Adverse Remodeling Research Articles

QRS prolongation is associated with associated with adverse cardiac remodeling in hypertrophic cardiomyopathy

BackgroundSignal-averaged electrocardiogram (SAECG) records myocardial depolarization, and can detect inhomogeneous/slow conduction in fibrotic myocardium, which promotes reentrant ventricular arrhythmias (VAs). Hypertrophic cardiomyopathy (HCM) is associated with a high prevalence of cardiac fibrosis and VAs, but abnormal SAECG has low predictive power for VAs. We hypothesized that HCM-specific structural/electrical remodeling underlies this result. MethodsWe tested our hypothesis by retrospectively studying HCM patients (n = 73) who underwent transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging within 12 months of SAECG and 12‑lead ECG. Patients were divided into 2 groups (normal-SAECG, abnormal-SAECG) based on filtered-QRS duration (fQRSd), root-mean-square-voltage (RMS40) and low-amplitude (<40 μV) signal of terminal 40 ms of filtered-QRS (late potentials). Abnormal SAECG was defined as fQRSd > 114 ms, RMS40 < 20 μV or LAS40 > 38 ms. ResultsAbnormal SAECG was seen in ~50 % of HCM patients (37/73). In the abnormal-SAECG group, 78 % (n = 29) only had prolonged fQRSd, and 22 % (n = 8) had prolonged fQRSd plus late potentials (RMS40 < 20 μV or LAS40 > 38 ms). Mean fQRSd and LAS40 were significantly higher in the abnormal-SAECG group. The abnormal-SAECG group had significantly larger LA size, lower global-LV longitudinal systolic strain/strain rate and early-diastolic strain rate by TTE; higher LV-mass index (LVMI) and LV-scar burden by CMR; higher prevalence of repolarization abnormalities on 12‑lead ECG. LVEF and adverse outcomes (VT/VF, heart failure, death) were similar in the 2 groups. Univariate analysis showed that fQRSd is positively correlated with LVMI, LV-scar mass, and negatively correlated with global-LV early diastolic strain rate. ConclusionsIn HCM, abnormal SAECG is associated with greater structural/electrical LV-remodeling, reflecting a severe global myopathy.

Relationship Between Renin, Aldosterone, Aldosterone-to-Renin Ratio and Arterial Stiffness and Left Ventricular Mass Index in Young Adults.

Primary aldosteronism, characterized by renin-independent aldosterone production, is associated with adverse cardiovascular remodeling and outcomes. Elevated cardiovascular risk is observed even in subclinical forms of primary aldosteronism according to studies conducted primarily in middle-aged and elderly populations. This study aimed to assess whether early changes in primary aldosteronism biomarkers during young adulthood are associated with arterial stiffness and left ventricular mass index (LVMI) before the onset of overt disease. The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analyzed the data from the offspring of these women at 17 (2006-2009) and 27 (2016-2018) years of age. Participants with elevated high-sensitivity C-reactive protein (>10 mg/L) and female participants who were on oral contraception were excluded. Pulse wave velocity and aortic augmentation index were measured by SphygmoCor Pulse Wave System at both ages, and aortic distensibility and LVMI were measured by cardiac magnetic resonance imaging at 27 years. Multivariable linear regression was used to examine the relationship between plasma renin, aldosterone, or aldosterone-to-renin ratio and arterial stiffness and LVMI. Mediation analysis was used to test the role of systolic blood pressure. This study included 859 participants at 17 (38.0% female) and 758 participants at 27 (33.2% female) years of age. Females had lower renin concentration at both 17 (20.7 mU/L versus 25.7 mU/L; P<0.001) and 27 (12.0 mU/L versus 15.4 mU/L; P<0.001) years of age; hence, the aldosterone-to-renin ratio was significantly higher at both 17 (18.2 versus 13.5; P<0.001) and 27 (21.0 versus 15.6; P<0.001) years of age in females compared with males. At 27 years of age, a significant association was detected between aldosterone and LVMI in males (β=0.009 [95% CI, 0.001-0.017]; P=0.027) and between aldosterone-to-renin ratio and LVMI in females (β=0.098 [95% CI, 0.001-0.196]; P=0.050) independently of systolic blood pressure and other confounders. No association was found between primary aldosteronism biomarkers and measures of arterial stiffness (pulse wave velocity, aortic augmentation index, and aortic distensibility) at either age. Aldosterone concentration and aldosterone-to-renin ratio were positively associated with the LVMI in young males and females, respectively, independently of systolic blood pressure. Long-term follow-up is required to determine whether the relationship persists over time, and clinical trials are needed to assess the cardiovascular benefits of early interventions to block aldosterone.

Defining Echocardiographic Degrees of Right Heart Size and Function in Pulmonary Vascular Disease From the PVDOMICS Study

BACKGROUND: Defining qualitative grades of echocardiographic metrics of right heart chamber size and function is critical for screening, clinical assessment, and measurement of therapeutic response in individuals with pulmonary vascular disease (PVD). In a population enriched for PVD, we sought to establish qualitative grades and prognostic value of right heart chamber size and function. METHODS: We investigated 1053 study participants in PVDOMICS (Redefining Pulmonary Hypertension Through the PVD Phenomics Program) to determine clinical and echocardiographic differences associated with increasing pulmonary vascular resistance severity. Right heart chamber size and function were qualitatively assessed using a percentile-based approach above the median values to create a clinical grading system for right heart adaptation. The relationship between echocardiographic categories and all-cause mortality was examined using survival analyses adjusted for potential confounders. RESULTS: A stepwise increase in adverse right heart remodeling was observed with a concomitant decrease in functional parameters by pulmonary vascular resistance strata ( P &lt;0.001 for all). Mild, moderate, and severe categories of right heart chamber size and dysfunction were defined using a percentile-based approach across the spectrum of PVD. During a median follow-up of 2.07 years (interquartile range, 1.23–3.01 years), 130 participants died (11.4%). Progressive pulmonary vascular resistance increase and 2DE evidence of right heart dysfunction inclusive of fractional area change, and right ventricular global longitudinal strain were independently associated with increased all-cause mortality risk in multivariate analysis adjusted for age, disease duration, and male sex. CONCLUSIONS: In this well-characterized sample of adults with diverse etiologies and varying PVD severity, we define categories of abnormal right heart chamber size and function. Further, we demonstrate a stepwise relationship between these categories of abnormal morphology and function and all-cause mortality. Defining grades of right ventricular dysfunction in individuals with known PVD has important clinical implications for monitoring disease progression and response to therapies.

Detection of Left Atrial Remodeling by Three-Dimensional Echocardiography in Symptomatic Patients Known to Had Non-Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is one of the most prevalent inherited disorders and a common cause of sudden heart death. Left atrial (LA) dilatation frequently occurs in patients with HCM as a result of impaired left ventricular (LV) relaxation or associated involvement of LA myocardium in HCM. We enrolled 170 patients known to had HCM (non-obstructive type) and 30 healthy subjects (control group). All of them underwent two-dimensional (2D) echocardiography to measure LV dimensions, function, LA dimension, LA deformations, pulmonary artery pressure (PAP) and LV global longitudinal strain (LVGLS). LA volumes and mechanics were also measured by three-dimensional (3D) echocardiography. By 2D echocardiography, patient group revealed significantly lower all LA functions vs. control group including reservoir (26 ± 4 vs. 43 ± 3, P < 0.001), conduit (-14 ± 2 vs. -25 ± 2, P < 0.001), and booster pump functions (-12 ± 2 vs. -18 ± 1, P < 0.001). PAP was significantly higher in patient group (42 ± 7 vs. 27 ± 4 in control group). LVGLS was significantly lower in patient group (-15±1.4% vs. -23±2% in control group). Using 3D speckle tracking echocardiography (STE), there were a significantly higher indexed maximum LA volume (Vmax indexed) (43.5 ± 5.6 vs. 28.7 ± 3.7, P < 0.001), but significantly lower left atrial strain at reservoir function (LASr) (24 ± 4 vs. 41 ± 3, P < 0.001), left atrial strain at conduit function (LAScd) (-13 ± 2 vs. -24 ± 2, P < 0.001), and left atrial strain at contractile function (LASct) (-11 ± 2 vs. -18 ± 1, P < 0.001). Three-dimensional transthoracic echocardiography (TTE) is a feasible method for the assessment of LA remodeling, but there is adverse LA remodeling in patients with long-standing non-obstructive HCM including impaired all LA mechanics and with increased septal thickness, there are more diastolic dysfunction and more reduction of LA mechanics.

Low birth weight associations with cardiac structure and function in adults after arterial switch for transposition of the great arteries

Background and aimsThe objective of this study was to assess the associations of birth weight with cardiac structure and function in adults with dextro-transposition of the great arteries (D-TGA) who underwent the arterial switch operation (ASO). Methods and resultsThirty-nine ASO patients (age 24.4 ± 3.3 years) were included during routine clinical follow-up from July 2019 to December 2021. All patients underwent cardiopulmonary exercise testing and cardiac magnetic resonance imaging at rest and during exercise. Early-life characteristics, including birth weight, were extracted from electronic medical health records. Linear regression analysis showed that lower birth weight was associated with smaller left ventricular (LV) and right ventricular (RV) end-diastolic volume index (LV: −14.5 mL/m2 [95 % confidence interval, CI: −26.5 to −2.5] per 1-kg decrease in birth weight, p = 0.04; RV: −11.2 mL/m2 [-20.7 to −1.7] per 1-kg decrease in birth weight, p = 0.03). Lower birth weight was associated with greater LV and RV ejection fraction at rest (LV: +8.5 % [+4.4 to +12.5] per 1-kg decrease in birth weight, p < 0.001); RV: +8.1 % [+2.8 to +13.4] per 1-kg decrease in birth weight, p = 0.005). Furthermore, lower birth weight was associated with an attenuated increase in LV stroke volume index from rest to peak exercise (−5.2 mL/m2 [-9.3 to −1.2] per 1-kg decrease in birth weight, p = 0.02). ConclusionsBirth weight may be a novel risk factor for adverse cardiac remodeling in adult ASO patients. Further research is needed to delineate the mechanisms underlying the associations between birth weight and cardiac remodeling ASO patients as well as the broader adult CHD population.

Interarm systolic blood pressure difference is associated with left ventricular concentricity and concentric remodeling.

Interarm systolic blood pressure difference (IASD) values >15 mmHg (IASD > 15) are associated with increased cardiovascular risk, yet the underlying mechanisms remain unclear. This report evaluated whether IASD >15, assessed by different protocols [sequential or simultaneous; based on one or several blood pressure (BP) readings], was associated with adverse left ventricular (LV) remodeling. This cross-sectional study evaluated 605 individuals who underwent clinical and echocardiography evaluation and three pairs of simultaneous arm BP readings. IASD was estimated by seven distinct protocols (three simultaneous and four sequential BP measurements criteria). The cohort had a mean age of 53.5 ± 15.4 years, with 51% being women, 23% with LV hypertrophy, 14% with LV concentricity, 69% with normal geometry, 8% with concentric remodeling, 17% with eccentric hypertrophy and 6% with concentric hypertrophy. Multivariable logistic regression revealed that IASD >15 defined by simultaneous measures of the last two pairs of BP readings (IASDsim2) and sequential arm BP readings (right-left-right arm sequence; IASDseq3) were related to LV concentricity (odds ratio [95% CI] = 3.24 [1.02-10.28], P = 0.046 and 2.56 [1.09-6.00], P = 0.030, respectively) and LV concentric remodeling (odds ratio [95% CI] = 4.12 [1.08-15.78], P = 0.039 and 4.16 [1.61-10.76], P = 0.003, respectively). Conversely, IASD >15 defined by any criteria showed no association with LV hypertrophy. Individuals with IASD >15 defined by IASDsim2 and IASDseq3 are associated with adverse LV remodeling, namely LV concentricity and LV concentric remodeling. These findings suggest that both criteria might be potentially used to preferentially assess abnormal IASD in the setting of clinical practice.

Multiscale Fiber Remodeling in the Infarcted Left Ventricle using a Stress-Based Reorientation Law

The organization of myofibers and extra cellular matrix within the myocardium plays a significant role in defining cardiac function. When pathological events occur, such as myocardial infarction (MI), this organization can become disrupted, leading to degraded pumping performance. The current study proposes a multiscale finite element (FE) framework to determine realistic fiber distributions in the left ventricle (LV). This is achieved by implementing a stress-based fiber reorientation law, which seeks to align the fibers with local traction vectors, such that contractile force and load bearing capabilities are maximized. By utilizing the total stress (passive and active), both myofibers and collagen fibers are reoriented. Simulations are conducted to predict the baseline fiber configuration in a normal LV as well as the adverse fiber reorientation that occurs due to different size MIs. The baseline model successfully captures the transmural variation of helical fiber angles within the LV wall, as well as the transverse fiber angle variation from base to apex. In the models of MI, the patterns of fiber reorientation in the infarct, border zone, and remote regions closely align with previous experimental findings, with a significant increase in fibers oriented in a left-handed helical configuration and increased dispersion in the infarct region. Furthermore, the severity of fiber reorientation and impairment of pumping performance both showed a correlation with the size of the infarct. The proposed multiscale modeling framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future. Statement of SignificanceThe organization of muscle and collagen fibers within the heart plays a significant role in defining cardiac function. This organization can become disrupted after a heart attack, leading to degraded pumping performance. In the current study, we implemented a stress-based fiber reorientation law into a computer model of the heart, which seeks to realign the fibers such that contractile force and load bearing capabilities are maximized. The primary goal was to evaluate the effects of different sized heart attacks. We observed substantial fiber remodeling in the heart, which matched experimental observations. The proposed computational framework allows for the effective prediction of adverse remodeling and offers the potential for assessing the effectiveness of therapeutic interventions in the future.

Body mass index as a determinant of scar formation post-AF ablation: Insights from DECAAF II.

Obesity is implicated in adverse atrial remodeling and worse outcomes in patients with atrial fibrillation. The objective of this study is to assess the effect of body mass index (BMI) on ablation-induced scar formation on late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR). We conducted an analysis of DECAAF II participants who underwent LGE-CMR scans to measure scar formation 3 months after catheter ablation. Ablation parameters and lesion delivery were not dependent on BMI. The effect of BMI on ablation success was explored. Our analyses included 811 patients. Comorbidities were more prevalent in obese patients. Baseline left atrial volume was higher in obese individuals, 118, 126, 135, 140, and 143 mm3 for normal weight, overweight, obese grade 1, 2, and 3, respectively (p < .001). BMI was associated with scar formation (R = -0.135, p < .001), with patients with Class 3 obesity having the lowest percentage of ablation-induced scar, 11.1%, 10.3%, 9.5%, 8.8%, 6.8% by ascending BMI group. There was an inverse correlation between BMI and the amount of fibrosis covered by ablation scar, 24%, 23%, 21%, and 18% by ascending BMI group (p = .001). For the fibrosis-guided ablation group, BMI was associated with residual fibrosis (R = 0.056, p = .005). Obese patients have lower ablation scar formation, covered fibrosis, and more residual fibrosis postablation compared to nonobese patients, regardless of ablation parameters including impedance drop.

Deletion of ASPP1 in myofibroblasts alleviates myocardial fibrosis by reducing p53 degradation

In the healing process of myocardial infarction, cardiac fibroblasts are activated to produce collagen, leading to adverse remodeling and heart failure. Our previous study showed that ASPP1 promotes cardiomyocyte apoptosis by enhancing the nuclear trafficking of p53. We thus explored the influence of ASPP1 on myocardial fibrosis and the underlying mechanisms. Here, we observed that ASPP1 was increased after 4 weeks of MI. Both global and myofibroblast knockout of ASPP1 in mice mitigated cardiac dysfunction and fibrosis after MI. Strikingly, ASPP1 produced the opposite influence on p53 level and cell fate in cardiac fibroblasts and cardiomyocytes. Knockdown of ASPP1 increased p53 levels and inhibited the activity of cardiac fibroblasts. ASPP1 accumulated in the cytoplasm of fibroblasts while the level of p53 was reduced following TGF-β1 stimulation; however, inhibition of ASPP1 increased the p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 is directly bound to deubiquitinase OTUB1, thereby promoting the ubiquitination and degradation of p53, attenuating myofibroblast activity and cardiac fibrosis, and improving heart function after MI.

Crotonylation of NAE1 Modulates Cardiac Hypertrophy via Gelsolin Neddylation.

Cardiac hypertrophy and its associated remodeling are among the leading causes of heart failure. Lysine crotonylation is a recently discovered posttranslational modification whose role in cardiac hypertrophy remains largely unknown. NAE1 (NEDD8 [neural precursor cell expressed developmentally downregulated protein 8]-activating enzyme E1 regulatory subunit) is mainly involved in the neddylation modification of protein targets. However, the function of crotonylated NAE1 has not been defined. This study aims to elucidate the effects and mechanisms of NAE1 crotonylation on cardiac hypertrophy. Crotonylation levels were detected in both human and mouse subjects with cardiac hypertrophy through immunoprecipitation and Western blot assays. Tandem mass tag (TMT)-labeled quantitative lysine crotonylome analysis was performed to identify the crotonylated proteins in a mouse cardiac hypertrophic model induced by transverse aortic constriction. We generated NAE1 knock-in mice carrying a crotonylation-defective K238R (lysine to arginine mutation at site 238) mutation (NAE1 K238R) and NAE1 knock-in mice expressing a crotonylation-mimicking K238Q (lysine to glutamine mutation at site 238) mutation (NAE1 K238Q) to assess the functional role of crotonylation of NAE1 at K238 in pathological cardiac hypertrophy. Furthermore, we combined coimmunoprecipitation, mass spectrometry, and dot blot analysis that was followed by multiple molecular biological methodologies to identify the target GSN (gelsolin) and corresponding molecular events contributing to the function of NAE1 K238 (lysine residue at site 238) crotonylation. The crotonylation level of NAE1 was increased in mice and patients with cardiac hypertrophy. Quantitative crotonylomics analysis revealed that K238 was the main crotonylation site of NAE1. Loss of K238 crotonylation in NAE1 K238R knock-in mice attenuated cardiac hypertrophy and restored the heart function, while hypercrotonylation mimic in NAE1 K238Q knock-in mice significantly enhanced transverse aortic constriction-induced pathological hypertrophic response, leading to impaired cardiac structure and function. The recombinant adenoviral vector carrying NAE1 K238R mutant attenuated, while the K238Q mutant aggravated Ang II (angiotensin II)-induced hypertrophy. Mechanistically, we identified GSN as a direct target of NAE1. K238 crotonylation of NAE1 promoted GSN neddylation and, thus, enhanced its protein stability and expression. NAE1 crotonylation-dependent increase of GSN promoted actin-severing activity, which resulted in adverse cytoskeletal remodeling and progression of pathological hypertrophy. Our findings provide new insights into the previously unrecognized role of crotonylation on nonhistone proteins during cardiac hypertrophy. We found that K238 crotonylation of NAE1 plays an essential role in mediating cardiac hypertrophy through GSN neddylation, which provides potential novel therapeutic targets for pathological hypertrophy and cardiac remodeling.

Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.

Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood. Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention. Cleavage-insensitive PAR2R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7fl/fl CX3CR1 (CX3C motif chemokine receptor 1)Cre mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)+ cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF+/TREM (triggered receptor expressed on myeloid cells) 1+ macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)+ macrophages and, conversely, to a reduction of TF+/TREM1+ macrophages, which were also reduced in PAR2R38E mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI. Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.

Late mitral leaflet tear after transcatheter edge-to-edge repair for acute ischemic mitral regurgitation: a case report

Abstract Background Acute mitral regurgitation due to papillary muscle rupture is a severe complication of acute myocardial infarction. Transcatheter edge-to-edge repair is emerging as an effective alternative to surgical treatment, with encouraging outcomes. Leaflet adverse events are rare and are associated with relapse of significant mitral regurgitation. Case summary A 54-year-old man arrived at our hospital with a late presentation of ST-elevation myocardial infarction. During primary percutaneous coronary intervention of the circumflex coronary artery, a partial papillary muscle rupture occurred with acute severe mitral regurgitation and cardiogenic shock. Due to the severe hemodynamic instability, the patient underwent an emergent transcatheter edge-to-edge repair with MitraClip device during Impella support with mitral regurgitation resolution and hemodynamic stabilization. At 2-month follow-up an interclip leaflet tear occurred with relapse of severe mitral regurgitation, requiring a mitral valve replacement surgery. Discussion Acute mitral regurgitation due to papillary muscle rupture is a serious complication of acute myocardial infarction. Management is based on hemodynamic stabilization and surgery. The transcatheter edge-to-edge repair is emerging as a therapeutic alternative in high-risk cases. Leaflet adverse events rarely occur during the transcatheter edge-to-edge repair procedure or before patient discharge. Our case is the first to report a late leaflet adverse event, occurring two months after the procedure and, interestingly, after an acute myocardial infarction conditioning an ischemic mitral regurgitation. This event may be the result of the progressive adverse remodeling of left ventricular inferolateral akinetic wall, with consequent increase of tethering forces on the posterior leaflet, tensioned in the opposite direction by the clip.

Bridging the Gap: Advances and Challenges in Heart Regeneration from In Vitro to In Vivo Applications.

Cardiovascular diseases, particularly ischemic heart disease, area leading cause of morbidity and mortality worldwide. Myocardial infarction (MI) results in extensive cardiomyocyte loss, inflammation, extracellular matrix (ECM) degradation, fibrosis, and ultimately, adverse ventricular remodeling associated with impaired heart function. While heart transplantation is the only definitive treatment for end-stage heart failure, donor organ scarcity necessitates the development of alternative therapies. In such cases, methods to promote endogenous tissue regeneration by stimulating growth factor secretion and vascular formation alone are insufficient. Techniques for the creation and transplantation of viable tissues are therefore highly sought after. Approaches to cardiac regeneration range from stem cell injections to epicardial patches and interposition grafts. While numerous preclinical trials have demonstrated the positive effects of tissue transplantation on vasculogenesis and functional recovery, long-term graft survival in large animal models is rare. Adequate vascularization is essential for the survival of transplanted tissues, yet pre-formed microvasculature often fails to achieve sufficient engraftment. Recent studies report success in enhancing cell survival rates in vitro via tissue perfusion. However, the transition of these techniques to in vivo models remains challenging, especially in large animals. This review aims to highlight the evolution of cardiac patch and stem cell therapies for the treatment of cardiovascular disease, identify discrepancies between in vitro and in vivo studies, and discuss critical factors for establishing effective myocardial tissue regeneration in vivo.

Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction

AbstractInflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease-specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF-specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global-longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.

Dual Time-Dependent Effects of Interleukin-33 Administration on the Kidney Postmyocardial Infarction.

Kidney damage is a serious prevalent complication that occurs after a myocardial infarction (MI) and is associated with worse outcomes. Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions as an alarmin that is released upon necrosis or tissue damage to alert immune cells expressing the ST2L receptor. IL-33 is increased in kidney disease, and recent studies have shown that the IL-33/ST2 axis is instrumental in both disease progression and repair. In this study, we investigated the effect of IL-33 administration on kidneys in C57BL6/J male mice 4 and 7 days after the induction of MI. The mice received either IL-33 or vehicle (PBS) treatment. Cardiac systolic function and systemic inflammation were assessed, and kidneys were subjected to histological and molecular analysis. The administration of IL-33 for 4 days post-MI improved renal structure consistent with reduced expression of profibrotic markers, reduced apoptosis, and increased expression of the anti-inflammatory cytokine IL-4. In addition, IL-33 administration enhanced the levels of Sirtuin3, nicotinamide phosphoribosyltransferase, and the renal nicotinamide adenine dinucleotide pool which are critical for mitochondrial function and energy production, indicating metabolic benefits. However, this protection seems to be lost with the continued administration of IL-33 for 7 days post-MI coinciding with aggravated cardiac dysfunction and increased systemic inflammation. These findings demonstrate that while IL-33 treatment can help improve kidney damage post-MI in the short term, extended treatment may not be beneficial. This may be due to the direct effects of IL-33 on the kidneys or indirectly mediated by adverse cardiac remodeling influencing the cardiorenal crosstalk.

Alteration of cardiac structure and function and its prognostic value in patients with Takayasu arteritis: a cardiac magnetic resonance study.

To investigate the prevalence and characteristics of late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) and its prognostic value in patients with Takayasu arteritis (TA). Sixty TA patients with a CMR examination were retrospectively included. All TA patients were divided into with LGE-positive and LGE-negative groups. Bi-ventricular function and location, distribution, and pattern of left ventricular (LV) LGE were evaluated in both LGE-positive and LGE-negative groups. Primary outcome was defined as a composite of cardiovascular death, hospitalization for heart failure, coronary artery revascularization, and stroke. Univariate and multivariate Cox proportional hazard regression analyses were used to evaluate the association between variables and primary outcomes. Sixty consecutive TA patients were enrolled in this study. The mean age was 38.2 ± 13.8 years and 54 patients (54/60, 90.0%) were female. LGE-positive was observed in twenty-one (21/60, 35%) patients in the total patients with TA. LGE was predominantly distributed in the middle wall and subendocardial. The patchy and infarcted LGE patterns were the most common. Compared with the LGE-negative group, the LGE-positive group had reduced LV ejection fraction (P = 0.033), elevated LV end-diastolic volume index (P = 0.008), LV end-systolic volume index (P = 0.012), and LV mass (P = 0.008). During a median follow-up period of 1,892 days (interquartile range: 1,764-1,988 days), the primary outcomes occurred in thirteen patients. In the univariate analysis, LGE-positive (hazard ratio [HR] = 4.478, 95% confidence interval [CI]: 1.376-14.570; P = 0.013) were independently associated with the primary outcomes. However, LGE-positive did not retain its value as an independent predictor of primary outcomes in the multivariate analysis. Instead, LVMI (HR = 1.030, 95%CI: 1.013-1.048; P = 0.001) was the strongest independent predictor of primary outcomes in patients with TA. The Kaplan-Meier plot revealed that patients with LVMI ≥ 57.5 g/m2 have a worse prognosis. LGE-positive detected by CMR was observed in 35% of total TA patients with different distributions and patterns. LGE is associated with adverse LV remodeling and worsen cardiac function. However, LVMI rather than LGE can provide independent prognostic information in patients with TA.

M2 Macrophage Exosomes Reverse Cardiac Functional Decline in Mice with Diet-Induced Myocardial Infarction by Suppressing Type 1 Interferon Signaling in Myeloid Cells.

Effective treatment strategies to alleviate heart failure that develops as a consequence of myocardial infarction (MI) remain an unmet need in cardiovascular medicine. In this study, we uncovered that exosomes produced by human THP-1 macrophages cultured with the cytokine IL-4 (THP1-IL4-exo), reverse cardiac functional decline in mice that develop MI as a consequence of diet-induced occlusive coronary atherosclerosis. Therapeutic benefits of THP1-IL4-exo stem from their ability to reprogram circulating Ly-6Chi monocytes into an M2-like phenotype and suppress Type 1 Interferon signaling in myeloid cells within the bone marrow, the circulation, and cardiac tissue. Collectively, these benefits suppress myelopoiesis, myeloid cell recruitment to cardiac tissue, and preserve populations of resident cardiac macrophages that together mitigate cardiac inflammation, adverse ventricular remodeling, and heart failure. Our findings introduce THP1-IL4-exo, one form of M2-macrophage exosomes, as novel therapeutics to preserve cardiac function subsequent to MI.

When the liver is in poor condition, so is the heart - cardiac remodelling in MASH mouse models.

Metabolic dysfunction-associated steatohepatitis (MASH) confers a risk for cardiovascular diseases in patients. Animal models may help exploring the mechanisms linking liver and heart diseases. Hence, we explored the cardiac phenotype in two MASH mouse models: foz/foz mice fed a high-fat diet (HFD) for 24 or 60 weeks and C57BL/6J mice fed a high-fat-, high-cholesterol-, and high-fructose diet for 60 weeks. Angiotensin II (AngII) was used as an additional cardiovascular stressor for 4 weeks in 10 weeks HFD-fed foz/foz mice. Foz/foz mice with fibrosing MASH developed cardiac hypertrophy with adverse cardiac remodelling not seen in WT similarly fed the HFD. AngII caused hypertension and up-regulated the expression of genes contributing to pathological cardiac hypertrophy (Nppa, Myh7) more severely so in foz/foz mice than in controls. After 60 weeks of HFD, while liver disease had progressed to burn-out non steatotic MASH with hepatocellular carcinoma in 50% of the animals, the cardiomyopathy did not. In an independent model (C57BL/6J mice fed a fat-, cholesterol- and fructose-rich diet), moderate fibrosing MASH is associated with cardiac fibrosis and dysregulation of genes involved in pathological remodelling (Col1a1, Col3a1, Vim, Myh6, Slc2a1). Thus, animals with MASH present consistent adverse structural changes in the heart with no patent alteration of cardiac function even when stressed with exogenous AngII. Liver disease, and likely not overfeeding or aging alone, is associated with this cardiac phenotype. Our findings support foz/foz mice as suitable for studying links between MASH and heart structural changes ahead of heart failure.

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.

Intestinal fatty acid binding protein is associated with infarct size and cardiac function in acute heart failure following myocardial infarction

BackgroundIn acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into...