior to treatment, EFs were reduced (mean 31%, from 63% in sham-operated animals). Mice randomized to receive UCn3 gene transfer showed increased plasma UCn3 (from 0.1 ± 0.01 ng/mL in the saline group to 5.6 ± 1.1 ng/mL; n = 12 each group; p < 0.0001). Compared to mice that received saline, UCn3 gene transfer was associated with higher values for EF (p = 0.0006); LV +dP/dt (p < 0.0001), and LV -dP/dt (p < 0.0001). Cardiac myocytes from mice that received UCn3 gene transfer showed higher peak Ca2+ transients (p = 0.0005), lower time constant of cytosolic Ca2+ decline (tau, p < 0.0001), and higher rates of sarcomere shortening (+dL/dt, p = 0.03) and lengthening (-dL/dt, p = 0.04). LV samples from mice that received UCn3 gene transfer contained higher levels of SERCA2a (p = 0.0004 vs. HF) and increased amounts of phosphorylated troponin I (p = 0.04 vs. HF). UCn3 gene transfer is associated with improved Ca2+ handling and LV function in mice with HF and reduced EF.

The role of inflammation in myocardial infarction

Coronary heart disease (CHD) is a major contributor of mortality and morbidity in the modern world and frequently develops into myocardial infarction (MI). The ischemic injury that characterizes MI is followed by an orchestrated, but highly heterogeneous, chain of events, in which the inflammatory response plays a pivotal role. The activation of the immune response is essential for the normal wound healing, a process that aims to replace the injured myocardial tissue following injury. Multiple cellular and molecular signals contribute vital functions throughout this process, the spatial and temporal aspects of which are tightly regulated. Inadequate or exaggerated response to inflammation can lead to adverse remodeling with devastating effects for the injured heart. Given the exceptional pathophysiologic complexity of the systems regulating the inflammatory response during atherogenesis and during the early wound healing following MI, several factors need to be considered in the quest for the optimal treatment. Furthermore, the currently available therapeutic arsenal targets—directly and indirectly—the inflammatory response; however, it is far from being regarded as adequate. Novel pharmacotherapeutic strategies are urgently needed in order to drastically reduce the burden of CHD. This chapter discusses the general concepts of atherosclerosis, which eventually lead to MI, and of the post-MI wound-healing process with special focus on the inflammatory components (cellular and molecular) that play decisive roles in the immune response as well as the current and innovative therapies in the field.