Aortic Banding Research Articles

RUNX2 is stabilised by TAZ and drives pulmonary artery calcification and lung vascular remodelling in pulmonary hypertension due to left heart disease.

Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding. Pulmonary artery samples were collected from patients and rats with pulmonary hypertension due to left heart disease. Genome-wide RNA sequencing was performed, and pulmonary artery calcification assessed. Osteogenic signalling via TAZ and RUNX2 was delineated by protein biochemistry. In vivo, the therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in the rat model. Gene ontology term analysis identified significant enrichment in ossification and osteoblast differentiation genes, including RUNX2, in pulmonary arteries of patients and lungs of rats with pulmonary hypertension due to left heart disease. Pulmonary artery calcification was evident in both patients and rats. Both TAZ and RUNX2 were upregulated and activated in pulmonary artery smooth muscle cells of patients and rats. Co-immunoprecipitation revealed a direct interaction of RUNX2 with TAZ in pulmonary artery smooth muscle cells. TAZ inhibition or knockdown decreased RUNX2 abundance due to accelerated RUNX2 protein degradation rather than reduced de novo synthesis. Inhibition of either TAZ or RUNX2 attenuated pulmonary artery calcification, distal lung vascular remodelling and pulmonary hypertension development in the rat model. Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ-RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease.

No Difference in Systolic Dysfunction from Left Ventricular Pressure-Volume Loop’s Area and Stroke Work Between Chronic Late Load vs. Early Systolic LV Load in Porcine Model

<i>Background: </i>in increased LV afterload as in hypertension, early systolic LV dysfunction (SD) in late compares to early peak systolic LV load for P-V area, stroke work, potential energy with effective LV work (EW) is not being defined (aortic stenosis, arterial hypertension or coarctation of the aorta) in LVH remodeling. <i>Objectives:</i> to assess in porcine model how LV stroke work, PVA and EW are related to LVH remodeling in developing early SD with HF, between 4<sup>th</sup> vs 8<sup>th</sup> week in chronic LL compares to EL. It is suggested that reduced proximal thoracic or asc. aortic compliance results with myocardial ischemia. However, difference for LV O<sub>2</sub> demand and effective LV work in different LV afterload is not understood in early development systolic HF. <i>Methods:</i> in fourteen domestic male pigs (28±3 kg) with moderate descending aortic banding having chronic late LV load (LL=8) or ascending aortic stenosis with early systolic LV load (EL=6) SD was assessed, from PVA, in invasive LV pressure-volume loops’ measurements, at 4<sup>th</sup> vs. 8<sup>th</sup> week, to assess LV maximal ESPVR, with Millar 5Fr P-V pig-tailed conductance catheter. LV stroke work, and pressure-volume area PVA, reflecting the maximal LV O<sub>2</sub> demand were assessed in chronic LL compares to EL from nonlinear regression analysis of maximal LV end-systolic stiffness, in special software. For variance analysis, two-way repeated measures ANOVA was performed, with normality assessment. Results are means±(SEM) or medians for significant p<0.05. <i>Results: </i>LV PVA was not different, in LL compared to EL at 4<sup>th</sup> vs. 8<sup>th</sup> week. LV stroke work with effective works were not different and potential energy, neither were changed between 4<sup>th</sup> vs. 8<sup>th</sup> week. No difference was found in different LV afterload, in both indexed and absolute LVO<sub>2</sub> demand, in LL vs. EL at 4<sup>th</sup> or 8<sup>th</sup> week. Indexed PVA parameters with LV stroke work, effective work and potential energy were not different or changed in LL compares to EL between 4<sup>th</sup> vs. 8<sup>th</sup> weeks, normalized per body surface-area (in m<sup>2</sup>). <i>Conclusion:</i> Both absolute and indexed LV stroke work, potential LV energy, PVA with EW and maximum LV O<sub>2</sub> demand are not different in LL compares to EL at 4<sup>th</sup> vs. 8<sup>th</sup> week of LVH remodeling, indicating no difference in early SD development in increased late vs. early LV afterload.

TCT-159 Comparison of the First- and Second-Generation Balloon-Expandable Transcatheter Aortic Valve in an Ovine, Aortic Banding Model

TCT-159 Comparison of the First- and Second-Generation Balloon-Expandable Transcatheter Aortic Valve in an Ovine, Aortic Banding Model

TCT-655 Hemodynamic Effects of Aortic Banding to Simulate Progressive Aortic Stenosis

TCT-655 Hemodynamic Effects of Aortic Banding to Simulate Progressive Aortic Stenosis

MiR-495-3p promotes cardiac hypertrophy by targeting Pum2.

Pathological cardiac hypertrophy (CH) may lead to heart failure and sudden death. MicroRNAs (miRNAs) have been documented to play crucial parts in CH. The objective of this research was to discuss the potential along with molecule mechanism of miR-495-3p in CH. In vivo CH model was induced by aortic banding (AB) in rats. Cellular hypertrophy in H9c2 rat cardiomyocytes was stimulated by angiotensin II (Ang II) treatment. Haematoxylin and eosin (HE), echocardiography and immunofluorescence staining were used to examine the alterations in cardiac function. The outcomes showed that miR-495-3p expression was high in rat model as well as in Ang II-stimulated cardiomyocytes. Besides, silenced miR-495-3p attenuated CH both in vitro and in vivo. Mechanically, miR-495-3p bound to pumilio RNA binding family member 2 (Pum2) 3'UTR and silenced its expression. Rescue assays further notarized that Pum2 silence abrogated the inhibitory impacts of miR-495-3p inhibitor on CH. In a word, the present research uncovered that miR-495-3p promoted CH by targeting Pum2. Therefore, miR-495-3p may be a novel therapeutic molecule for this disease.

VE81 Leveraging urological robotic expertise in robot assisted aortic banding for type IA EVAR endoleak

VE81 Leveraging urological robotic expertise in robot assisted aortic banding for type IA EVAR endoleak

Shorten τ<sub>1</sub> in Chronic Early vs. Late Systolic LV Load for Systolic Dysfunction in Ascending vs. Descending Thoracic Aortic Stenosis

<i>Background:</i> Arterial hypertension (HTA) results with diastolic LV dysfunction (DD), important to develop systolic LV dysfunction and exercise intolerance with HF. Separating between chronic late (LL) to early LV load (EL) during systole, impaired LV relaxation is present earlier in chronic LL vs. EL, having early HF, as result of myocardial ischemia and systolic LV dysfunction in HTA. <i>Objective and Methods:</i> to assess early systolic in diastolic LV dysfunction from biexponential τ regression assessment, using single beat and mono-exponential regression analysis, with nonzero asymptote with special software in LL and EL, between 4<sup>th</sup> and 8<sup>th</sup> week in a porcine model. This assesses early HF and systolic LV pump dysfunction, from fast_τ (τ<sub>1</sub>), for early systolic LV dysfunction, in LVH remodeling in moderate LV afterload increase. Fourteen domestic male pigs, underwent LV pressure measurements with conductance Millar 5F catheter having moderate ascending aortic banding (EL=6), and in descending thoracic aortic stenosis, as in hypertension (LL=8). τ<sub>1</sub> (τ_fast) and τ<sub>2</sub> (for τ_slow) component of bi-exponential τ analyzed LV dysfunction at 4<sup>th</sup> vs. 8<sup>th</sup> week. Under reduced LV load (m3), during ventilation preserved (m1) or suspended transitionally (m2), fast τ assess early systolic dysfunction in LL vs. EL. Associated murmurs were assessed to detect LV valves dysfunction. Data was compared statistically, using two-way repeated measurement ANOVA, after Leven normality test. Results are means±SEM or medians (quartiles), for significant p<0.05. <i>Results:</i> mono-exponential τ was not different, neither changed in LL vs. EL at 4<sup>th</sup> and 8<sup>th</sup> week in m1, m2 or m3, that reduced in both groups with mechanical LV load reduction at 4<sup>th</sup> and 8<sup>th</sup> week (p<0.05). Prolonged bi-exponential asynchronous τ<sub>2</sub>/τ<sub>1</sub> ratio in EL was different from LL at 8<sup>th</sup> week, resulted from LV afterload (τ<sub>2</sub>τ<sub>1</sub> interaction p<0.05). τ_fast was different, being shorten in EL vs. LL at 4<sup>th</sup> and 8<sup>th</sup> week. Reduced bi-exponential τ<sub>2</sub>τ<sub>1</sub> ratio in EL and increased in LL, with mechanical load reduction, improved LV ischemia with DD in EL at 4<sup>th</sup> and 8<sup>th</sup> week of moderate LV afterload increase, but did not respond in LL. There was predominant systolic murmur in EL and diastolic murmur in LL, pronounced with load reduction. <i>Conclusion:</i> Prolonged bi-exponential τ<sub>1</sub> in LL shows early systolic LV dysfunction within DD. LV ischemia and systolic with diastolic LV pump dysfunction in EL presents shorten fast_τ, being unresponsive to mechanical LV load reduction in LL.

A common gene signature of the right ventricle in failing rat and human hearts

The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans.

USP38 exacerbates pressure overload-induced left ventricular electrical remodeling

BackgroundUbiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF.MethodsCardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses.ResultsWe observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway.ConclusionOur data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.

Soft robotic platform for progressive and reversible aortic constriction in a small-animal model.

Our understanding of cardiac remodeling processes due to left ventricular pressure overload derives largely from animal models of aortic banding. However, these studies fail to enable control over both disease progression and reversal, hindering their clinical relevance. Here, we describe a method for progressive and reversible aortic banding based on an implantable expandable actuator that can be finely tuned to modulate aortic banding and debanding in a rat model. Through catheterization, imaging, and histologic studies, we demonstrate that our platform can recapitulate the hemodynamic and structural changes associated with pressure overload in a controllable manner. We leveraged soft robotics to enable noninvasive aortic debanding, demonstrating that these changes can be partly reversed because of cessation of the biomechanical stimulus. By recapitulating longitudinal disease progression and reversibility, this animal model could elucidate fundamental mechanisms of cardiac remodeling and optimize timing of intervention for pressure overload.

Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

KV4.3 PROTECTS AGAINST OXIDATIVE CAMKII ACTIVATION IN HEART FAILURE

Objective: Oxidative stress causes excessive CaMKII activation in heart failure which exacerbates cardiac dysfunction. We determined whether restoration of down-regulated membrane Kv4.3 expression in ventricular myocytes can block oxidative CaMKII activation in heart failure. Design and method: Heart failure was induced in mice by severe thoracic aortic banding. Transjugular injection of AAV-Kv4.3 was performed in mice 1 week after banding. Fluorescence spectra were measured using F-4600 spectrophotometer (Hitachi). The slit width and excitation wavelength were set to 5 mm and 270 nm, respectively. Emission spectra were increased from 280 nm to 400 nm (step = 1nm). The spectra of purified proteins were examined, including CaMKII, CaMKII and Ca2+/CaM, CaMKII and Kv4.3, CaMKII, Kv4.3, and Ca2+/CaM. Results: Dissociation of Kv4.3 from Kv4.3-CaMKII molecular complex or down-regulation of Kv4.3 in mouse ventricular myocytes enhanced H2O2-induced CaMKII oxidation and autophosphorylation. Only non-oxidized and unphosphorylated forms of CaMKII have been detected from the Kv4.3 immunoprecipitates in ventricular myocytes with H2O2 Incubation. Fluorescence spectra assay showed that Kv4.3 prevented the transformational change of inactive CaMKII to its active conformation in the presence of Ca2+/CaM and H2O2. In vivo transfection with AAV9-Kv4.3 had no impact on reactive oxygen species in heart failure myocardium but effectively suppressed CaMKII oxidation and activation. Conclusions: Kv4.3 is a potent native suppressor for oxidative CaMKII activation by binding to the regulatory domain and preventing the opening of inhibitory domain in response to Ca2+/CaM and H2O2.

Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation.

Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule-load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression. KEY POINTS: Excised papillary muscle experiments demonstrated a bell-shaped relationship between cardiomyocyte t-tubule density and workload (preload or afterload), which was only present when muscles were electrically stimulated. The in vivo heart at baseline is positioned on the rising phase of this curve because moderate increases in preload (mice with brief aortic shunt surgery, patients with mitral valve regurgitation) resulted in t-tubule growth. Moderate increases in afterload (mice and patients with mild aortic banding/stenosis) similarly increased t-tubule density. T-tubule proliferation was associated with larger Ca2+ transients, with upregulation of the L-type Ca2+ channel, Na+-Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients placed the heart on the declining phase of the t-tubule-load relationship, promoting heart failure progression. The dependence of t-tubule structure on preload and afterload thus enables both compensatory and maladaptive remodelling, in rodents and humans.

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.

HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Robotic Assisted Aortic Banding for Type Ia Endoleak

Robotic Assisted Aortic Banding for Type Ia Endoleak

Long-term bio-functional performance of a novel, self-positioning balloon expandable transcatheter biological aortic valve system in the ovine aortic banding model.

The aim of the study was to evaluate bio-functionality of a novel, proprietary balloon-expandable biological transcatheter aortic valve implantation (TAVI) system (InFlow, CardValve Consortium, Poland) in an ovine model of aortic banding. Surgical ascending aorta banding was created in 21 sheep. Two weeks later, 18 biological valves were implanted within the model using 15-16 F InFlow TAVI systems and carotid cut-down approach. Follow-up transthoracic echocardiography was performed at 30, 90, and 180-day. At designated time, animals were euthanized and valves harvested for analysis. All sheep survived the banding procedure. There were 4 (22%) procedure related deaths within a 7-day period. During the observation an additional 2 sheep died. In one, the valve dislocated after the procedure - the animal was excluded. Two animals completed 30-day follow up, five 90-day follow-up and four terminal follow-up of 180 days. Valves examined via transesophageal echocardiography showed proper hemodynamic parameters without evidence of structural valve deterioration. The maximum and average flow gradients at 180 days were 31.4 (23.3-37.7) and 17.5 (13.1-20.2) mmHg, respectively. There was one case of moderate insufficiency and no case of perivalvular leaks. By histopathology, there were no inflammation, thrombosis, nor calcifications in any tested valves at long-term follow-up. Neointimal coverage of stent struts increased with time from basal part in "early" groups to nearly 3/4 of stent length in the 180-day group. The pannus tissue showed maturation that increased with time with no stenotic "collar" visible in orthotopically implanted valves. The study showed good hemodynamic performance, durability and biocompatibility of the novel biological THV.

An updated review of experimental rodent models of pulmonary hypertension and left heart disease.

Left heart disease (LHD) is the leading cause of pulmonary hypertension (PH). Its recent growth has not been matched by the design of therapeutic agents directly targeting the disease. Effective therapies approved for pulmonary arterial hypertension (PAH) have been shown to be inefficient in patients with PH-LHD. Hence, there is a need for an animal model that would closely mimic PH-LHD in preclinical experiments. The current study describes and compares a number of rodent models of left ventricular failure and their potential to induce PH. It also evaluates whether, and to what extent, common PH models could develop LV failure. Articles were identified in the Pubmed/Medline and Web of Science online electronic databases following the PRISMA Protocol between 1992 and 2022. Quality assessment was carried out using the SYRCLE risk-of-bias tool for animal studies. Publication bias across studies using Egger's regression test statistic, was performed together with sensitivity analysis. A wide spectrum of protocols-135 studies and 207 interventions, was examined, including systemic hypertensive models, pressure-overload-induced HF, model of ischemic heart failure, and metabolic approaches based on high fat diet or metabolic syndrome. The most pronounced alterations in PH-related parameters were demonstrated for the common PH models, but were also seen in animals with LV failure induced by ischemic conditions, pressure overload or metabolic conditions. Models based on aortic banding, transverse aortic constriction (TAC), or with myocardial infarction (MI) caused by coronary artery ligation, demonstrated more pronounced worsening in PH due to LV failure; however, they also demonstrated poor survival, especially the ischemic-HF model. Common PH models, excluding prolonged exposure to monocrotaline, do not promote LV hypertrophy. Prolonged exposure to a high-fat diet, or a two-hit model of an obese ZSF1 rat combined with SU5416-induced pulmonary endothelial impairment (a VEGF receptor antagonist) worsened PH and impaired diastolic dysfunction. Due to the limited number of protocols, further trials are needed to confirm the utility of such approaches for modeling PH in subjects with metabolic syndrome. This would provide a clearer insight into the complexity of LHD, PH and metabolic disorders in PH-LHD, and thus accelerate the development of new therapies in clinical trials.

Porcine Model of Hypertrophy-Independent Left Ventricular Stiffening via Repetitive Pressure Overload.

Diastolic dysfunction arising from alterations in myocardial structure and/or function is a central component of several cardiovascular disorders, including heart failure with preserved ejection fraction (HFpEF). Basic research aimed at understanding underlying mechanisms contributing to the development of diastolic dysfunction has generally centered upon models of left ventricular (LV) hypertrophy arising from persistent and severe elevations in myocardial afterload (e.g., aortic banding). Mechanisms of hypertrophy-independent diastolic dysfunction, on the other hand, have received less attention, even though overt anatomic LV hypertrophy is absent in many HFpEF patients. Here, we describe the development of a novel porcine model of repetitive pressure overload (RPO) in which chronic, intermittent exposure to transient episodes of hypertension produces an increase in LV stiffness, interstitial fibrosis, cardiomyocyte hypertrophy, and capillary rarefaction without significant changes in LV mass. This model offers important insight into how diastolic dysfunction and HFpEF may develop in the absence of comorbidities, sustained hypertension, or LV hypertrophy, while also providing a useful translational research tool for investigation of novel therapeutic approaches to restore myocardial compliance and improve diastolic function.

Ubiquitin-specific protease 38 promotes inflammatory atrial fibrillation induced by pressure overload.

Atrial structural and electrical remodelling is a major reason for the initiation and perpetuation of atrial fibrillation (AF). Ubiquitin-specific protease 38 (USP38) is a deubiquitinating enzyme, but its function in the heart remains unknown. The aim of this study was to investigate the effect of USP38 in pressure overload-induced AF. Cardiac-specific knockout USP38 and cardiac-specific transgenic USP38 mice and their corresponding control mice were used in this study. After 4 weeks with or without aortic banding (AB) surgery, atrial echocardiography, atrial histology, electrophysiological study, and molecular analysis were assessed. Ubiquitin-specific protease 38 knockout mice showed a remarkable improvement in vulnerability to AF, atrial weight and diameter, atrial fibrosis, and calcium-handling protein expression after AB surgery. Conversely, USP38 overexpression further increased susceptibility to AF by exacerbating atrial structural and electrical remodelling. Mechanistically, USP38 interacted with and deubiquitinated nuclear factor-kappa B (NF-κB), and USP38 overexpression increased the level of p-NF-κB in vivo and in vitro, accompanied by the upregulation of NOD-like receptor protein 3 (NLRP3) and inflammatory cytokines, suggesting that USP38 contributes to adverse effects by driving NF-κB/NLRP3-mediated inflammatory responses. Overall, our study indicates that USP38 promotes pressure overload-induced AF through targeting NF-κB/NLRP3-mediated inflammatory responses.