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The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. Here we show that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts. Mice with cardiac-specific deletion of Mpc2 (CS-MPC2 -/- ) exhibited normal cardiac size and function at 6 weeks old, but progressively developed cardiac dilation and contractile dysfunction, which was completely reversed by a high-fat, low-carbohydrate ketogenic diet. Diets with higher fat content, but enough carbohydrate to limit ketosis, also improved heart failure, while direct ketone body provisioning provided only minor improvements in cardiac remodelling in CS-MPC2 -/- mice. An acute fast also improved cardiac remodelling. Together, our results reveal a critical role for mitochondrial pyruvate use in cardiac function, and highlight the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency.

Background: To better understand reverse left ventricular (LV) remodeling, we developed a murine model wherein mice develop LV remodeling after transverse aortic constriction (TAC) and a small apical myocardial infarct (MI) and undergo reverse LV remodeling after removal of the aortic band., Methods and Results: Mice studied were subjected to sham (n=6) surgery or TAC+MI (n=12). Two weeks post-TAC+MI, 1 group underwent debanding (referred to as heart failure debanding [HF-DB] mice; n=6), whereas the aortic band remained in a second group (heart failure [HF] group; n=6). LV remodeling was evaluated by 2D echocardiography at 1 day, 2 weeks and 6 weeks post-TAC+MI. The hearts were analyzed by transcriptional profiling at 4 and 6 weeks and histologically at 6 weeks. Debanding normalized LV volumes, LV mass, and cardiac myocyte hypertrophy at 6 weeks in HF-DB mice, with no difference in myofibrillar collagen in the HF and HF-DB mice. LV ejection fraction and radial strain improved after debanding; however, both remained decreased in the HF-DB mice relative to sham and were not different from HF mice at 6 weeks. Hemodynamic unloading in the HF-DB mice was accompanied by a 35% normalization of the HF genes at 2 weeks and 80% of the HF genes at 4 weeks., Conclusions: Hemodynamic unloading of a pathophysiologically relevant mouse model of HF results in normalization of LV structure, incomplete recovery of LV function, and incomplete reversal of the HF transcriptional program. The HF-DB mouse model may provide novel insights into mechanisms of reverse LV remodeling., (© 2018 American Heart Association, Inc.)

Mouse surgical models are important tools for evaluating mechanisms of human cardiac disease. The clinically relevant comorbidities of hypertension and ischaemia have not been explored in mice. We have developed a surgical approach that combines transverse aortic constriction and distal left anterior coronary ligation (MI) to produce a gradual and predictable progression of adverse left ventricular (LV) remodelling that leads to heart failure (HF). Mice received either sham, MI alone, transverse aortic constriction alone or HF surgery. Infarct size and LV remodelling were evaluated by serial 2-D echocardiograms. Transverse aortic constriction gradients were measured by the Doppler velocity-time integral ratio between constricted and proximal aortic velocities. At 4 weeks, hearts were weighed and analysed for histology and brain natriuretic peptide, a molecular marker of HF. Echocardiographic analysis of segmental wall motion scores showed similarly small apical infarct sizes in the MI and HF groups at day 1 postsurgery. MI alone showed little change in infarct size over 4 weeks (0.26 ± 0.02 to 0.27 ± 0.04, P = 0.77); however, HF mice showed infarct expansion (0.25 ± 0.06 to 0.39 ± 0.09, P < 0.05). HF mice also showed LV remodelling with increases in LV volumes (1 day = 36.5 ± 5.2 mL, 28 days = 89.1 ± 16.0 mL) versus no significant changes in the other groups. Furthermore, systolic function progressively deteriorated in the HF group only (ejection fraction, 1 day = 55.6 ± 3.6%, 28 days = 17.6 ± 4.1%, P < 0.05) with an increase of brain natriuretic peptide by 3.5-fold. This surgical model of pressure overload in the setting of a small infarction causes progressive deterioration of cardiac structural and functional properties, and provides a clinically relevant tool to study adverse LV remodelling and heart failure., (© 2014 Wiley Publishing Asia Pty Ltd.)

Animal models have become a popular platform for the investigation of the molecular and systemic mechanisms of pathological cardiovascular physiology. Chronic pacing studies with implantable pacemakers in large animals have led to useful models of heart failure and atrial fibrillation. Unfortunately, molecular and genetic studies in these large animal models are often prohibitively expensive or not available. Conversely, the mouse is an excellent species for studying molecular mechanisms of cardiovascular disease through genetic engineering. However, the large size of available pacemakers does not lend itself to chronic pacing in mice. Here, we present the design for a novel, fully implantable wireless-powered pacemaker for mice capable of long-term (>30 days) pacing. This design is compared to a traditional battery-powered pacemaker to demonstrate critical advantages achieved through wireless inductive power transfer and control. Battery-powered and wireless-powered pacemakers were fabricated from standard electronic components in our laboratory. Mice (n = 24) were implanted with endocardial, battery-powered devices (n = 14) and epicardial, wireless-powered devices (n = 10). Wireless-powered devices were associated with reduced implant mortality and more reliable device function compared to battery-powered devices. Eight of 14 (57.1%) mice implanted with battery-powered pacemakers died following device implantation compared to 1 of 10 (10%) mice implanted with wireless-powered pacemakers. Moreover, device function was achieved for 30 days with the wireless-powered device compared to 6 days with the battery-powered device. The wireless-powered pacemaker system presented herein will allow electrophysiology studies in numerous genetically engineered mouse models as well as rapid pacing-induced heart failure and atrial arrhythmia in mice. [ABSTRACT FROM AUTHOR]

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2−) macrophages. Herein, we identified an essential role for CCR2− macrophages in the chronically failing heart. Depletion of CCR2− macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2− macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation. [Display omitted] • The failing heart contains heterogeneous subsets of resident and recruited macrophages • Resident cardiac macrophages promote adaptation and survival of the failing heart • Resident cardiac macrophages interact with cardiomyocytes via focal adhesion complexes • Resident cardiac macrophages sense mechanical stretch through TRPV4 channels Resident cardiac macrophages are key regulators of heart development and homeostasis; however, the role of these cells during disease is presently unclear. Wong, Mohan, Kopecky, et al. reveal that resident cardiac macrophages orchestrate adaptive remodeling and survival of the failing heart by sensing mechanical stimuli through a TRPV4 dependent mechanism. [ABSTRACT FROM AUTHOR]