Distinguishing pathophysiological features of heart failure with reduced and preserved ejection fraction: A comparative analysis of two mouse models.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

Mitochondrial Ca2+ Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling. Moreover, we identified a calcium/calmodulin-independent protein kinase II/cyclic adenosine monophosphate response element-binding protein signaling modulating MCU upregulation by ANGII. Additionally, we found upregulation of MCU in ANGII-induced left ventricular HF in mice, and in the LV of HF patients, which was correlated with pathological remodeling. Following left ventricular assist device implantation, MCU expression decreased, suggesting tissue plasticity to modulate MCU expression.

Exploring the mechanisms underlying stroke volume variability reduction in a murine model of heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is accompanied by disregulation of cardiovascular function. Heart rate variability (HRV) is commonly used to assess autonomic dysfunction in HFrEF. However, analysis of stroke volume variability (SVV) may provide additional insights. We examined HRV and SVV in a mouse model of HFrEF. HFrEF mice exhibited reduced stroke volume and ejection fraction versus controls, confirming cardiac contractile dysfunction. HRV was preserved in HFrEF mice. However, SVV was markedly diminished, indicating dissociation between HRV and SVV regulation. Using a mathematical model, we propose that Frank-Starling mechanism abnormalities in HFrEF disrupt SVV independent of HRV. Assessing SVV could thus provide unique insights beyond HRV into cardiovascular control deficits in HFrEF.

The Hemodynamic Mass Action of a Central Pattern Generator.

The hemodynamic response is a neurovascular and metabolic process in which there is rapid delivery of blood flow to a neuronal tissue in response to neuronal activation. The functional magnetic resonance imaging (fMRI) and the functional near-infrared spectroscopy (fNIRS), for instance, are based on the physiological principles of such hemodynamic responses. Both techniques allow the mapping of active neuronal regions in which the neurovascular and metabolic events are occurring. However, although both techniques have revolutionized the neurosciences, they are mostly employed for neuroimaging of the human brain but not for the spinal cord during functional tasks. Moreover, little is known about other techniques measuring the hemodynamic response in the spinal cord. The purpose of the present study was to show for the first time that a simple optical system termed direct current photoplethysmography (DC-PPG) can be employed to detect hemodynamic responses of the spinal cord and the brainstem during the functional activation of the spinal central pattern generator (CPG). In particular, we positioned two DC-PPG systems directly on the brainstem and spinal cord during fictive scratching in the cat. The optical DC-PPG systems allowed the trial-by-trial recording of massive hemodynamic signals. We found that the "strength" of the flexor-plus-extensor motoneuron activities during motor episodes of fictive scratching was significantly correlated to the "strengths" of the brainstem and spinal DC-PPG signals. Because the DC-PPG was robustly detected in real-time, we claim that such a functional signal reflects the hemodynamic mass action of the brainstem and spinal cord associated with the CPG motor action. Our findings shed light on an unexplored hemodynamic observable of the spinal CPGs, providing a proof of concept that the DC-PPG can be used for the assessment of the integrity of the human CPGs.

Nanoparticle delivery of cardioprotective therapies.

Acute myocardial infarction (AMI), and the heart failure (HF) that often follows, are leading causes of death and disability worldwide. Crucially, there are currently no effective treatments, other than myocardial reperfusion, for reducing myocardial infarct (MI) size and preventing HF following AMI. Thus, there is an unmet need to discover novel cardioprotective therapies to reduce MI size, and prevent HF in AMI patients. Although a large number of therapies have been shown to reduce MI size in experimental studies, the majority have failed to benefit AMI patients. Failure to deliver cardioprotective therapy to the ischemic heart in sufficient concentrations following AMI is a major factor for the lack of success observed in previous clinical cardioprotection studies. Therefore, new strategies are needed to improve the delivery of cardioprotective therapies to the ischemic heart following AMI. In this regard, nanoparticles have emerged as drug delivery systems for improving the bioavailability, delivery, and release of cardioprotective therapies, and should result in improved efficacy in terms of reducing MI size and preventing HF. In this article, we provide a review of currently available nanoparticles, some of which have been FDA-approved, in terms of their use as drug delivery systems in cardiovascular disease and cardioprotection.

Resetting the Respiratory Rhythm with a Spinal Central Pattern Generator.

There is evidence that a variety of central and afferent stimuli, including swallowing, can produce phase resetting in the respiratory rhythmicity. Also, there are reports about the intrinsic linkage between locomotion and respiration. However, little is known about the interaction between the central pattern generators (CPGs) for scratching and respiration. The present study aims to examine whether the activation of scratching CPG produces phase resetting of the respiratory rhythm. We employed decerebrate cats to apply brief tactile stimuli to the pinna during the inspiratory-expiratory transition. We observed that those stimuli to the pinna not eliciting fictive scratching did not reset the respiratory rhythm. However, when the pinna stimuli elicited fictive scratching, then the respiratory rhythm exhibited a significant phase resetting. We also found interneurons in the medulla oblongata exhibiting phase resetting related to scratching-CPG episodes. This second finding suggests that this type of resetting involves brainstem components of the respiratory CPG. These results shed new light on the resetting action from a spinal CPG on the respiratory rhythm.

Afterdischarges of Spinal Interneurons Following a Brief High-Frequency Stimulation of Ia Afferents in the Cat.

Spinal motoneurons exhibit sustained afterdischarges and plateau potentials following a brief high-frequency stimulation of Ia afferents. Also, there is evidence that spinal cord interneurons exhibit plateau potentials. However, to our knowledge, there are no reports about the possible afterdischarge behavior of lumbar spinal interneurons activated by Ia afferents. Given that there are spinal interneurons receiving monosynaptic inputs from Ia afferents, these cells could then be activated in parallel to motoneurons after repetitive muscle stretch. We explored this possibility in cats with a precollicular-postmammillary decerebration. We found that a brief high-frequency stimulation of Ia afferents produces afterdischarges that are highly correlated to a DC slow potential recorded at the cord dorsum. We conclude that in the cat spinal cord, not only the motoneurons but also the interneurons from the superficial and deep dorsal horn produce sustained afterdischarges, thus highlighting the importance of interneurons in the spinal neuronal circuitry. The significance of our finding is that it opens the possibility that the spinal cord interneurons activated by Ia afferents could also exhibit bistability, a relevant phenomenon well-characterized in the motoneurons.

Brownian Optogenetic-Noise-Photostimulation on the Brain Amplifies Somatosensory-Evoked Field Potentials.

Stochastic resonance (SR) is an inherent and counter-intuitive mechanism of signal-to-noise ratio (SNR) facilitation in biological systems associated with the application of an intermediate level of noise. As a first step to investigate in detail this phenomenon in the somatosensory system, here we examined whether the direct application of noisy light on pyramidal neurons from the mouse-barrel cortex expressing a light-gated channel channelrhodopsin-2 (ChR2) can produce facilitation in somatosensory evoked field potentials. Using anesthetized Thy1-ChR2-YFP transgenic mice, and a new neural technology, that we called Brownian optogenetic-noise-photostimulation (BONP), we provide evidence for how BONP directly applied on the barrel cortex modulates the SNR in the amplitude of whisker-evoked field potentials (whisker-EFP). In all transgenic mice, we found that the SNR in the amplitude of whisker-EFP (at 30% of the maximal whisker-EFP) exhibited an inverted U-like shape as a function of the BONP level. As a control, we also applied the same experimental paradigm, but in wild-type mice, as expected, we did not find any facilitation effects. Our results show that the application of an intermediate intensity of BONP on the barrel cortex of ChR2 transgenic mice amplifies the SNR of somatosensory whisker-EFPs. This result may be relevant to explain the improvements found in sensory detection in humans produced by the application of transcranial-random-noise-stimulation (tRNS) on the scalp.