Pressure Overload Research Articles

Loss of cardiomyocyte-specific adhesion G-protein-coupled receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure.

Adhesion G-protein-coupled receptors (AGPCRs), containing large N-terminal ligand-binding domains for environmental mechano-sensing, have been increasingly recognized to play important roles in numerous physiologic and pathologic processes. However, their impact on the heart, which undergoes dynamic mechanical alterations in healthy and failing states, remains understudied. ADGRG1 (formerly known as GPR56) is widely expressed, including in skeletal muscle where it was previously shown to mediate mechanical overload-induced muscle hypertrophy; thus, we hypothesized that it could impact the development of cardiac dysfunction and remodeling in response to pressure overload. In this study, we generated a cardiomyocyte (CM)-specific ADGRG1 knockout mouse model, which, although not initially displaying features of cardiac dysfunction, does develop increased systolic and diastolic LV volumes and internal diameters over time. Notably, when challenged with chronic pressure overload, CM-specific ADGRG1 deletion accelerates cardiac dysfunction, concurrent with blunted CM hypertrophy, enhanced cardiac inflammation and increased mortality, suggesting that ADGRG1 plays an important role in the early adaptation to chronic cardiac stress. Altogether, the present study provides an important proof-of-concept that targeting CM-expressed AGPCRs may offer a new avenue for regulating the development of heart failure.

Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

Pressure overload–induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)–induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

GQ262 Attenuates Pathological Cardiac Remodeling by Downregulating the Akt/mTOR Signaling Pathway.

Cardiac remodeling, a critical process that can lead to heart failure, is primarily characterized by cardiac hypertrophy. Studies have shown that transgenic mice with Gαq receptor blockade exhibit reduced hypertrophy under induced pressure overload. GQ262, a novel Gαq/11 inhibitor, has demonstrated good biocompatibility and specific inhibitory effects on Gαq/11 compared to other inhibitors. However, its role in cardiac remodeling remains unclear. This study aims to explore the anti-cardiac remodeling effects and mechanisms of GQ262 both in vitro and in vivo, providing data and theoretical support for its potential use in treating cardiac remodeling diseases. Cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) for 4 weeks and in H9C2 cells through phenylephrine (PE) induction, confirmed with WGA and H&E staining. We found that GQ262 improved cardiac function, inhibited the protein and mRNA expression of hypertrophy markers, and reduced the levels of apoptosis and fibrosis. Furthermore, GQ262 inhibited the Akt/mTOR signaling pathway activation induced by TAC or PE, with its therapeutic effects disappearing upon the addition of the Akt inhibitor ARQ092. These findings reveal that GQ262 inhibits cardiomyocyte hypertrophy and apoptosis through the Akt/mTOR signaling pathway, thereby reducing fibrosis levels and mitigating cardiac remodeling.

Role and Mechanism of Lamellar Derived Growth Factor /AKT Pathway in Ventricular Remodeling Induced by Pressure Overload

Role and Mechanism of Lamellar Derived Growth Factor /AKT Pathway in Ventricular Remodeling Induced by Pressure Overload

Matairesinol blunts adverse cardiac remodeling and heart failure induced by pressure overload by regulating Prdx1 and PI3K/AKT/FOXO1 signaling

BackgroundPathological cardiac remodeling is a critical process leading to heart failure, characterized primarily by inflammation and apoptosis. Matairesinol (Mat), a key chemical component of Podocarpus macrophyllus resin, exhibits a wide range of pharmacological activities, including anti-hydatid, antioxidant, antitumor, and anti-inflammatory effects. PurposeThis study aims to investigate whether Matairesinol alleviate cardiac hypertrophy and remodeling caused by pressure overload and to elucidate its mechanism of action. MethodsAn in vitro pressure loading model was established using neonatal rat cardiomyocytes treated with angiotensin Ⅱ, while an in vivo model was created using C57 mice subjected to transverse aortic constriction (TAC). To activate the PI3K/Akt/FoxO1 pathway, Ys-49 was employed. Moreover, small interfering RNA (siRNA) and short hairpin RNA (shRNA) were utilized to silence Prdx1 expression both in vitro and in vivo. Various techniques, including echocardiography, wheat germ agglutinin (WGA) staining, HE staining, PSR staining, and Masson trichrome staining, were used to assess cardiac function, cardiomyocyte cross-sectional area, and fibrosis levels in rats. Apoptosis in myocardial tissue and in vitro was detected by TUNEL assay, while reactive oxygen species (ROS) content in tissues and cells was measured using DHE staining. Furthermore, the affinity of Prdx1 with Mat and PI3K was analyzed using computer-simulated molecular docking. Western blotting and RT-PCR were utilized to evaluate Prdx1 levels and proteins related to apoptosis and oxidative stress, as well as the mRNA levels of cardiac hypertrophy and fibrosis-related indicators. ResultsMat significantly alleviated cardiac hypertrophy and fibrosis induced by TAC, preserved cardiac function, and markedly reduced cardiomyocyte apoptosis and oxidative damage. In vitro, mat attenuated ang Ⅱ - induced hypertrophy of nrvms and activation of neonatal rat fibroblasts. Notably, activation of the PI3K/Akt/FoxO1 pathway and downregulation of Prdx1 expression were observed in TAC mice; however, these effects were reversed by Mat treatment. Furthermore, Prdx1 knockdown activated the PI3K/Akt/FoxO1 pathway, leading to exacerbation of the disease. Molecular docking indicated that Molecular docking indicated that Mat upregulated Prdx1 expression by binding to it, thereby inhibiting the PI3K/Akt/FoxO1 pathway and protecting the heart by restoring Prdx1 expression levels. ConclusionMatairesinol alleviates pressure overload-induced cardiac remodeling both in vivo and in vitro by upregulating Prdx1 expression and inhibiting the PI3K/Akt/FoxO1 pathway. This study highlights the therapeutic potential of Matairesinol in the treatment of cardiac hypertrophy and remodeling, providing a promising avenue for future research and clinical application.

An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress

Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.

Effect of fibroblasts small- conductance Ca2+ -activated potassium channel subtype 2 (SK2) on myocardial fibrosis in pressure overload mouse

Studies have shown that Small conductance Ca2 + −activated K+ (SK) channel are expressed in fibroblasts. We aimed to determine the expression of SK2 channels in cardiac fibroblasts during myocardial hypertrophy and investigate its relationship with fibrotic remodeling. Myocardial hypertrophy and fibrotic remodeling induced by transverse aortic constriction (TAC) were assessed by echocardiography, Masson's trichrome staining and Western blot. Knockdown and overexpression of the SK2 protein were used to assess relationship between SK2 expression in fibroblasts and myocardial fibrosis. There is a positive correlation between myocardial fibrosis and SK2 channel protein expression during the development of myocardial hypertrophy. The differentiation and secretion of fibroblasts in mice with cardiac hypertrophy are enhanced, and the expression of SK2 channel protein is increased. Manipulating SK2 levels in fibroblasts can either promote or inhibit their differentiation and secretory function. Knocking down SK2 reduces the up-regulation of TGF β1, p-Smad2/3/GAPDH, p-p38/GAPDH, p-ERK1/2/GAPDH, and p-JNK/GAPDH proteins induced by Ang II in cardiac fibroblasts without significantly affecting total protein levels. AAV9-SK2-RNAi injection in mice improves cardiac function. Collectively, our study suggests that the expression of the SK2 channel is significantly increased in fibroblasts of mice with myocardial hypertrophy, potentially impacting myocardial fibrosis remodeling via the TGF-β signaling pathway.

Cell-based therapies reverse the heart failure-altered right ventricular proteome.

Background Congenital heart defects can lead to right ventricular (RV) pressure-overload and heart failure. Cell-based therapies, including mesenchymal stromal cells (MSCs) and c-kit positive cells (CPCs) have been studied clinically as options to restore heart function in disease states. Many studies have indicated these cells act through paracrine mechanisms to prevent apoptosis, promote cellular function, and regulate gene/protein expression. We aimed to determine the proteomic response of diseased hearts to cell therapy Methods We utilized an animal model of RV pressure overload created by banding the pulmonary artery (PAB). Two weeks post-banding, bone marrow-derived mesenchymal stromal cells (MSCs) and 3 populations of CPCs (nCPCs, cCPCs, ES-CPCs) were delivered to the RV free wall. RV function and cellular retention were measured for four weeks post-injection, at which point hearts were extracted and the RV was excised for liquid chromatography and tandem mass spectrometry. Resulting RV proteomes were compared and analyzed using systems biology and bioinformatics. Results Proteomic profiling identified 1156 total proteins from the RV, of which 5.97% were significantly changed after PAB. This disease-altered proteome was responsive to cellular therapy, with 72% of the PAB-altered proteome being fully or partially reversed by MSC therapy. This was followed by nCPCs (54%), ES-CPCs (52%), and cCPCs (39%). Systems biology and bioinformatics analysis showed MSC, nCPC, or ES-CPC cell therapy is associated with a decrease in predicted adverse cardiac effects. We also observed an effect of cell therapy on the non-altered RV proteome, however, this was associated with minor predicted pathological endpoints. Conclusions Our data indicate MSCs, ES-CPCs, and nCPCs significantly reverse the PAB-altered proteome towards a pre-disease state. These results indicate cell-based therapies show promise in improving RV function after pressure overload through partial restoration of the disease-altered cardiac proteome.

Cardiac fibroblasts: answering the call.

Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the American Journal of Physiology-Heart and Circulatory Physiology issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types. This mini-review summarizes those articles and places the new findings in the context of what is currently known for cardiac fibroblasts and what future directions remain.

Abstract P419: Left Ventricular Diastolic Dysfunction in Preeclamptic Patients: A Systematic Review and Meta-Analysis

Introduction: Preeclamptic (PE) patients are at a 4-fold higher risk for developing heart failure later in life. Pathological cardiac remodeling, and the ensuing left ventricular (LV) dysfunction during hypertensive pregnancy are thought to precede heart failure in these patients. Specifically, several observational studies employing echocardiography demonstrate exaggerated LV diastolic function alterations in PE patients suggestive of diastolic dysfunction. Objective: Thus, to consolidate the evidence supporting diastolic dysfunction in preeclampsia, we sought to systematically review the clinical literature, and conduct a meta-analysis on the pooled data pertaining to LV diastolic function. Methods: Three databases, MEDLINE (Ovid), Embase (Elsevier), and Scopus (Elsevier) were searched from inception to January 26, 2024 and the search results were uploaded to Covidence for screening. The diastolic function data—early diastole mitral flow to annulus velocity ratio (E/e’), isovolumic relaxation time (IVRT), early to late diastole mitral flow velocity ratio (E/A), and E wave deceleration time (DT)—were extracted, and subsequently used to perform meta-analysis using Cochrane’s RevMan Web (Mean Difference, MD; random effects models with inverse variance weighting). Results: A total of 63 from 5013 screened studies were eligible for inclusion and of these, only the studies reporting E/e’ (34/63), IVRT (18/63), E/A (38/63), and DT (16/63) were included in the meta-analysis. Our analysis showed that E/e’ is increased (MD of 2.33 [95% CI, 1.77 to 2.89], p<0.00001) in PE patients when compared to healthy pregnant women indicating elevated LV filling pressures. Further, PE patients exhibited significantly higher IVRT (MD of 8.88 msec [95% CI, 6.07 to 11.68], p<0.00001) and lower E/A (MD of -0.16 [95% CI, -0.25 to -0.06], p=0.001), collectively suggesting that the myocardial relaxation is impaired in preeclampsia. Interestingly, DT (MD of 3.10 msec [95% CI, -5.43 to 11.62], p=0.48) was not found to be different between the groups. Conclusions: Our findings demonstrate that PE patients develop LV diastolic dysfunction during pregnancy which may be mediated by hypertension caused pressure overload. Given that diastolic dysfunction is a hallmark characteristic of heart failure with preserved ejection fraction (HFpEF), future longitudinal studies examining cardiac function during pregnancy and postpartum will help determine if PE patients are destined to develop HFpEF.

P195 CARDIOVASCULAR OUTCOMES IN PATIENTS WITH AORTIC STENOSIS AND HYPERTENSION UNDERGOING AORTIC VALVE REPLACEMENT

Background and Objective: Aortic valve stenosis (AS) is most common valvular heart disease and in its severe form requires aortic valve replacement (AVR). The prevalence of both AS and arterial hypertension (HTN) increases with age and the conditions therefore often co-exist. Co-existence of AS and HTN is associated with higher global left ventricular (LV) pressure overload, more abnormal LV geometry and function, and more adverse cardiovascular outcome. Management of HTN in AS has historically been associated with prudence and concerns, mainly related to drug-induced potential adverse consequences. We evaluated the cardiovascular outcomes of patients with AS and HTN undergoing to AVR Methods: A retrospective cohort study where all the patients who underwent AVR between 2019- 2024, in a 4-level center in Bogotá, Colombia. A descriptive analysis was performed. Continuous variables were expressed as mean or median with their respective measure of dispersion, standard deviation or interquartile range (ICR), the categorical variables were expressed in proportions and absolute numbers. Results: We analyzed 1043 Patients with moderate/severe AS undergoing AVR, 64.3% (671 with HTN), median age for all of 69.8 years ICR (61.7-77.4) Hypertensive patient being older (72 years p<0.0001). In the HTN group 57.8% were men, and more frequently they had diabetes and dyslipidemia comorbidities (p<0.001) as well as greater baseline renal involvement (p<0.001) comparatively with NO-HTN. In addition, hypertensive patient had better LVEF and were treated with ARA II/IECA (55,6% vs 19.4% p<0.001), beta blockers (60.4% vs 47.3% p< 0.001) and anti-calcium medication (13,1% vs 19,5% p<0.001).Table 1. Cardiovascular outcomes showed greater tendency towards worsening of renal function. There were no statistically significant differences in mortality. Conclusions: AVR is presented as a safe procedure in patients with AS and HTN in developing countries. The institutional results show a safe technique, associated with low mortality rates. Hypertensive patients had more acute kidney injury in the post-surgical period, which leads us to propose kidney protection strategies in this group.

Fading Focus: Addressing the Association Between Challenge Stressors, Role Blurring, Insomnia, Fatigue, and Workplace Cognitive Failure.

The primary goal of the present study is to inspect the plausible job-related (i.e., challenge stressors and role blurring) and individual factors (i.e., fatigue and insomnia) that potentially lead to work-related cognitive failures among healthcare staff. Through the judgmental sampling technique, data was collected from healthcare personnel in Iran. The results revealed that challenge stressors in the form of time pressure, job responsibility, and work overload are significantly related to role blurring. Moreover, role blurring increases fatigue and insomnia among medical staff, and both insomnia and fatigue cause workplace cognitive failure. The results also confirm the mediation effect of role blurring in the association between challenge stressors, insomnia, and fatigue. According to the results, insomnia and fatigue similarly mediate the role blurring on workplace cognitive failure association. Theoretical implications, useful suggestions for practitioners, and prospective research avenues are debated in the study.

Barriers to Communication in Undergraduate Medical Education: Perspectives of Students From Karnataka, India.

Background Communication barriers in medical education can impede learning. Understanding these barriers from students' perspectives is crucial for developing effective solutions. The objectives of this study were to identify the barriers to communication in undergraduate medical education and their solutions from students' perspectives as well as to determine the demographic factors associated with these barriers. Materials and methods A cross-sectional study was conducted from May 2018 to July 2019 among undergraduate students at a medical college in Karnataka. Using a stratified sampling method, data was collected from 400 students via a pretested semi-structured questionnaire. The data was analyzed using descriptive statistics, and logistic regression analysis was performed to determine the association between demographic factors and barriers to communication. Results Students identified several communication barriers, primarily in the domains of language, environment, psychology, and teacher-related issues. Key barriers in theory classes included the use of medical jargon, overcrowding, faulty microphones, absent-mindedness, peer pressure, fast-paced teaching, monotonous sessions, and information overload. In practical classes, barriers were overcrowding, absent-mindedness, and fast-paced teaching, and for clinical case discussions, barriers included difficulty understanding the local language, overcrowding, and leg pain. Proposed solutions by students for theory classes included simpler explanations, smaller batches, microphone maintenance, interactive lectures, and breaks between classes. For practical classes, solutions were smaller practical batches, interactive sessions, and simpler explanations of topics, while for case discussion, solutions included optional local language classes, smaller groups, and better seating arrangements. Conclusion This study highlights key communication barriers in medical education and underscores the influence of demographic factors such as gender and academic year. The solutions proposed by the students are practical and could enhance communication and the overall educational experience if implemented in medical colleges across India.

Sex-related disparities in aortic stenosis from disease awareness to treatment: a state-of-the-art review.

This state-of-the-art review aimed to synthesize evidence from various sex-stratified studies on aortic stenosis (AS), focusing on the difference in clinical presentation, anatomical characteristics, pathophysiology, and management of AS. In comparison to men, women with AS are present at later stages, are older, more symptomatic, frailer, and exhibit higher operative risk [Society of Thoracic Surgeons (STS) score]. Women tend to have smaller aortic valve (AV) areas and left ventricular (LV) outflow tract, leading to lower stroke volumes (SVs) than men and have a higher prevalence of paradoxical, low-flow, low-gradient AS. In women, chronic pressure overload due to AS results in concentric LV remodelling and hypertrophy, characterized by reduced LV cavities, higher filling pressures, lower wall stress, and more diastolic dysfunction. Conversely, men exhibit more dilated eccentric LV remodelling and hypertrophy. AVs in women are less calcified but more fibrotic. Moreover, women are often underdiagnosed, have severity underestimated, and experience delays or receive fewer referrals for AV replacement (AVR). However, women tend to benefit from transcatheter AVR (TAVR) with a long-term survival advantage over men, although the incidence of vascular complications and bleeding events in 30 days after TAVR is higher in women. Surgical AVR (SAVR) in women has high operative risk, is technically demanding and has poorer outcomes with increased mortality at 30 days compared to men. According to the STS score and EuroSCORE, the female sex itself is considered a risk factor for SAVR. Therefore, addressing sex-related disparities in AS and increasing awareness among physicians promises improved diagnosis and treatment, facilitating equitable care and the development of sex-specific personalized medicine.

Follicle-stimulating hormone promotes atrial fibrosis in menopausal women with atrial fibrillation

BackgroundPostmenopausal women with atrial fibrillation (AF) exhibit a higher level of atrial fibrosis and a higher recurrence rate after ablation compared with men. However, the underlying mechanism remains unclear. ObjectiveThe purpost of this study was to investigate the mechanism through which menopause promotes atrial fibrosis. MethodsIn a prospective cohort of women with AF, regression analyses were conducted to assess the relationship between low-voltage area (LVA) and sex hormone levels. CREM-IbΔC-X mice, a spontaneous AF model, underwent bilateral ovariectomy (OVX). Electrocardiograms, echocardiograms, and Masson staining were performed. Follicle-stimulating hormone (FSH) stimulation was applied in male mice for 3 months. OVX was also applied in an angiotensin II (Ang II)–induced pressure overload mouse model, after programmed electrical stimulation and structural analyses. Bulk RNA sequencing (RNA-seq) was performed to elucidate potential mechanisms. ResultsWomen demonstrated a significantly higher LVA burden than men (P < .001). A positive correlation was observed between LVA burden and FSH level (P = .002). Mice in the OVX group exhibited a significantly higher incidence of AF (P = .040) and atrial fibrosis (P = .021) compared with the Sham group, which could be attenuated by adeno-associated virus encoding small interfering RNA against Fshr. In male CREM-IbΔC-X mice, FSH stimulation promoted the occurrence of AF (P = .035) and atrial fibrosis (P = .002). In Ang II–induced female mice, OVX prompted atrial fibrosis, increased AF inducibility, and shortened atrial effective refractory period, which could be attenuated with knockdown of Fshr. RNA-seq indicated mitochondrial dysfunction. ConclusionPostmenopausal women exhibited a higher LVA burden than men, which was positively correlated with FSH level. FSH promoted atrial fibrosis through oxidative stress.

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia using Pulmonary Artery Banding.

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described. Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung. In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

Empagliflozin and left atrial function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink‐6 randomized clinical trial

BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated reduction in heart failure outcomes in patients with type 2 diabetes mellitus, although the exact mechanism of benefit remains unclear. Alteration in left atrial (LA) function due to chronic pressure or volume overload is a hallmark of heart failure.ObjectiveTo evaluate the effect of the SGLT2 inhibitor empagliflozin on LA volume and function.Methods90 patients with coronary artery disease and type 2 diabetes (T2DM) were randomized to empagliflozin (n = 44) or placebo (n = 46), and underwent cardiac magnetic resonance (CMR) imaging at baseline and after 6 months. The main outcome was change in LA volume; LA function, including active and passive components, was also measured by a blinded reader.ResultsAt baseline, there was no significant difference in LA volumes between the empagliflozin (indexed maximum LA volume 26.4 ± 8.4mL/m2, minimum LA volume 11.1 ± 5.7mL/m2) and placebo (indexed maximum LA volume 28.7 ± 8.2mL/m2, minimum LA volume 12.6 ± 5.0mL/m2) groups. After 6 months, changes in LA volumes did not differ with adjusted difference (empagliflozin minus placebo): 0.99 mL/m2 (95% CI: -1.7 to 3.7 mL/m2; p = 0.47) for indexed maximum LA volume, and 0.87 mL/m2 (95% CI: -0.9 to 2.6 mL/m2; p = 0.32) for indexed minimum LA volume. Changes in total LA emptying fraction were also similar, with between-group adjusted mean difference − 0.01 (95% CI: -0.05 to 0.03, p = 0.59).ConclusionSGLT2 inhibition with empagliflozin for 6 months did not have a significant impact on LA volume and function in patients with T2DM and coronary artery disease. (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes [EMPA-HEART]; NCT02998970).

The Monocrotaline Rat Model of Right Heart Disease Induced by Pulmonary Artery Hypertension.

Pulmonary artery hypertension (PAH) is characterised by increased pulmonary vascular resistance (PVR) resulting in elevated pressure in the pulmonary artery supplying the pulmonary circulation. Disease of the right ventricle (RV) often manifests as a result of PAH placing excessive pressure on the right side of the heart. Although a relatively rare disease in humans, the impact of sustained PAH is severe, with poor outcomes even in treated individuals. As PAH develops, the blood flow is restricted through the pulmonary arteries and the right ventricle hypertrophies due to the increased strain of pumping blood through the pulmonary circulation. With time, RV hypertrophy progresses to right heart failure, impacting the supply of blood to the left ventricle and systemic circulation. Although right heart failure can currently be treated, it cannot be cured. There is therefore a need for more research into the physiological changes that cause the heart to fail under pressure overload. This review aims to evaluate the monocrotaline (MCT) rat model of PAH as a means of studying the cellular mechanisms associated with the development of RV hypertrophy and right heart failure.

MYH11 rare variant augments aortic growth and induces cardiac hypertrophy and heart failure with pressure overload.

Smooth muscle cell-specific myosin heavy chain, encoded by MYH11, is selectively expressed in smooth muscle cells (SMCs). Pathogenic variants in MYH11 predispose to a number of disorders, including heritable thoracic aortic disease associated with patent ductus arteriosus, visceral myopathy, and megacystis-microcolon-intestinal hypoperistalsis syndrome. Rare variants of uncertain significance occur throughout the gene, including MYH11 p.Glu1892Asp, and we sought to determine if this variant causes thoracic aortic disease in mice. Genomic editing was used to generate Myh11 E1892D/E1892D mice. Wild-type (WT) and mutant mice underwent cardiovascular phenotyping and with transverse aortic constriction (TAC). Myh11 E1892D/E1892D and WT mice displayed similar growth, blood pressure, root and ascending aortic diameters, and cardiac function up to 13 months of age, along with similar contraction and relaxation on myographic testing. TAC induced hypertension similarly in Myh11 E1892D/E1892D and WT mice, but mutant mice showed augmented ascending aortic enlargement and increased elastic fragmentation on histology. Unexpectedly, male Myh11 E1892D/E1892D mice two weeks post-TAC had decreased ejection fraction, stroke volume, fractional shortening, and cardiac output compared to similarly treated male WT mice. Importantly, left ventricular mass increased significantly due to primarily posterior wall thickening, and cardiac histology confirmed cardiomyocyte hypertrophy and increased collagen deposition in the myocardium and surrounding arteries. These results further highlight the clinical heterogeneity associated with MYH11 rare variants. Given that MYH11 is selectively expressed in SMCs, these results implicate a role of vascular SMCs in the heart contributing to cardiac hypertrophy and failure with pressure overload.

Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding (lnc) RNAs, termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knock-out mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 knock-out mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene-expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene-expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.