Markers Of Cardiac Remodeling Research Articles

Non-lipid metabolomic biomarkers are associated with adverse cardiac remodelling and cardiovascular outcomes

Abstract Background Metabolomics is the detailed profiling of circulating metabolites including carbohydrates, lipids, amino and fatty acids, and ketones, all of which are substrates used in energy metabolism by cardiomyocytes. Purpose The role of cholesterol fractions with cardiovascular risk is well-established. This novel study examines the association between non-lipid circulating metabolites and markers of cardiac remodelling as assessed by cardiovascular magnetic resonance (CMR) imaging. Metabolites associated with adverse remodelling were taken forward to examine their impact on incident cardiovascular disease (CVD); ischaemic heart disease (IHD) and heart failure (HF). Methods This study used data from the UK Biobank. After exclusions (prevalent IHD, HF; outliers), there were a maximum of 34,727 individuals for CMR analyses and 262,536 individuals for incident CVD analysis. For CMR analyses, outcome variables were LV end-diastolic volume (EDV), LV mass, LV mass:volume ratio (MVR), LV global longitudinal strain (GLS) and native T1. Separate regression models were built for each of the 40 scaled metabolite biomarkers. Each model incorporated one metabolite at a time with additional covariates: age, sex, ethnicity, systolic blood pressure, cholesterol medication use, type 2 diabetes, dietary intake, smoking status, fasting time, and time between recruitment and CMR examination. A Bonferroni-corrected significance threshold of 2.4x10-4 was used. To account for correlation between metabolites, Lasso regression with 10 fold cross-validation to identify the most important predictors was performed for LV MVR, LV GLS and native T1 whereby all metabolites and above covariates were included in the model. Metabolite predictors of adverse remodelling were included in an adjusted logistic regression model with incident CVD as an outcome. Results Metabolites demonstrating significant (p < 2.4x10-4) associations with CMR parameters are presented in Fig 1. For higher LV MVR and more positive LV GLS, the metabolites with the largest effect were monounsaturated fatty acids and glycoprotein acetyls. Higher omega-6:omega-3 ratio was associated with higher T1 values. The Lasso model identified 8 important predictors for adverse cardiac remodelling. Of these, two were routine biomarkers (creatinine, glucose). Of the remainder, monounsaturated fatty acids, glycoprotein acetyls and apolipoprotein B:apolipoprotein A1 ratio were significantly associated with increased risk of incident CVD (Fig 2). Current evidence regarding monounsaturated fatty acids in CVD is mixed. Glycoprotein acetyls are implicated in vascular inflammation. Apolipoproteins are thought to be a potential therapeutic target for CVD risk reduction. Conclusion This study demonstrates a role of non-lipid metabolites on subclinical CVD as assessed by adverse remodelling with CMR as well as associations with incident CVD. We highlight potential novel biomarkers for identification of CVD.Metabolite association with LV MVR/GLSMetabolite association with incident CVD

#2167 Polyclonal immunoglobulin free light chains: an evidence of cardiac remodeling in patients with glomerular diseases

Abstract Background and Aims It was previously shown, that polyclonal immunoglobulin free light chains (FLC) are the independent predictor of mortality in patients with decompensated heart failure, chronic kidney disease (CKD) and also in general population. Mechanisms of this phenomenon are still unknown. The aim of our study is to reveal the possible relationships between FLC and cardiac remodeling in patients with glomerular diseases. Method We included 97 patients with biopsy-proven diagnosis of different immune-mediated glomerular diseases, 53% were men, mean age was 48 ± 14.6 years. Serum Freelite FLC levels were measured as well as standard clinical and laboratory investigation. At the time of biopsy transthoracic echocardiography was also performed. Glomerular filtration rate (eGFR) was estimated by “2021 CKD-EPI Creatinine” equation. Results Median of eGFR was 46.8 ml/min/1.73 m² (28.7-80.0), FLC-kappa level was 27.4 mg/l (16.8- 48.4), FLC-lambda level was 28.2 mg/l (20.8-43.3). FLC-kappa levels were above reference range in 65%, FLC-lambda levels – in 54%. LV diastolic dysfunction (DD) was present in 68%. Comparison in groups showed that the elevation of FLC-kappa more than 19.4 mg/l was associated with bigger LV mass index (LVMI) – 138.3 ± 30.2 g/m² vs 99.9 ± 31.2 g/m² р = 0.022, the parallel correlation was found between LVMI and levels of FLC-lambda higher than 26.3 mg/l (136.2 ± 64.8 g/m² vs 104.0 ± 36.6 g/m², р = 0.023). Spearman analysis has shown statistically significant correlations between FLC levels and E/e’- Rs = 0.501 p = 0.0001 for FLC-kappa, Rs = 0.343 p = 0.012 for FLC-lambda. Combined FLC level higher than 52.9 mg/l was a significant predictor of DD with area under the ROC curve (AUC) 0.703 (sensitivity 76.5%, specificity 62.5%). Conclusion Elevation of serum pFLC level could be a promising marker of cardiac remodeling, especially, of DD in patients with glomerular diseases. Possible pathogenic role of FLC in cardiorenal relationships may be revealed in further studies.

Unveiling the Therapeutic Potential of SGLT2 inhibitors and Oral Ketone Ester in Heart Failure with Preserved Ejection Fraction: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

BackgroundThis study investigated the potential efficacy of SGLT2 inhibitors empagliflozin and oral ketone supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is often associated with obesity and type 2 diabetes mellitus. Methods20-week-old obese ZSF-1 rats were given different treatments for 12 weeks, including vehicle, empagliflozin, ketone ester (KE), or a combination of empagliflozin and KE. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism, while histological and molecular markers of cardiac remodeling were assessed in the left ventricle. ResultsThe untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, and increased cardiomyocyte size and cardiac expression of atrial natriuretic peptide (ANP) and fibrosis marker col1a1 and TIMP1. The treatment groups exhibited decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly attenuated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, all treatments significantly reduced cardiomyocyte size and the expression of ANP and fibrosis marker. The combination of empagliflozin and KE showed the greatest improvement in diastolic function and cardiac ATP levels. Interestingly, hyperpolarized [1-13C] pyruvate detected a decrease in lactate/pyruvate ratio in the hearts treated with empagliflozin. ConclusionObese ZSF1 rats exhibit features of clinical HFpEF with predominant background of obesity and diabetes. A combination of empagliflozin and KE has greater benefits in treating HFpEF. Targeting cardiometabolic dysregulation may be a promising approach for HFpEF treatment.

Abstract 11896: Contribution of Amino Acid Transporter SLC7A5 to Pathological Ventricular Hypertrophy and Heart Failure

Introduction: Transition from compensatory to pathological ventricular hypertrophy and heart failure (HF) is associated with metabolic remodeling. It has been described that hypoxia signaling induces the expression of the amino acid (AA) transporter SLC7A5 (LAT1) and the activation of its downstream pro-hypertrophic target mTORC1. Hypothesis: Chronic pathologic stimuli induce AA metabolism reprogramming comprising increased AA transport through LAT1, which plays a key role in the development of hypertrophy and its progression to HF. Methods: C57BL/6N mice were subjected to chronic pressure overload by constriction of the aorta (TAC). The selective LAT1 inhibitor JPH203 was chronically administered (ip) after TAC surgery. Dynamics of leucine were determined in heart samples from mice treated with 13C,15N-leucine using LC-MS/MS. Microarray-based gene expression profile, echocardiographic data, and markers of cardiac remodeling were measured at different time points. Results: Microarray results showed a profound AA metabolism remodeling consisting of a general increase in the expression of AA transporters, with LAT1 as the most overexpressed and reduced expression of enzymes involved in BCAA catabolism. Overexpression of LAT1 was confirmed in isolated cardiomyocytes. These changes correlated with a marked increase in labeled leucine uptake with respect to sham mice (310%), a moderate reduction in the formation of its ketoacid (51% α-ketoisocaproate), and potent inhibition of its catabolism (21% isovalerate and 13% 3-hydroxy-3-methyl-glutarate), and enhanced activation of mTOR pathway. Administration of JPH203 reduced leucine transport and mTOR activation, partially reversed the inhibition of BCAA catabolism, and attenuated hypertrophy and cardiac dysfunction induced by TAC. Conclusions: Pressure overload induces AA metabolic reprogramming characterized by enhanced AA transport and inhibited BCAA catabolism. LAT1 overexpression occurs in cardiomyocytes and contributes to adverse cardiac remodeling via mTOR pathway activation. We propose LAT1 inhibition as a novel therapeutic strategy against HF.

Abstract 13962: Exploring the Therapeutic Potential of SGLT2 Inhibitors and Oral Ketone Ester in HFpEF: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

Introduction: This study aimed to assess the potential efficacy of the SGLT2 inhibitor empagliflozin and oral ketone ester supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is commonly associated with obesity and type 2 diabetes mellitus. Methods: Twenty-week-old obese ZSF-1 rats were initially fed a high-fat diet (HFD) to establish and maintain the phenotype. Subsequently, the rats were randomly assigned to different treatment groups. These groups consisted of a control group receiving only the high-fat diet (HFD), as well as groups receiving empagliflozin, ketone ester (DeltaG®, KE), or a combination of both in addition to the HFD. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism. Histological and molecular markers of cardiac remodeling were assessed in the left ventricle. Results: Untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, increased cardiomyocyte size and fibrosis, as well as elevated expression of atrial natriuretic peptide (ANP), col1a1 (fibrosis marker), and TIMP1. The treatment groups displayed decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly mitigated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, they reduced cardiomyocyte size, ANP expression, fibrosis marker expression, and increased cardiac ATP levels. CMR revealed that the combination of empagliflozin and KE resulted in improvement in diastolic function. Hyperpolarized [1-13C] pyruvate imaging revealed a decrease in lactate/pyruvate ratio in empagliflozin-treated hearts, indicating improved oxidative metabolism. Conclusions: The findings of this study suggest that targeting cardiometabolic dysregulation holds promise as an effective approach for the treatment of HFpEF. While both empagliflozin or KE alone demonstrated improvements in cardiac energetics and remodeling, the combination of empagliflozin and KE yielded the most notable benefits in enhancing cardiac diastolic function.

Sotagliflozin attenuates cardiac dysfunction and remodeling in myocardial infarction rats

ObjectiveSotagliflozin is a dual sodium-glucose co-transporter-1 and 2 (SGLT1/2) inhibitor with selectivity towards SGLT2. Previous studies showed that SGLT2 inhibitors can improve cardiac function and reduce myocardial infarction size in animal models of myocardial infarction (MI). However, it remains unknown whether the dual inhibition of SGLT1/2 by sotagliflozin has beneficial effects in this context. In this study, we investigated the potential cardioprotective effects of sotagliflozin in an animal model of MI. MethodsSprague Dawley (SD) rats underwent left anterior descending coronary artery ligation or sham ligation then were randomly assigned to receive either sotagliflozin (10 mg/kg) or vehicle via intraperitoneal injection. Fourteen days post-MI, we assessed cardiac function using echocardiography and evaluated histological and molecular markers of cardiac remodeling and inflammation in the left ventricle. ResultsOur findings indicate that sotagliflozin treatment resulted in improved cardiac function and reduced infarct size compared with the vehicle-treated group. Additionally, sotagliflozin improved cardiac remodeling as shown by the decreased cardiac hypertrophy and cardiac apoptosis in the post-MI heart. Mechanistically, an apparent reduction in the cardiac inflammatory response in sotagliflozin-treated hearts was observed in the post-MI rats. ConclusionOverall, our results suggest that sotagliflozin may have cardioprotective effects against myocardial infarction.

CASK silencing favors systolic function by regulating junction's signaling

Although the organization of the cardiomyocyte (CM) membrane into functional microdomains directly influences the anisotropic propagation of the AP, the mechanisms underlying the rod-like structural organization of CMs during post-natal development are poorly understood. We have previously shown in the adult CM that CASK regulates sodium channel expression at the lateral membrane in interaction with focal adhesion complexes. In addition, preliminary results have shown that the expression level of CASK evolves during postnatal development and is altered during post-infarction myocardial remodeling in rat. To unravel the implication of CASK in postnatal cardiomyocyte differentiation and in the acquisition of structural and electrical function. CASK viral constructs were designed to inhibit the expression of CASK in neonatal cardiomyocytes, both in vitro (Ad-shCASK) and in vivo (AAV-shCASK). Western blots on human heart samples of arrythmogenic cardiomyopathy, dilated cardiomyopathy and atrial fibrilation patients revealed strong decrease of CASK expression. Proteomic analysis showed that CASK invalidation strongly modify immature CM proteome, notably junction signaling. Immunostaining experiments on neonatal CMs confirmed that CASK is required for the correct organization of the cytoskeleton and differentially regulates both mechanical and electrical junction formation of the intercalated disc. Neonatal CMs invalidated for CASK displayed abnormal contractility and cell adhesion fragility. Stiffness measurements using SICM shows increased stiffness at the junction site, validating the modification of the cell-cell contacts’ physical properties. Echocardiography phenotyping of CASK-invalidated rats at the neonatal stage reveals eccentric ventricular remodeling, decreased systolic performance but a preserved contractile reserve. Pressure-volume measurements confirmed that CASK invalidation increased myocardium contractility and compliance. In addition, CASK silencing does not trigger electrical remodeling or spontaneous arrhythmias, despite the reduced Nav1.5/Kir2.1 expression level. This study demonstrates that CASK confers the ability to orchestrate both CM molecular organization and tissue cohesion. As the decrease of CASK expression appears to be a marker of cardiac remodeling, CASK overexpression therapy could be promising regarding hereditary cardiomyopathies.

Evaluation of the main regulators of extracellular matrix metabolism in healthy adolescents in the Far North

Myocardial remodeling is well-known to be both an adaptive option under certain conditions of life (sports, pregnancy, etc.), and the result of cardiovascular pathology. The study of the features of cardiac remodeling includes the involvement of cardiomyocytes in the process by the level of troponins, creatine phosphokinase, and its cardiac isoform as markers of ischemia and necrosis. Also, neurohormonal rearrangement is evaluated using a natriuretic peptide, and endothelial dysfunction is determined using a C–reactive protein. The level of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) reflects the degree of the proteolytic activity and collagen fibers’ degradation. However, there are no clear biochemical markers of “adaptive heart” and pathological changes in different age periods, in the climatic environment, various types and severity of sports loads, especially when evaluating matrix metalloproteinases and their tissue inhibitors. The primary task in determining the criteria for pathological remodeling of the myocardium becomes the definition of normative indicators.The aim of the study was to determine the reference values of the main biochemical markers of cardiac remodeling in healthy adolescents living in the Far North. The levels of troponin I, creatine phosphokinase-MV, aspartate aminotransferase did not exceed the generally accepted standard values. There were correlations between lactate dehydrogenase, aspartate aminotransferase, and mass-growth indicators of adolescents. Markers of extracellular matrix degradation (MMP-9, TIMP-1 and TIMP-4, MMP-9/ TIMP-1) differed from the data available in the published studies, which is probably due to the influence of tissue hypoxia associated with the climatic living conditions and the age in children of the study group.

Cryptotanshinone Attenuated Pathological Cardiac Remodeling In Vivo and In Vitro Experiments.

Cardiac remodeling has been demonstrated to be the early stage and common pathway for various types of cardiomyopathy, but no specific treatment has been suggested to prevent its development and progress. This study was aimed at assessing whether Cryptotanshinone (CTS) treatment could effectively attenuate cardiac remodeling in vivo and in vitro. Aortic banding (AB) surgery was performed to establish a pressure-overload-induced mouse cardiac remodeling model. Echocardiography and pressure-volume proof were used to examine mouse cardiac function. Hematoxylin and eosin (HE) and Picro-Sirius Red (PSR) staining were used to assess cardiac remodeling in vivo. Mouse hearts were collected to analysis signaling pathway and cardiac remodeling markers, respectively. Furthermore, neonatal rat cardiomyocyte (NRCMs) and cardiac fibroblast (CF) were isolated to investigate the roles and mechanisms of CTS treatment in vitro. CTS administration significantly alleviated pressure-overload-induced mouse cardiac dysfunction, inhibited cardiac hypertrophy, and reduced cardiac fibrosis. Mechanically, CTS treatment significantly inhibited the STAT3 and TGF-β/SMAD3 signaling pathways. In vitro experiments, CTS treatment markedly inhibited AngII-induced cardiomyocyte hypertrophy and TGF-β-induced myofibroblast activation via inhibiting STAT3 phosphorylation and its nuclear translocation. Finally, CTS treatment could not protect against pressure overload-induced mouse cardiac remodeling after adenovirus-associated virus (AAV)9-mediated STAT3 overexpression in mouse heart. CTS treatment might attenuate pathological cardiac remodeling via inhibiting STAT3-dependent pathway.

Assessing clinical and biomarker characteristics to optimize the benefits of sacubitril/valsartan in heart failure.

Of the various medical therapies for heart failure (HF), sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor that combines sacubitril, a pro-drug that is further metabolized to the neprilysin inhibitor sacubitrilat, and the angiotensin II type 1 receptor blocker valsartan. Inhibition of neprilysin and blockade of the angiotensin II type 1 receptor with sacubitril/valsartan increases vasoactive peptide levels, increasing vasodilation, natriuresis, and diuresis. Left ventricular ejection fraction (LVEF) is widely used to classify HF, to assist with clinical decision-making, for patient selection in HF clinical trials, and to optimize the benefits of sacubitril/valsartan in HF. However, as HF is a complex syndrome that occurs on a continuum of overlapping and changing phenotypes, patient classification based solely on LVEF becomes problematic. LVEF measurement can be imprecise, have low reproducibility, and often changes over time. LVEF may not accurately reflect inherent disease heterogeneity and complexity, and the addition of alternate criteria to LVEF may improve phenotyping of HF and help guide treatment choices. Sacubitril/valsartan may work, in part, by mechanisms that are not directly related to the LVEF. For example, this drug may exert antifibrotic and neurohumoral modulatory effects through inhibition or activation of several signaling pathways. In this review, we discuss markers of cardiac remodeling, fibrosis, systemic inflammation; activation of neurohormonal pathways, including the natriuretic system and the sympathetic nervous system; the presence of comorbidities; patient characteristics; hemodynamics; and HF signs and symptoms that may all be used to (1) better understand the mechanisms of action of sacubitril/valsartan and (2) help to identify subsets of patients who might benefit from treatment, regardless of LVEF.

Sodium houttuyfonate against cardiac fibrosis attenuates isoproterenol-induced heart failure by binding to MMP2 and p38

BackgroundHeart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model. PurposeTo investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF. MethodsWe analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes. ResultsThere were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-β-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-β (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-β-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38. ConclusionsIn addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.

Predictive value of novel circulating biomarkers in Chagas disease: The Brazilian Chagas disease cohort

Abstract Introduction Chagas disease, caused by the protozoan Trypanosoma cruzi (T. cruzi), is the leading causes of non-ischemic heart failure and premature cardiac deaths in Latin America. Identifying predictive biomarkers of morbidity and progression of Chagas cardiomyopathy (CCC) is important to deciphering novel pathways and aid in early identification of patients at highest risk for future adverse cardiovascular (CV) outcomes. Objectives To determine the association of novel circulating biomarkers with CCC and disease survival. Methods Serum levels of 184 unique cardiometabolic and inflammation proteins were measured using proximity extension immunoassay using age- and sex- matched patients without history of any other cardiovascular or infectious diseases as well as diabetes mellitus, who were identified and selected at the referral outpatient center for Chagas Disease at a clinical hospital in Brazil. Univariable linear regression using standardized protein levels were compared between patients with and without CCC. All p-values were adjusted for multiple testing and in findings with p value<0.0002 were considered statistically significant. Proteins that reached significance level were further compared between disease mortalities and survival. We also performed network analysis using STRING-DB on overexpressed proteins to determine its interaction. Results We used data from 44 with CCC and 44 with asymptomatic T. cruzi-positive patients (indeterminate). Among individuals with CCC, 22 patients had a fatal cardiovascular event during follow-up period of 4.1 (SD ±1.4) years. In linear regression analyses, we identified 45 candidate biomarkers associated with chronic CC (all p values <0.0002). Among these, only three proteins (IL33, CD40, REG1A) were significantly different between individuals with CCC who died vs survived over a period of 4.1 years. We used 38 overexpressed proteins in network analysis. THBS4, marker of cardiac remodeling, was overexpressed in CCC. CXCL11 were seen co-expressed with CXCL9 and CXCL10, all are known activators of CD4+ Th1 cells in CCC. Conclusion We identified 45 novel cardiometabolic and inflammatory markers that are associated with chronic Chagas cardiomyopathy. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Leading House of Latin America of the Swiss State Secretariat for Education, Research and Innovation (SERI)

ECHOCARDIOGRAPHIC EVALUATION OF LEFT VENTRICULAR REMODELING AFTER VALSARTAN/SACUBITRIL INITIATION IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

ECHOCARDIOGRAPHIC EVALUATION OF LEFT VENTRICULAR REMODELING AFTER VALSARTAN/SACUBITRIL INITIATION IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

Reverse Remodeling Assessed by Left Atrial and Ventricular Strain Reflects Treatment Response to Sacubitril/Valsartan

BackgroundThe left ventricular global longitudinal strain (LVGLS) and left atrial reservoir strain (LARS) are considered as sensitive and reliable markers of cardiac remodeling and function. However, their temporal changes during optimal management of heart failure with reduced ejection fraction (HFrEF) are unknown. ObjectivesThis study investigated the time trajectories of the LARS and LVGLS in patients with HFrEF treated with angiotensin receptor–neprilysin inhibitors, and assessed whether the LARS and LVGLS could define left heart reverse remodeling (LHRR) and reflect the treatment response and prognosis. MethodsUsing a retrospective cohort of patients with HFrEF prescribed sacubitril/valsartan, we assessed the time trajectories of the LVGLS and LARS in 409 patients (1,258 echocardiograms), and investigated their association with the occurrence of cardiovascular death and hospitalization for heart failure (HHF), after the determination of LHRR, during a median follow-up of 27.1 (IQR: 18.3-36.3) months. ResultsAmong patients with HFrEF prescribed sacubitril/valsartan, both the LVGLS and LARS improved over time. The improvements in the LVGLS and LARS were prominent within 6 months of sacubitril/valsartan treatment: the LVGLS improved from 10.2% (IQR: 7.9%-12.7%) to 13.9% (IQR: 10.5%-16.3%) (P < 0.001), and the LARS improved from 11.4% (IQR: 8.4%-15.6%) to 15.9% (IQR: 11.5%-21.4%) (P < 0.001). These improvements were larger among patients who did not experience the study outcome than in patients with events. Improvement in the LVGLS to ≥13% and LARS to ≥12.5% (ie, complete LHRR) was significantly associated with a lower risk of cardiovascular death and HHF, and this association was stronger than that of changes in other conventional echocardiographic parameters. ConclusionsIn patients with HFrEF treated with sacubitril/valsartan, the LVGLS and LARS were improved, typically within 6 months of treatment. Complete LHRR, defined by improvement in the LVGLS and LARS, can be an indicator of treatment response and prognosis.

Relationship of Quantitative Retinal Capillary Network and Myocardial Remodeling in Systemic Hypertension.

BackgroundThis study examined the associations between quantitative optical coherence tomography angiography (OCTA) parameters and myocardial abnormalities as documented on cardiovascular magnetic resonance imaging in patients with systemic hypertension.Methods and ResultsWe conducted a cross‐sectional study of 118 adults with hypertension (197 eyes). Patients underwent cardiovascular magnetic resonance imaging and OCTA (PLEX Elite 9000, Carl Zeiss Meditec). Associations between OCTA parameters (superficial and deep retinal capillary density) and adverse cardiac remodeling (left ventricular mass, remodeling index, interstitial fibrosis, global longitudinal strain, and presence of left ventricular hypertrophy) were studied using multivariable linear regression analysis with generalized estimating equations. Of the 118 patients with hypertension enrolled (65% men; median [interquartile range] age, 59 [13] years), 29% had left ventricular hypertrophy. After adjusting for age, sex, systolic blood pressure, diabetes, and signal strength of OCTA scans, patients with lower superficial capillary density had significantly higher left ventricular mass (β=−0.150; 95% CI, −0.290 to −0.010), higher interstitial volume (β=−0.270; 95% CI, −0.535 to −0.0015), and worse global longitudinal strain (β=−0.109; 95% CI, −0.187 to −0.032). Lower superficial capillary density was found in patients with hypertension with replacement fibrosis versus no replacement fibrosis (16.53±0.64 mm‐1 versus 16.96±0.64 mm‐1; P=0.003).ConclusionsWe showed significant correlations between retinal capillary density and adverse cardiac remodeling markers in patients with hypertension, supporting the notion that the OCTA could provide a non‐invasive index of microcirculation alteration for vascular risk stratification in people with hypertension.

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

Introduction: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. Results: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3–12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. Conclusion: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Adipose Lipolysis Regulates Cardiac Glucose Uptake and Function in Mice under Cold Stress.

The heart primarily uses fatty acids as energy substrates. Adipose lipolysis is a major source of fatty acids, particularly under stress conditions. In this study, we showed that mice with selective inactivation of the lipolytic coactivator comparative gene identification-58 (CGI-58) in adipose tissue (FAT-KO mice), relative to their littermate controls, had lower circulating FA levels in the fed and fasted states due to impaired adipose lipolysis. They preferentially utilized carbohydrates as energy fuels and were more insulin sensitive and glucose tolerant. Under cold stress, FAT-KO versus control mice had >10-fold increases in glucose uptake in the hearts but no increases in other tissues examined. Plasma concentrations of atrial natriuretic peptide and cardiac mRNAs for atrial and brain-type natriuretic peptides, two sensitive markers of cardiac remodeling, were also elevated. After one week of cold exposure, FAT-KO mice showed reduced cardiac expression of several mitochondrial oxidative phosphorylation proteins. After one month of cold exposure, hearts of these animals showed depressed functions, reduced SERCA2 protein, and increased proteins for MHC-β, collagen I proteins, Glut1, Glut4 and phospho-AMPK. Thus, CGI-58-dependent adipose lipolysis critically regulates cardiac metabolism and function, especially during cold adaptation. The adipose-heart axis may be targeted for the management of cardiac dysfunction.

Abstract 11209: KER-012, a Novel Modified ActrII Ligand Trap, Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model of Right Ventricle Overload

Pulmonary arterial hypertension (PAH) is a debilitating disorder, characterized by right ventricle (RV) pressure overload, cardiac hypertrophy, and progressive RV dysfunction. PAH is associated with unbalanced TGFß signaling, favoring signaling of SMAD2/3 and opposing SMAD1/5/9. The result is an increase in vascular proliferation and disruption of vascular homeostasis. KER-012 is a modified ActRII ligand trap designed to inhibit ligands that signal through SMAD2/3 to promote restoration of vascular homeostasis. To investigate the cardio-protective effects of RKER-012, a research version of KER-012, we evaluated the effect of treatment in a pulmonary arterial banding (PAB) model. In this study, 8-week-old, male C57BL/6 mice underwent sham or PAB surgery to increase RV pressure and induce cardiac remodeling. The sham cohort received vehicle (VEH) treatment and PAB mice received either vehicle (VEH) or 10 mg/kg RKER-012 twice weekly for 3 weeks. Relative to sham mice, all PAB mice had elevated pulmonary arterial pressures on day 1 (all ps&lt;0.0001) that persisted until day 21 (all ps&lt;0.01), indicating that the PAB procedure was effective. VEH PAB mice also exhibited diminished cardiac function, including increased end systolic pressure volume relationship (ESPVR; +79.3%; p&lt;0.001) and increased myocardial performance index (MPI; +45.6%; p&lt;0.0001) compared to Sham VEH. Additionally, VEH PAB mice had markers of cardiac remodeling, including increased Fulton Indices (+54.8%; p&lt;0.0001), increased RV free wall thickness (RVFWT; +95.8%; p&lt;0.0001) and increased cardiac fibrotic tissue (+529.9%; p&lt;0.0001). In contrast, RKER-012 treatment was cardioprotective and prevented changes in cardiac function and tissue remodeling. In treated mice, there was a trend for decreased ESPVR (-14.2%), decreased MPI (-13.2%, p&lt;0.01), decreased Fulton Index (-13.5%; p&lt;0.01), and decreased RVFWT (-22.9%; p&lt;0.0001) compared to VEH PAB. Treated mice also had reduced cardiac fibrotic tissue (-38.9%, p&lt;0.01). Taken together, these data provide evidence that KER-012 has the potential to reduce cardiac remodeling and improve cardiac performance in pathologies involving constricted pulmonary arterial blood flow and could provide benefit in diseases such as PAH.

Prognostic Significance of Pulmonary Artery to Aorta Ratio and Other CT Markers in Pulmonary Fibrosis With and Without Emphysema.

Pulmonary hypertension (PH) is associated with decreased survival in patients with pulmonary fibrosis and combined pulmonary fibrosis and emphysema. Main pulmonary artery (PA) diameter and PA diameter/ascending aortic diameter (PA/AA) ratio, as measured on CT, have recently emerged as specific markers for PH. Our single-center retrospective study found that PA/AA ratio > 1 is associated with decreased survival in individuals with pulmonary fibrosis, with or without emphysema. Our study also describes markers of cardiac remodeling, and the echocardiographic diagnosis of PH in this patient population.

Increased left and right atrial volume indices are associated with decreased survival times post-cardiac arrest

BackgroundLeft and right atrial volume indices (LAVI and RAVI) are markers of cardiac remodeling. LAVI and RAVI are associated with worse outcomes in other cardiac conditions. This study aimed to determine the associations of these atrial volume indices with survival time post-cardiac arrest. MethodsThis was a single center, retrospective study of patients with a sudden cardiac arrest event during index hospitalization from 2014-2018 based on pre-arrest parameters. The analysis was stratified based on whether a pulseless ventricular tachycardia/ventricular fibrillation (pVT/VF) event or a pulseless electrical activity (PEA)/asystole event occurred. Cox proportional hazards regression and model selection with best subsets approach evaluated the association of atrial volume parameters with survival times in the context of other covariates. ResultsOf 305 patients studied (64 ± 14 years, 37% female), the mean LAVI was 34.0 ± 15.8 mL/m2 (based on 162 reliable measurements), and mean RAVI was 25.0 ± 15.6 mL/m2 (based on 163 measurements). Increased atrial volume indices were most strongly associated with survival in patients who had sustained pVT/VF (LAVI HR 0.47, 95% CI 0.25–0.90, p = 0.020; RAVI HR 0.57, 95% CI 0.30–1.05, p = 0.074). In multivariable best subsets Cox regression with LAVI, RAVI, and 13 other scaled covariates, LAVI < 34 ml/m2 was by far the best single predictor of survival (p < 0.0001), and the next best predictor was the absence of pulmonary hypertension. ConclusionAmong patients with cardiac arrest from ventricular arrhythmias, those with no more than mild left atrial enlargement pre-arrest by LAVI measurement had the best prognosis. Additional studies are indicated to validate the importance of this finding for clinical management decisions. Condensed abstractIn patients with sudden cardiac arrest associated with ventricular arrhythmias, a left atrial volume index (LAVI) < 34 mL/m2 prior to the arrest had the strongest association with survival among fifteen candidate predictors. Pulmonary hypertension was more common in patients with an elevated right atrial volume index (RAVI), and the absence of pulmonary hypertension was the next best pre-arrest parameter predictive of survival. Larger studies are indicated to validate the use of LAVI for clinical management decisions in this condition.