Clinical and necropsy evaluation of endocardial fibroelastosis in a mixed-breed cat with left side heart failure

A two-month-old, male intact, mixed-breed cat weighing 0.6 kg was presented with respiratory distress and anorexia. From the transthoracic echocardiographic, reduced fractional shortening (FS) and increased endocardial echogenicity were recognised with severe congestive heart failure (CHF). The kitten was administered an antibiotic and pimobendane under oxygen supplementation in an ICU cage. However, the respiratory condition worsened and the cat died the next day, and the subsequent necropsy and histopathology examinations confirmed endocardial fibroelastosis (EFE). There is a lack of information regarding the antemortem cardiac function evaluated by tissue Doppler imaging (TDI) in EFE cases. We report on the echocardiographic findings including the TDI in the EFE cat with a concomitant necropsy and histopathology confirmation in this paper. The echocardiographic findings showed presence of a ventricular false tendon within the left ventricle, a decrease in the left ventricular contractility (FS 11.1%, and a marked CHF). In this case, the echocardiographic findings were consistent with the human counterpart. However, these findings were like those of dilated cardiomyopathy and, hence, non-specific to EFE. As a result, veterinarians should keep in mind that endocardial fibroelastosis might be a possible reason for respiratory distress resulting from CHF with a low fractional shortening in young cats.

Mitral Plasticity: The Way to Prevent the Burden of Ischemic Mitral Regurgitation?

The ischemic impairment of the left ventricular contractility, followed by an adverse remodeling leading to the displacement of the papillary muscles (PMs), increased tethering forces and loss of valve competence has been the long-term accepted definition of ischemic mitral regurgitation (IMR). Over the years, different approaches of management have attempted to address valve regurgitation, nevertheless failing to achieve satisfactory outcomes. Recent studies have observed some structural and molecular changes of the mitral valve (MV), challenging the concept of a bystander passive to the subvalvular involvement. Indeed, the solely mechanical stretch of the PMs, as in the dilated left ventricle because of the aortic valve regurgitation, is not enough in causing relevant MV regurgitation. This setting triggers a series of structural changes called “mitral plasticity,” leaflets increase in their size among others, ensuring an adequate systolic area closure. In contrast, the ischemic injury not only triggers the mechanical stretch on the subvalvular apparatus but is also a powerful promotor of profibrotic processes, with an upregulation of the transforming growth factor (TGF)-β signaling pathway, leading to a MV with exuberant leaflet thickness and impaired mobility. In this article, we revise the concept of IMR, particularly focusing on the new evidence that supports dynamic changes in the MV apparatus, discussing the consequent clinical insights of “mitral plasticity” and the potential therapeutic implications.

Circulating Transcriptional Profile Modulation in Response to Metabolic Unbalance Due to Long-Term Exercise in Equine Athletes: A Pilot Study

Physical exercise has been associated with the modulation of micro RNAs (miRNAs), actively released in body fluids and recognized as accurate biomarkers. The aim of this study was to measure serum miRNA profiles in 18 horses taking part in endurance competitions, which represents a good model to test metabolic responses to moderate intensity prolonged efforts. Serum levels of miRNAs of eight horses that were eliminated due to metabolic unbalance (Non Performer-NP) were compared to those of 10 horses that finished an endurance competition in excellent metabolic condition (Performer-P). Circulating miRNA (ci-miRNA) profiles in serum were analyzed through sequencing, and differential gene expression analysis was assessed comparing NP versus P groups. Target and pathway analysis revealed the up regulation of a set of miRNAs (of mir-211 mir-451, mir-106b, mir-15b, mir-101-1, mir-18a, mir-20a) involved in the modulation of myogenesis, cardiac and skeletal muscle remodeling, angiogenesis, ventricular contractility, and in the regulation of gene expression. Our preliminary data open new scenarios in the definition of metabolic adaptations to the establishment of efficient training programs and the validation of athletes’ elimination from competitions.

Development of a Spinal Cord Injury Model Permissive to Study the Cardiovascular Effects of Rehabilitation Approaches Designed to Induce Neuroplasticity

As primary medical care for spinal cord injury (SCI) has improved over the last decades there are more individuals living with neurologically incomplete (vs. complete) cervical injuries. For these individuals, a number of promising therapies are being actively researched in pre-clinical settings that seek to strengthen the remaining spinal pathways with a view to improve motor function. To date, few, if any, of these interventions have been tested for their effectiveness to improve autonomic and cardiovascular (CV) function. As a first step to testing such therapies, we aimed to develop a model that has sufficient sparing of descending sympathetic pathways for these interventions to target yet induces robust CV impairment. Twenty-six Wistar rats were assigned to SCI (n = 13) or naïve (n = 13) groups. Animals were injured at the T3 spinal segment with 300 kdyn of force. Fourteen days post-SCI, left ventricular (LV) and arterial catheterization was performed to assess in vivo cardiac and hemodynamic function. Spinal cord lesion characteristics along with sparing in catecholaminergic and serotonergic projections were determined via immunohistochemistry. SCI produced a decrease in mean arterial pressure of 17 ± 3 mmHg (p < 0.001) and left ventricular contractility (end-systolic elastance) of 0.7 ± 0.1 mmHg/µL (p < 0.001). Our novel SCI model produced significant decreases in cardiac and hemodynamic function while preserving 33 ± 9% of white matter at the injury epicenter, which we believe makes it a useful pre-clinical model of SCI to study rehabilitation approaches designed to induce neuroplasticity.

Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy

Heart failure (HF) is a major cause of morbidity and mortality worldwide, highlighting an urgent need for novel treatment options, despite recent improvements. Aberrant Ca2+ handling is a key feature of HF pathophysiology. Restoring the Ca2+ regulating machinery is an attractive therapeutic strategy supported by genetic and pharmacological proof of concept studies. Here, we study antisense oligonucleotides (ASOs) as a therapeutic modality, interfering with the PLN/SERCA2a interaction by targeting Pln mRNA for downregulation in the heart of murine HF models. Mice harboring the PLN R14del pathogenic variant recapitulate the human dilated cardiomyopathy (DCM) phenotype; subcutaneous administration of PLN-ASO prevents PLN protein aggregation, cardiac dysfunction, and leads to a 3-fold increase in survival rate. In another genetic DCM mouse model, unrelated to PLN (Cspr3/Mlp−/−), PLN-ASO also reverses the HF phenotype. Finally, in rats with myocardial infarction, PLN-ASO treatment prevents progression of left ventricular dilatation and improves left ventricular contractility. Thus, our data establish that antisense inhibition of PLN is an effective strategy in preclinical models of genetic cardiomyopathy as well as ischemia driven HF.

The effect of left ventricular contractility on arterial hemodynamics: A model-based investigation

Ventricular-arterial coupling is a major determinant of cardiovascular performance, however, there are still inherent difficulties in distinguishing ventricular from vascular effects on arterial pulse phenotypes. In the present study, we employed an extensive mathematical model of the cardiovascular system to investigate how sole changes in cardiac contractility might affect hemodynamics. We simulated two physiologically relevant cases of high and low contractility by altering the end-systolic elastance, Ees, (3 versus 1 mmHg/mL) under constant cardiac output and afterload, and subsequently performed pulse wave analysis and wave separation. The aortic forward pressure wave component was steeper for high Ees, which led to the change of the total pressure waveform from the characteristic Type A phenotype to Type C, and the decrease in augmentation index, AIx (-2.4% versus +18.1%). Additionally, the increase in Ees caused the pulse pressure amplification from the aorta to the radial artery to rise drastically (1.86 versus 1.39). Our results show that an increase in cardiac contractility alone, with no concomitant change in arterial properties, alters the shape of the forward pressure wave, which, consequently, changes central and peripheral pulse phenotypes. Indices based on the pressure waveform, like AIx, cannot be assumed to reflect only arterial properties.