Left Ventricular Fibrosis Research Articles

Abstract We078: Endothelial-specific PHD2 Modulates Cardiac Inflammation, Hypertrophy, and Dysfunction in an Age-dependent Manner

Background: Prolyl hydroxylase domain proteins (PHD) are oxygen-sensing molecules that degrade hypoxia-inducible factor-α. Deletion of endothelial-specific PHD2 (PHD2ECKO) shows different degrees of pulmonary arterial hypertension and cardiac hypertrophy. Whether EC-specific PHD2 deletion plays a role in regulating cardiac inflammation and dysfunction is still unclear. We investigated the effect of endothelial-specific PHD2 deficiency on cardiac inflammation and dysfunction in mice. Methods: Briefly, PHD2ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin-Cre transgenic mice. The effect of PHD2ECKO on cardiac structure and function was determined in male young (6 months old) and old (12-16 months old) mice. Results: While PHD2ECKO caused significant left ventricular (LV) hypertrophy in mice at 6 months, PHD2ECKO had no significant impact on LV fibrosis and dysfunction in these mice. However, PHD2ECKO caused significant LV leukocyte infiltration, fibrosis, cardiomyocyte hypertrophy, and LV dysfunction in mice over 12 months. Most interestingly, we found that PHD2ECKO caused a significant increase of cardiac CD4 + T cells and CD8 + T cells, activation, and their proinflammatory cytokine productions in mice at the age of 12 months. Moreover, we found that PHD2ECKO resulted in a significant upregulation of several adhesion molecules important for CD4 + and CD8 + T cell homing, retention, and proliferation. However, the cytokine production by other immune cell subsets was largely unaffected. Conclusions: Our findings demonstrated that endothelial-PHD2 exerts an important role in proliferation, activation, and proinflammatory cytokine production by CD4 and CD8 T cells, and the aging-dependent LV hypertrophy and dysfunction.

Abstract Tu075: Cardiac macrophages expressing CD206 and IL-4Ra are required for adverse LV remodeling in HF

Cardiac macrophages significantly expand in chronic heart failure (HF). We tested the hypothesis that CD206 + macrophages expressing interleukin (IL)-4Ra in the failing heart are key drivers of left ventricular (LV) remodeling and ischemic cardiomyopathy. Cardiac macrophages were profiled using flow cytometry in adult male C57BL/6 (WT) mice following non-reperfused myocardial infarction (MI) to induce HF or sham operation. CD206 + macrophages progressively expanded in post-MI hearts during the progression of LV remodeling and comprised ~85% of macrophages at 8 w. These macrophages were exclusively proliferative and predominantly C-C motif chemokine receptor (CCR2) – and major histocompatibility complex (MHC)II hi in failing hearts, with the majority (92%) of CD206 + CCR2 – macrophages expressing LYVE-1, an embryonically-derived resident macrophage marker. Nearly half of cardiac CD206 + macrophages expressed IL-4Ra; the abundance of CD206 + IL-4Ra + directly correlated with LV dysfunction and fibrosis. Intramyocardial adoptive transfer of IL-4-polarized bone marrow derived CD206 + macrophages induced progressive LV dilation, dysfunction and fibrosis over 4 w in naïve recipient mice. To evaluate the role of CD206 + IL-4Ra + macrophages in LV remodeling, we used male and female LysM CreERT2 ;IL-4Ra F/F mice that allow for inducible myeloid-specific IL-4Ra gene deletion. Administration of tamoxifen from at 4 to 10 w post-MI (in established HF), effectively deleted IL-4Ra in cardiac macrophages and significantly reduced CD206 + macrophage abundance and proliferation in the remodeling heart. Myeloid-specific IL-4Ra deletion further prevented LV remodeling progression, improved fibrosis and neovascularization, and alleviated LV systolic dysfunction, while suppressing expansion of cardiac immune cells and blood Ly6C high monocytosis. We conclude that an expanded and proliferative population of CD206 + IL-4Ra + macrophages primarily derived from resident macrophages are key mediators of pathological LV remodeling and fibrosis. Inhibition of CD206 + macrophage IL-4Ra signaling may be a fruitful therapeutic approach to alleviate disease progression in HF.

Abstract We079: Program Macrophage Phenotypes and Cardiac Remodeling After Myocardial Infarction with Interleukin-10

Introduction: Macrophages (Mφ) and their phenotypic polarization play essential roles in modulating cardiac inflammation and recovery after myocardial infarction (MI). Interleukin-10 (IL-10) is a potent immunomodulatory cytokine that directs Mφ polarization to beneficial reparative phenotypes and is widely investigated in diseases involving extensive inflammation. However, high-dose IL-10 treatment may not lead to the expected therapeutic outcome, raising the question of whether IL-10 has dose-dependent effects on Mφ polarization and cardiac remodeling post-MI. Hypothesis: IL-10 can program Mφ phenotypes under inflammation and has functional impact in cardiac remodeling post-MI in dose-dependent manner. Goals: We use RAW264.7 Mφ and mouse permanent MI models to test our hypothesis. Approach: We applied 25-1000 ng/mL IL-10 in vitro before or after inducing M1 (with interferon-g) and M2 (with interleukin-4) polarization for pro-inflammatory and anti-inflammatory phenotypes, respectively. We intramyocardially administered 25-2000 ng IL-10 in vivo immediately after inducing MI and examined cardiac function, inflammatory responses, fibrosis and revascularization for 6 weeks (n=5/group). Results: IL-10 at 100-250 ng/mL directed Mφ phenotype shift from M1 to M2 most effectively after inducing polarization in vitro (both p <0.01); groups with ≥500 ng/mL IL-10 exhibited high M1/low M2 phenotypes, similar to no IL-10 controls. Cells treated with ≥100 ng/mL IL-10 before polarization exhibited a notable reduction in M1 phenotype after induction (all p <0.05). Echocardiography showed that with single IL-10 administration, only 250 ng IL-10 notaly improved left ventricular (LV) function and reduced LV chamber size compared with the saline control ( p <0.05) whilst ≥1000 ng caused a transient negative impact in LV function at 5 days post-MI ( p <0.05), Phagocyte infiltration at MI was notably diminished in ≥100 ng groups at 6 weeks post-MI (all p <0.05). Only 250 ng IL-10 led to a notable 53% reduction in LV fibrosis ( p =0.05) and nearly 200% increase in CD31+ cell counts at MI ( p =0.013). Conclusion: Our results suggest an optimal range of IL-10 doses for macrophage polarization and cardiac benefits post-MI, with risks of side effects from IL-10 overdose.

Abstract Tu099: GDF11 accelerates NF-kB-mediated inflammation prior to reduction in cardiac fibrosis in response to experimental pressure overload.

Background: Cardiac fibrosis is a common pathophysiology in a broad variety of heart diseases. GDF11, a member of the TGF-beta superfamily, can reduce cardiac hypertrophy and fibrosis in the pressure overload model of experimental Trans Aortic Constriction (TAC). However, the molecular mechanisms by which GDF11 can reduce cardiac fibrosis are incompletely described. Hypothesis: GDF11 is known to activate both NF-kB as well as SMAD2/3 signaling which are essential in cardiac fibrosis and hypertrophy processes. We hypothesized that exogenous GDF11 can change the dynamics of early inflammatory NF-kB target genes during the response to pressure overload. Methods: We used mice implanted with AngII-osmotic pumps to induce left ventricular fibrosis. The mice were harvested at different time points: 3, 7, 14, and 28 days post-pump implantation (ppi) to follow the evolution of cardiac fibrosis and cardiac hypertrophy, and to identify the role of GDF11 in modulating these processes. Results: GDF11 delivery (1mg/kg every other day) in AngII mice (AngII+GDF11) induced earlier expression of NF-kB target genes (IL-1beta, IL-6, TNF-alpha – p>0.05) compared to AngII+Veh control group at 3d ppi, revealing accelerated activation of NF-kB response pathways in AngII+GDF11 group. This is associated with faster recruitment of the M1 macrophage population observed by an increased expression of CD86 or iNOS at 3d ppi. We also observed decreased markers of fibroblast activation after GDF11 supplementation, with less collagen deposition (F-CHP) and fibrosis (Masson Trichrome) at 28 days. Conclusions: Our data suggest that exogenous GDF11 changes the dynamics of NF-kB inflammatory mechanisms while reducing later fibrosis. This new finding could suggest that the dynamics of the inflammatory response early after pressure overload is a critical factor in cardiac fibrosis.

Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.

Arrhythmogenic Mitral Valve Prolapse Revisited: A Not Uncommon Cause of Youthful Sudden Death in Athletes and Women

BackgroundSudden deaths (SDs) in young people, including competitive athletes, albeit uncommon, are usually attributable to genetic, congenital or acquired cardiovascular conditions. However, it is under-appreciated that mitral valve prolapse (MVP), a relatively common valvular heart disease, is associated with SD in this youthful population. MethodsForty-three MVP-related SDs were identified from 2 large cardiovascular registries with pathologic, clinical, and demographic findings reported. ResultsEvents occurred in both sexes, but females were unexpectedly common (49%); median age was 22 ± 8 years, and 29 (67%) were engaged in competitive sports, including 17 with preparticipation examination. Of the 43 MVP cases, 21 died suddenly during or just after vigorous exercise, including 6 during organized sports. Sixteen (37%) had been evaluated by a cardiologist, resulting in confirmed MVP diagnosis in 11. Pathologic findings characteristic of MVP included bileaflet myxomatous involvement (in all cases) and areas of interstitial or replacement myocardial fibrosis (in 79%), most evident in posterolateral left ventricular wall. ConclusionsArrhythmogenic myxomatous degeneration (MVP) is an under-recognized cause of SD in young people, including competitive athletes, disproportionally affecting females and requires a high index of clinical suspicion. Frequency of left ventricular fibrosis in these young people with MVP suggests a mechanism for ventricular tachyarrhythmias and SD, relevant to future risk stratification.

Left Ventricular Fibrosis by Cardiac Magnetic Resonance Tissue Characterization in Chronic Mitral Regurgitation Patients.

Background: Left ventricular remodeling in chronic mitral regurgitation (MR) encompasses two types of myocardial fibrosis: replacement fibrosis, identified by late gadolinium enhancement (LGE), and diffuse interstitial fibrosis, assessed by pre- and postcontrast T1 mapping techniques. These may explain irreversible LV dysfunction after MR correction. We aimed to assess the presence of myocardial fibrosis in patients with moderate and severe MR with no criteria for surgery versus mild MR controls. Methods: We enrolled 137 patients with chronic primary MR and 130 controls; all underwent cardiac magnetic resonance, and were followed up in a median of 2.9 years to assess mortality and the need for mitral valve replacement. Results: Patients in the study group displayed significantly higher degrees of LGE (28.4% vs 7.69%, p < 0.05), higher native T1 values (1167 ± 58.5 versus 971 ± 51.4 (p < 0.05)), and higher extracellular volumes compared to controls (32.3% ± 3.5 versus 23.9 ± 2.2, (p < 0.05)). The composite outcome occurred in 28 patients in the study group (20.4%), and significantly higher with LGE+ (78.5%). Replacement fibrosis (HR = 1.83, 95% CI, p < 0.01) and interstitial fibrosis (HR = 1.61, 95% CI, p < 0.01) were independent predictors for the composite outcome. Conclusions: Patients with moderate and severe MR with no criteria for surgery still exhibit a significant degree of both replacement and interstitial fibrosis, with prognostic implications.

Acute sleep deprivation (ASD) and cardioprotection: Impact of ASD on oxytocin-mediated sympathetic nervous activation preceding myocardial infarction

IntroductionThis study explored how acute sleep deprivation (ASD) before myocardial ischemia influences oxytocin release from paraventricular (PVN) neurons and its correlation with sympathetic nervous system (SNS) activity post-acute sleep loss, impacting subsequent left ventricular (LV) remodeling following myocardial infarction (MI). MethodsThe study was conducted in two phases: induction of ASD, inducing MI, blood sampling, euthanizing animals and collecting their heart and brain for histological and gene expression evaluations. The animals in first and second phase were euthanized 24 h and 14 days after MI, respectively. ResultsPre-MI ASD, accompanied by increased serum epinephrine levels within 24 h of MI, upregulated oxytocin and cFos expression in the PVN. Also, pre-MI ASD resulted in decreased serum PAB levels 14 days post-MI (P < 0.001). While notable echocardiographic changes were seen in MI versus sham groups, ASD demonstrated protective effects. This was evidenced by reduced infarct size, elevated TIMP1, MMP2, and MMP9 in the LV of SD + MI animals versus MI alone (P < 0.05). Additionally, histological analysis showed reduced LV fibrosis in pre-MI ASD subjects (P < 0.05). ConclusionOur study supports the notion that activation of oxytocin neurons within the PVN subsequent to ASD interacts with autonomic centers in the central nervous system. This enhanced sympathetic outflow to the heart prior to MI triggers a preconditioning response, thereby mediating cardioprotection through decreased oxidative stress biomarkers and regulated extracellular matrix (ECM) turnover.

Impaired Myocardial Work in Children with Hypertrophic Cardiomyopathy and Left Ventricular Fibrosis on Cardiac Magnetic Resonance Imaging.

Echocardiography is pivotal for diagnosis and monitoring of hypertrophic cardiomyopathy (HCM) and can evaluate myocardial function using myocardial work (MW) calculations. Echocardiography is often supplemented by cardiovascular magnetic resonance (CMR) imaging, which can detect myocardial fibrosis using late gadolinium enhancement (LGE). We sought to study the relationship between baseline LGE and MW at baseline and during follow-up in pediatric HCM patients. During the study period (2008-2023), 75 patients were followed up for HCM. In 14 patients (age 14.2 ± 2.8years, 50.0% male, 6.4 ± 2.9years follow-up), both LGE-CMR and echocardiography were performed. Global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency (GWE) were measured, and myocardial fibrosis was estimated by qualitative assessment of LGE. Patients with LGE (n = 7) exhibited significantly impaired baseline MW, including GWI (mean difference, MD - 487.4mmHg %, 95% CI [- 866.8mmHg % to - 108.3mmHg %], p = 0.027), GCW (MD - 536.8mmHg %, 95% CI [- 929.8mmHg % to - 144.4mmHg %], p = 0.020), and GWE (MD - 4.4%, 95% CI [- 8.1% to - 0.7%], p = 0.039). Regional analysis revealed impaired MW indices in segments with LGE, notably basal and mid septal segments. GWI demonstrated high diagnostic performance for LGE presence (sensitivity 93%, specificity 88%, and area under receiver operating characteristic curve 0.85). Baseline LGE presence had no significant impact on MW deterioration during follow-up. MW is significantly impaired in HCM patients with myocardial fibrosis, highlighting potential utility of echocardiography-derived MW analysis as a valuable tool.

CMR-based cardiac phenotyping in different forms of heart failure

Heart failure (HF) is a heterogenous disease requiring precise diagnostics and knowledge of pathophysiological processes. Since structural and functional imaging data are scarce we hypothesized that cardiac magnetic resonance (CMR)-based analyses would provide accurate characterization and mechanistic insights into different HF groups comprising preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction (HFrEF). 22 HFpEF, 17 HFmrEF and 15 HFrEF patients as well as 19 healthy volunteers were included. CMR image assessment contained left atrial (LA) and left ventricular (LV) volumetric evaluation as well as left atrioventricular coupling index (LACI). Furthermore, CMR feature-tracking included LV and LA strain in terms of reservoir (Es), conduit (Ee) and active boosterpump (Ea) function. CMR-based tissue characterization comprised T1 mapping as well as late-gadolinium enhancement (LGE) analyses. HFpEF patients showed predominant atrial impairment (Es 20.8%vs.25.4%, p = 0.02 and Ee 8.3%vs.13.5%, p = 0.001) and increased LACI compared to healthy controls (14.5%vs.23.3%, p = 0.004). Patients with HFmrEF showed LV enlargement but mostly preserved LA function with a compensatory increase in LA boosterpump (LA Ea: 15.0%, p = 0.049). In HFrEF LA and LV functional impairment was documented (Es: 14.2%, Ee: 5.4% p < 0.001 respectively; Ea: 8.8%, p = 0.02). This was paralleled by non-invasively assessed progressive fibrosis (T1 mapping and LGE; HFrEF > HFmrEF > HFpEF). CMR-imaging reveals insights into HF phenotypes with mainly atrial affection in HFpEF, ventricular affection with atrial compensation in HFmrEF and global impairment in HFrEF paralleled by progressive LV fibrosis. These data suggest a necessity for a personalized HF management based on imaging findings for future optimized patient management.

Ventricular late gadolinium enhancement by cardiac MRI as a predictor of atrial fibrillation in hypertrophic cardiomyopathy

BackgroundAtrial fibrillation (AF) increases stroke and mortality in patients with hypertrophic cardiomyopathy (HCM). Cardiac MRI (CMR) is increasingly used to detect late gadolinium enhancement (LGE) as a reliable indicator of left ventricular fibrosis, a potential predisposing factor of AF. Our research explored the correlation between left ventricular LGE and AF prevalence in HCM. MethodsThis retrospective study involved 351 HCM patients who underwent CMR. LGE percentages (0%, 1–5%, 6–14%, ≥15%) on CMR were compared with AF prevalence in HCM patients. Demographic, comorbidity, and imaging data were analyzed using appropriate univariate and multivariate analyses assessing for significant differences in AF prevalence. The predetermined significance level was p < 0.05. ResultsCMR demonstrated increased LGE in those with AF (p = 0.004). Increased LGE correlated with increased AF rates: 27.6% (0% LGE), 38.5% (1–5% LGE), 44.4% (6–14% LGE), and 54.7% (≥15% LGE) (p = 0.101, p = 0.043, p = 0.002, respectively, vs. 0% LGE). Adjusted for age, differences persisted and were most evident for LGE >15% (p = 0.001). Multivariate analysis, factoring age, gender, BMI, RVSP, and LVEF, supported LGE (odds ratio of 1.20, p = 0.036) and LAVI (odds ratio 1.05, 1.02–1.07, p < 0.001) as predictive markers for AF prevalence. ConclusionsOur study suggests a correlation between ventricular LGE and AF in patients with HCM. LGE exceeding 15% was associated with a significant increase in AF prevalence. These patients may require more frequent AF monitoring.

Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure.

Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles, including small extracellular vesicles or exosomes, and their molecular cargo are known to modulate cell-to-cell communication during multiple cardiac diseases. However, the role of systemic extracellular vesicle biogenesis inhibition in HF models is not well documented and remains unclear. We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of tipifarnib, a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a [Ras associated binding protein 27a], nSMase2 [neutral sphingomyelinase 2], and Alix [ALG-2-interacting protein X]) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery were randomly assigned to groups with and without tipifarnib treatment (10 mg/kg 3 times/wk) and monitored for 8 weeks, and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced left ventricular dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of tipifarnib in TAC mice reduced circulating exosomes to baseline and remarkably improved left ventricular functions, hypertrophy, and fibrosis. Tipifarnib treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR 331-5p, which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR 331-5p is crucial for inhibiting the fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR 331-5p that acts as a potent repressor for one of the fibrotic mechanisms mediated by HOXC8. Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.

Angiotensin II receptor blockers is associated a decreased left ventricular fibrosis in patients with obstructive hypertrophic cardiomyopathy

Angiotensin II receptor blockers is associated a decreased left ventricular fibrosis in patients with obstructive hypertrophic cardiomyopathy

The role of the kynurenine pathway in cardiovascular disease.

The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in various physiological and pathological processes. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) serve as the initial and pivotal enzymes of the KP, with IDO playing important and intricate roles in cardiovascular diseases. Multiple metabolites of KP have been observed to exhibit elevated concentrations in plasma across various cardiovascular diseases, such as atherosclerosis, hypertension, and acute myocardial infarction. Multiple studies have indicated that kynurenine (KYN) may serve as a potential biomarker for several adverse cardiovascular events. Furthermore, Kynurenine and its downstream metabolites have complex roles in inflammation, exhibiting both inhibitory and stimulatory effects on inflammatory responses under different conditions. In atherosclerosis, upregulation of IDO stimulates KYN production, mediating aromatic hydrocarbon receptor (AhR)-induced exacerbation of vascular inflammation and promotion of foam cell formation. Conversely, in arterial calcification, this mediation alleviates osteogenic differentiation of vascular smooth muscle cells. Additionally, in cardiac remodeling, KYN-mediated AhR activation exacerbates pathological left ventricular hypertrophy and fibrosis. Interventions targeting components of the KP, such as IDO inhibitors, 3-hydroxyanthranilic acid, and anthranilic acid, demonstrate cardiovascular protective effects. This review outlines the mechanistic roles of KP in coronary atherosclerosis, arterial calcification, and myocardial diseases, highlighting the potential diagnostic, prognostic, and therapeutic value of KP in cardiovascular diseases, thus providing novel insights for the development and application of related drugs in future research.

Ablation of Vitamin D Signaling in Cardiomyocytes Leads to Functional Impairment and Stimulation of Pro-Inflammatory and Pro-Fibrotic Gene Regulatory Networks in a Left Ventricular Hypertrophy Model in Mice.

The association between vitamin D deficiency and cardiovascular disease remains a controversial issue. This study aimed to further elucidate the role of vitamin D signaling in the development of left ventricular (LV) hypertrophy and dysfunction. To ablate the vitamin D receptor (VDR) specifically in cardiomyocytes, VDRfl/fl mice were crossed with Mlcv2-Cre mice. To induce LV hypertrophy experimentally by increasing cardiac afterload, transverse aortic constriction (TAC) was employed. Sham or TAC surgery was performed in 4-month-old, male, wild-type, VDRfl/fl, Mlcv2-Cre, and cardiomyocyte-specific VDR knockout (VDRCM-KO) mice. As expected, TAC induced profound LV hypertrophy and dysfunction, evidenced by echocardiography, aortic and cardiac catheterization, cardiac histology, and LV expression profiling 4 weeks post-surgery. Sham-operated mice showed no differences between genotypes. However, TAC VDRCM-KO mice, while having comparable cardiomyocyte size and LV fibrosis to TAC VDRfl/fl controls, exhibited reduced fractional shortening and ejection fraction as measured by echocardiography. Spatial transcriptomics of heart cryosections revealed more pronounced pro-inflammatory and pro-fibrotic gene regulatory networks in the stressed cardiac tissue niches of TAC VDRCM-KO compared to VDRfl/fl mice. Hence, our study supports the notion that vitamin D signaling in cardiomyocytes plays a protective role in the stressed heart.

Human epididymis protein 4 is a useful predictor of post-operative prognosis in patients with severe aortic stenosis.

The human epididymis protein 4 (HE4), a novel fibrosis marker, is expressed only in activated fibroblasts and is thought to reflect ongoing left ventricular (LV) fibrosis. LV fibrosis is a feature of severe aortic stenosis (AS) and is related to the post-operative outcome of patients with AS. We investigated the relationship between serum levels of HE4 and the post-operative prognosis of patients with severe AS. We measured the serum HE4 levels of 55 participants (80.8±8.0years old, male n=26, 46%) with severe AS prior to surgical aortic valve replacement (n=31, 56%) or transcatheter aortic valve implantation (n=24, 44%) at Kumamoto University Hospital in 2018. We followed them for cardiovascular (CV) death or hospitalization for heart failure (HF) for 3years. Serum HE4 levels were positively correlated with computed tomography-extracellular volume (CT-ECV) values (r=0.53, P=0.004). Kaplan-Meier curves demonstrated a significantly higher probability of hospitalization for HF or CV-related death in the patients with high HE4 (greater than the median HE4 value) compared with the patients with low HE4 (lower than the median HE4 value) (log-rank P=0.003). Multivariate analysis showed HE4 (log(HE4)) to be an independent prognostic factor [hazard ratio (HR): 7.50; 95% confidence interval (CI): 1.81-31.1; P=0.005]. Receiver operating characteristic (ROC) curve analysis suggested that HE4 is a marker of increased risk of CV-related death or hospitalization for HF at 3years after surgery, with an area under the curve (AUC) of 0.76 (95% CI: 0.62-0.90; P=0.003). We found that HE4 is a potentially useful biomarker for predicting future CV events in patients scheduled for AS surgery. Measuring serum HE4 values could help consider AS surgery.

Non-invasive assessment of the ventricular tachycardia isthmus during sinus rhythm

Abstract Background The ablation of ventricular tachycardias (VT) presents significant challenges due to the complex and time-consuming approaches involved in identifying arrhythmogenic regions. Combining non-invasive electrocardiographic imaging (ECGI) with endocardial mapping could potentially enhance the efficacy of interventions. Objective To evaluate the capability of ECGI in guiding operators towards areas of VT isthmuses during sinus rhythm. Methods Patients with scar-related VT, confirmed by late gadolinium enhancement cardiac magnetic resonance, were prospectively enrolled. We compared the areas of slowed conduction identified by ECGI with the VT sustaining regions identified endocardially. Simultaneous Electroanatomical Mapping (EAM) and ECGI mapping were performed during VT ablation procedures. In patients in whom a hemodynamically stable VT was maintained, the reentry circuit was mapped endocardially, and the ablation target was identified. The left ventricle was segmented into 9 regions, categorized as either VT-isthmus or non-VT isthmus based on EAM findings. Prior to ablation, local activation times (LAT) and conduction velocity (CV) ECGI sinus maps were computed. Slow conduction was quantified non-invasively by computing different ECGI metrics per region, including the mean and the standard deviation (SD) of LAT and CV, the regional Total Activation Time (rTAT) – time span between the earliest and latest activated nodes–, and the Slow Conduction Velocity (SCV) – the percentage of nodes where velocity falls below 60 cm/s -. Results The study included 20 consecutive patients with ischemic cardiomyopathy who were referred for VT ablation. A total of 21 regions linked to the VT isthmus were identified endocardially in 17 patients (age: 66.1±8.8 years, 94.1% male, left ventricular ejection fraction: 26.4±7.3%). Figure 1 illustrates the correlation between the VT circuit and the ECGI sinus map in two patients with extensive left ventricular fibrosis. ECGI metrics related to VT isthmuses exhibited a higher standard deviation in both LAT (18.1±2.0 vs 9.8±1.2 ms; p=0.001), and CV (50.4±4.7 vs 37.1±2.8 cm/s; p=0.011), and a greater percentage of nodes with slowed conduction (13.7±2.7 vs 7.4±1.6 %; p=0.029), compared to non-VT isthmus regions, Figure 2. Multivariate logistic regression analysis revealed that SD-LAT was the strongest predictor of VT isthmus localization. Conclusion ECGI has demonstrated the capability to pinpoint slowed conduction areas responsible for VT in sinus rhythm, showing promise in planning and guiding VT ablation strategies. This advancement paves the way for further research into using this non-invasive tool to improve risk stratification methods for ventricular arrhythmias.

#1311 Cardiac damage in a multifactorial DKD/CKD mouse model resembles HFpEF and can be reduced by standard-of-care treatment

Abstract Background and Aims We developed a diet-induced hypertension-accelerated mouse model of diabetic kidney disease characterized by progressive loss of GFR resulting in chronic kidney disease. Since cardiovascular disease is the major cause of death in CKD, we characterized the functional and structural cardiac damage in this model. Additionally, we studied the efficacy of combination therapy with an ACE-inhibitor (Lisinopril) and SGLT2-inhibitor (Dapagliflozin) on cardiac histopathology. Method Male KKAy mice underwent uninephrectomy. After recovery mice received high fat diet (45% LARD) and drinking water with or without 50 mg/L LNNA (wk0). At 12 weeks, imaging was performed to study cardiac function and mice were terminated at week 13. In the intervention study, at week 4, lisinopril (2.5 mg/kg/day; drinking water) and at week 8 dapagliflozin (5 and 20 mg/kg/day; foodadmix) treatment were started. At week 16 mice were terminated and lung and heart weight and cardiac histology were determined. Results Upon termination, macroscopic evaluation of the hearts showed extensive scar tissue formation on the outside of the left ventricle. Histological evaluation showed the presence left ventricular hypertrophy, coronary calcification and myocardial fibrosis in male KKAy mice with UNX, HFD and LNNA. KKAy mice with UNX and HFD but without LNNA also showed myocardial fibrosis, monocyte infiltration and focal mineralization. Imaging showed preserved ejection fraction, a significant reduction, increased left ventricle posterior wall thickness and decrease left ventricle inner diameter. Treatment with combination therapy reduced lung wet weight, significantly reduced heart weight and significantly decreased cardiac fibrosis. Macroscopically, less scar tissue was observed after treatment. Conclusion This multifactorial mouse model shows cardiac damage on a background of hypertension, diabetes, renal dysfunction and obesity. Functional measurement including preserved ejection fraction, left ventricle hypertrophy, diastolic dysfunction and increased fibrosis resembling the clinical HFpEF phenotype. Combination therapy with Lisinopril and Dapagliflozin reduced cardiac weight and cardiac fibrosis. This indicates cardiac involvement in the DKD mouse model which confirms that this multifactorial model is clinically relevant.

Assessing Regurgitation Severity, Adverse Remodeling, and Fibrosis with CMR in Primary Mitral Regurgitation.

This review offers an evidence-based analysis of established and emerging cardiovascular magnetic resonance (CMR) techniques used to assess the severity of primary mitral regurgitation (MR), identify adverse cardiac remodeling and its prognostic effect. The aim is to provide different insights regarding clinical decision-making and enhance the clinical outcomes of patients with MR. Cardiac remodeling and myocardial replacement fibrosis are observed frequently in the presence of substantial LV volume overload, particularly in cases with severe primary MR. CMR serves as a useful diagnostic imaging modality in assessing mitral regurgitation severity, early detection of cardiac remodeling, myocardial dysfunction, and myocardial fibrosis, enabling timely intervention before irreversible damage ensues. Incorporating myocardial remodeling in terms of left ventricular (LV) dilatation and myocardial fibrosis with quantitative MR severity assessment by CMR may assist in defining optimal timing of intervention.

Exogenous Thyroxine Normalizes Decreased Heart Rate in Insulin Resistant OLETF Rats

Diabetic cardiomyopathy (DCM) is defined as heart failure in the absence of overt clinical coronary artery disease, valvular disease, hypertension, and dyslipidemia in diabetic patients. Patients with T2DM display left ventricular dysfunction, fibrosis, and abnormal cell signaling leading to diastolic and systolic dysfunction. Increased left ventricular mass and fibrosis potentially leads to abnormal diastolic function. Substantial data exists demonstrating both insulin-dependent and non-insulin dependent diabetes impairs left ventricular function. During insulin resistance, a metabolic shift occurs favoring fatty acid metabolism at the expense of impaired glucose metabolism, leading to lipotoxicity, increased oxidative stress, and inflammation. Thyroid hormones have shown to be cardioprotective. We have previously shown exogenous thyroxine treatment increased GLUT4 translocation and nuclear factor erythroid 2-related factor 2 (Nrf2) in cardiac tissue, demonstrating the potential to improve glucose metabolism and increase antioxidant defense mechanisms. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on left ventricular cardiac function and hemodynamics to assess if the previously observed improvements in cellular metabolism translated to functional improvements. Rats were assigned to three groups: (1) lean, Long Evans Tokushima Otsuka (LETO; n=7), (2) untreated OLETF (n=6), and (3) OLETF + T4 (8 μg/100g BM/d × 6 wks, n=7). Left ventricular function was measured by the pressure-volume system. Heart mass increased in untreated OLETF (1.46 ± 0.08) and treated OLETF (1.61 ± 0.16) compared to LETO (1.19 ± 0.08). Cardiac output (CO) and stroke volume were 26% and 56% greater in untreated OLETF compared to LETO. Heart rate (HR) was 27% lesser in untreated OLETF compared to LETO. While exogenous T4 did not alter CO and SV compared to untreated OLETF, it did normalize HR to LETO levels. The differences in CO between LETO and OLETF suggest that elevated T4 alters the mechanisms (SV vs HR) by which CO is elevated during MetS. The changes may be compensatory to accommodate the cardiac hypertrophy observed in the strain. American Heart Association Award # 946746 APS Porter Physiology Development Fellow (2nd year). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.