Decrease In Ejection Fraction Research Articles

Deciphering the Dilemma: Anticoagulation for Heart Failure With Preserved Ejection Fraction (HFpEF).

Impairment in ventricular relaxation and preserved left ventricular ejection fraction are the two main features of heart failure with preserved ejection fraction (HFpEF)a difficult clinical condition. Therapeutic choices for HFpEF patients are still scarce despite itsrising frequency and negative effects on morbidity and mortality, necessitating creative methods to enhance results. The increased thromboembolic risk seen in these individuals raises questions about the relevance of anticoagulation in the therapy of HFpEF. Although anticoagulation has been shown to be beneficial in heart failure with decreased ejection fraction (HFrEF) and other high-risk cardiovascular disorders, its efficacy and safety in HFpEF present a challenging therapeutic challenge. Anticoagulants have been the subject of clinical trials in HFpEF, but the results have been conflicting, giving clinicians only a little information with which to make decisions. The decision-making process is made more difficult by worries about potential bleeding hazards, particularly in susceptible elderly HFpEF patients with other comorbidities. The link between heart failure and anticoagulant medication in HFpEF is thoroughly analyzed in this narrative review. In HFpEF, cardiac fibrosisand endothelial dysfunction create a prothrombotic milieu, as is highlighted in this passage. Also covered are recent developments in innovative biomarker research and cutting-edge imaging techniques, which may provide ways to spot HFpEF patients who might benefit from anticoagulation. This therapeutic conundrum may be resolved by using precision medicine strategies based on risk classification and individualized therapy choices. This review emphasizes the need for more research to establish the best use of anticoagulation in HFpEF within the framework of personalized therapy and shared decision-making. To successfully manage thromboembolic risk and reduce bleeding consequences in HFpEF patients, it is essential to perform well-designed clinical studies and advance our understanding of the pathophysiology of HFpEF. These developments may ultimately improve the prognosis and quality of life for people who suffer from this difficult and mysterious ailment.

E45 Kawasaki syndrome-related heart disease before and during the COVID-19 pandemic

Abstract Introduction Kawasaki disease (kDa) is an acute febrile systemic panvascularitis that affects medium-caliber arteries with a strong predilection for the coronary arteries. It is the leading cause of acquired heart disease in children under 5 years of age. However, after the COVID-19 pandemic, we see a change in the profile of cardiac involvement. Objective To describe the clinical, paraclinical, and evolutionary characteristics of cardiac damage in children managed for Kawasaki or Kawasaki-Like syndrome before and during the Covid19 pandemic. Materials and Methods This is a retrospective, descriptive study conducted over a period of five years (1st January 2017 to 31st December 2021). Result We collected 30 cases of patients hospitalized with Kawasaki disease, between January 2017 and December 2021: 11 cases with Kawasaki syndrome before COVID-19; and 19 cases with Kawasaki syndrome after COVID-19. The mean age and standard deviation (SD) at diagnosis was 42 (±37.8) months before the pandemic vs 81 (±34.7) months after the pandemic. The sex ratio was 0.5 (4 girls and 7 boys) before the pandemic vs 0.7 (8 girls and 11 boys) after the pandemic. Heart damage was found in 2 cases before the pandemic (coronary aneurysm type) vs 3 cases after the pandemic, mainly cardiogenic shock. The mean time from the first transthoracic ultrasound to fever was 11.3 days before the pandemic, vs 5.8 days after the pandemic. Transthoracic ultrasound showed 2 cases of coronary aneurysm before the pandemic, with a Z score exceeding 2.5SD; vs 7 cases of heart failure after the pandemic with a decrease in left ventricular ejection fraction. The ASAI score (a score that assesses the risk of coronary artery disease) was >6 in 1 case before the pandemic vs in 0 cases after the pandemic. The average predictive score for cardiac involvement was 4.2 (±1.4) before the pandemic, vs 3.5 (±1.5) after the pandemic. The outcome was favorable in all cases despite a more severe picture after the COVID-19 pandemic. Conclusion The change in the pattern of cardiac involvement in Kawasaki disease following the emergence of COVID-19 must be taken into account in order to manage an influx of patients with severe Kawasaki disease.

Incidence and Predictors of Relapse After Weaning Immune Suppressive Therapy in Cardiac Sarcoidosis

Cardiac sarcoidosis (CS) is a relapsing-remitting disease, and immune suppression (IS) is the mainstay of therapy. Predictors of relapse for patients with CS in remission are not well characterized. We assessed incidence of relapse in consecutive patients with CS treated with high-dose steroids and/or steroid-sparing agents (SSA) in our center from 2000 to 2020. Remission was defined as reaching maintenance therapy (no IS, SSA, and/or prednisone ≤5mg/d) for ≥1month. Relapse was defined as recurrence of CS syndrome requiring IS intensification: heart failure, ventricular arrhythmia, decrease in left ventricular ejection fraction, or increased disease burden on imaging. Among 68 patients, the mean age was 50.7±9.0years; 25 (37%) were women, and 32 (47%) were Black. In total, 59 patients (87%) reached remission. Over a median follow-up of 39.5months (interquartile range 17.6, 92.5), 28 (48%) relapsed. Greater percentage of late gadolinium enhancement (LGE) on pretreatment magnetic resonance imaging corresponded with increased likelihood of relapse (odds ratio 1.396 per 5% increase [95% confidence interval (CI) 1.04 to 1.88]; p=0.028). LGE ≥11% predicted elevated risk of relapse (adjusted odds ratio 4.998 [1.34 to 18.64]; p=0.017). Shorter time to relapse was observed with isolated CS (adjusted hazard ratio 4.084 [1.44,11.56]; p=0.008) and LGE ≥11% (adjusted hazard ratio 3.007 [1.01, 8.98]; p=0.049). Approximately 1 in 2 patients with CS in remission experienced relapse. Greater burden of LGE on cardiac magnetic resonance imaging and isolated CS are associated with greater risk of relapse. Future work is needed to refine risk stratification for relapse and to optimize surveillance strategies on the basis of the burden of disease.

Investigation of QT Dispersion and T-Peak to T-End/Corrected QT Ratio in Multisystem Inflammatory Syndrome in Children.

Introduction Multisystem inflammatory syndrome in children (MIS-C) is characterized by hyperinflammation, heart involvement, and multiorgan failure, which develop following coronavirus disease 2019. Ventricular arrhythmias have been identified during this syndrome. It is known that the risk of ventricular arrhythmia is associated with ventricular repolarization changes. The aim of this study was to investigate the corrected QT interval, QT dispersion, T wave peak-to-end interval, and T-peak to T-end/corrected QT ratio in MIS-C. Methods The study included 35 patients diagnosed with MIS-C and 35 subjects as the control group. The ventricular diameters, ejection fraction, valve insufficiency, and coronary artery were examined in both groups using echocardiography. Corrected QT interval, QT dispersion, T wave peak-to-end interval, and T-peak to T-end/corrected QT ratio were determined by 12-lead electrocardiogram. Results The patient group had increased corrected QT interval (p<0.05), QT dispersion (p = 0.001), T-peak to T-end interval (p=0.001), and T-peak to T-end/corrected QT ratio (p = 0.001) compared to the control group. Moreover, there was a correlation between increased QT dispersion, T-peak to T-end, T-peak to T-end/corrected QT ratio, and decreased ejection fraction (r = -0.51 and p = 0.001, r = -0.71 and p < 0.001, r = -0.69 and p < 0.001, r = -0.56 and p < 0.001, respectively). Conclusions Our study demonstrated increased QTc interval, QT dispersion, T-peak to T-end interval, T-peak to T-end/corrected QT ratio in MIS-C. This result may indicate an increased risk of ventricular arrhythmia for these patients.

Abstract P2059: Perm1 Regulates O-glcnacylation Of Pgc-1alpha In The Heart

O-GlcNAcylation (O-GlcNAc) is a post-translational modification of proteins where N-acetylglucosamines are added to serine and threonine residues in proteins. This modification is regulated by two enzymes: O-GlcNAc transferase (OGT) that adds O-GlcNAc to proteins; O-GlcNAcase (OGA) that removes O-GlcNAc from proteins. A recent study demonstrated that overexpression of OGT in the heart leads to excessive O-GlcNAcylation, resulting in mitochondrial dysfunction and the development of heart failure. However, what regulates OGT expression in the heart remains elusive. Perm1 is a striated-muscle-specific regulator of mitochondrial bioenergetics. Here, we found that Perm1 suppresses O-GlcNAcylation via gene repression of OGT. Adenovirus-mediated overexpression of Perm1 suppressed O-GlcNAcylation of proteins in H9c2 cells (47% of control, p&lt;0.05), concurrent with downregulation of OGT (52% from control, p&lt;0.05). Luciferase gene reporter assay revealed that Perm1 reduces the promoter activity of OGT, indicating that Perm1 acts as a gene repressor of OGT. Furthermore, phenylephrine-induced O-GlcNAcylation in cardiomyocytes was reversed by Perm1 overexpression through repressing OGT expression. Conversely, loss of Perm1 (Perm1-KO) in mice led to upregulation of OGT and the increase of O-GlcNAcylated proteins in the heart (176% and 144% from WT, respectively, both p&lt;0.05, n=6 in WT, n=7 in KO). Concomitantly, Perm1-KO mice exhibited reduced contractility and mitochondrial function, manifested by a significant decrease in ejection fraction and succinate dehydrogenase activity, respectively (87% and 53% of WT, both p&lt;0.05). Lastly, subcellular fractionation and co-immunoprecipitation assay of mouse hearts revealed that loss of Perm1 specifically increases O-GlcNAcylation of nuclear proteins, concurrent with excessive O-GlcNAcylation of PGC-1α, a master regulator of mitochondrial bioenergetics (2-fold increase in O-GlcNAcylated PGC-1α/total PGC-1α, p&lt;0.05, n=3/group). Our results suggest that Perm1 is a novel regulator of O-GlcNAcylation in the heart that transcriptionally represses OGT expression, which presumably prevents excessive O-GlcNAcylation of PGC-1α and mitochondrial dysfunction under pathological stress.

Abstract P2171: Lentivirus TAZ Gene Therapy Restores Metabolic Functions In Taz Ko Mice Model Of Barth Syndrome

Introduction: Barth Syndrome is an X-linked disorder caused by mutation in thegene encoding tafazzin (or TAZ ), characterized by dilated cardiomyopathy, muscularhypotonia and cyclic neutropenia. TAZ is a mitochondrial acyltransferase that generatesmature cardiolipin (CL) from monolysocardiolipin (MLCL) and is essential formitochondrial morphology and function. Patients with BTHS exhibit a characteristicreduction in the levels of CL and an accumulation of MLCL. Currently, there is no targetedtreatment exists for these patients. We characterized a global TAZ knockout mousemodel of BTHS and tested the efficacy of Lentivirus-mediated TAZ gene therapy. Methods: We generated third generation lentiviral constructs without an insert, withGreen Fluorescent Protein, with recombinant tafazzin and with recombinant tafazzinmodified to contain a cellular penetrating peptide (hTAZ-CPP) that promotes uptake intotafazzin-deficient cells. We tested the efficacy of these recombinant lentiviruses, first inmouse embryo fibroblasts (MEF) isolated from tafazzin knockout mice and then intafazzin knockout mice after systemic administration. Results: We have found that treatment with hTAZ-CPPs reduces the MLCL/CL ratio tonear wild type levels, thereby rescuing the defect in cardiolipin remodeling in TAZ KOMEFs. Serial echocardiograms revealed significant increase in septal wall thickness andsignificant decrease in ejection fraction, fractional shortening and global longitudinal strainin TAZ KO mice. The TAZ KO mice were treated systemic lentivirus at 5 weeks of ageand then echocardiograms were performed at every 4 weeks until 16 weeks. After thetreatment septal wall thickness continued to increase and ejection fraction, fractionalshortening and global longitudinal strain continued to decrease in the empty virus or GFPtreated mice, whereas they are remained stable in those treated with hTAZ-CPPs. Conclusion: These findings suggest that Lentivirus-mediated TAZ gene replacementtherapy enhanced with cell penetrating peptides has potential as a future treatment forBTHS.

Abstract P3064: Cytotoxic T-cells Drive Doxorubicin Induced Cardiac Fibrosis And Systolic Dysfunction

Background: Doxorubicin (DR), the most commonly prescribed chemotherapy, results in dose-dependent cardiotoxicity and heart failure (HF), and patients respond less frequently to standard HF treatments. DR causes oxidative stress and myocyte death, both potent inducers of a T-cell immune response and cardiac inflammation in other causes of HF. However, mechanistic depth on the immune response elicited by DR is limited. We hypothesized that an aberrant T-cell immune response secondary to cardiac damage by DR contributes to DR-induced HF and cardiac remodeling. Methods and Results: We treated wild type (WT) and T-cell deficient ( Tcra -/- ) mice with 5.0 mg/kg DR or PBS weekly by intraperitoneal injection for 4 or 8 weeks. We found at both time points Tcra -/- mice had preserved ejection fraction (EF) by echocardiography and decreased cardiac fibrosis by picrosirius red staining, compared to WT. At 8 weeks, Tcra -/- mice had fewer TUNEL + cardiac cells than WT mice. DR treated mice had increased frequency of activated effector CD8 + CD62L lo CD44 hi cells in the cardiac draining lymph nodes, increased circulating CD8 + T-cells, and cardiac CD8 + T-cell infiltration at both time points. Histologic analysis demonstrated localization of CD8 + T-cells adjacent to cardiac fibroblasts (CFB) in the hearts of DR treated mice. Targeted antibody depletion of CD8 + but not CD4 + cells prior to 4 week DR treatment resulted in improved EF and decreased cardiac fibrosis. Moreover, cardiac CD8 + T-cells expressed higher IFNγ in vivo in DR compared to PBS treated mice, and DR hearts had increased gene expression of the IFNγ inducible chemokines Cxcl9 and Cxcl10 . Ex vivo DR (0.1 μg/mL) treatment of CD8 + T-cells during TCR activation with αCD3/CD28 increased IFNγ expression at the protein and transcript level. The same dose of DR also increased surface expression of ICAM-1 on CFB, and CD8 + T-cells adhered to DR treated CFB in vitro in greater numbers than untreated CFB, and induced more αSMA expression. Lastly, in patients treated with DR, plasma levels of CXCL9 and CXCL10 correlated with decreases in EF after 3 months of treatment. Conclusion: These data outline a novel CD8 T-cell-driven inflammatory mechanism in DR cardiotoxicity, driven by IFNγ-inducible chemokines in animal models and patients.

Abstract P3108: Mouse In Utero Plus Neonatal Sertraline Exposure May Result In A Sex-dependent Risk Of Myocardial Infarction In Adulthood

Background: We previously reported that sertraline reduced left ventricular size, acutely slowed down mouse pup growth, and significantly reduced calcium oscillations in cardiomyocytes (p&lt;0.05), and that the sertraline-induced up-regulations of certain miRNAs might epigenetically modulate cardiac functional gene expression of serotonin signaling pathway with down-regulation of Htr2a, Htr2b and Slc6a4 mRNAs and corresponding proteins (p&lt;0.05). Here we hypothesize that sertraline effect is gender related when subjected to a stress at adult. Method: C57BL/6 adult female mice received sertraline (5 mg/kg/d IP) or saline 5 days before mating, throughout pregnancy until time of delivery, and the pups were given 1/3 adult dose before weaning. At age of 10 weeks, offspring mice were subjected to echocardiograms before myocardial infarction (MI) induced by left anterior descending coronary artery ligation. Mice were divided into groups according to sex, and treatments (saline vs sertraline, &amp; MI vs sham). Ten weeks post-MI, echocardiograms were performed again for the survived mice. Results: Female mice before MI had significantly reduced heart rates (649±18 vs 691±7 bmp), increased end systolic volumes (4.5±0.6 vs 3.2±0.1 μL), and decreased ejection fractions (EF) (80.6±0.7% vs 83.9±0.6%) (n=34, p&lt;0.05). Male mice did not show the significant effects on baseline. Two weeks post-MI, Females had survival rates reduced by sertraline (74.3% vs saline 100%, p=0.0833). Males exhibited MI intolerance with lower survival rates (66.8% vs saline 67.2%), and ODD ratio was deteriorated (24.35 vs female 1.00, p=0.0317). At the end point, the survived mice showed variable MI-induced ischemia zones (47.5±13.2%) corresponding to variable EF (30.0±14.9%). The cardiac functions became not significant different in both male and female survived mice. Concluding Remarks: The cardiac potential risk was observed in the baseline and in the earlier MI phase of female mice with in utero plus neonatal sertraline exposure, while male mice showed different pattern of sertraline effect. Such sex-dependent cardiac effects of maternal SSRI exposure in adult offspring deserve to be detailly studied by using mouse models for heavy use of SSRIs in pregnant women.

Abstract P2135: A Novel Pkp2 Mouse Model Of Genetic Arrhythmogenic Right Ventricular Cardiomyopathy And Its Rescue By Gene Therapy

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder in which cardiomyocytes lack structural integrity and signaling is compromised resulting in the disruption of normal rhythms and formation of fibrosis. Patients suffer from arrhythmia and are at increased risk of sudden cardiac death and heart failure. Previous work has demonstrated that heterozygous mutations in the desmosomal gene, plakophilin-2 ( PKP2 ), are the most common cause of ARVC. Our objective was to investigate the mechanisms of ARVC development and test a potential ARVC gene therapy strategy using a novel mouse model of Pkp2. Methods: A knock-in (KI) mouse model with a point mutation corresponding to human PKP2 ( PKP2 c.2146-1G&gt;C or Pkp2 KI) was generated via CRISPR/Cas9 technology. High fat diet (HFD) was used to induce the ARVC phenotype in the Pkp2 KI heterozygous (het) mice. The Pkp2 KI het mice were crossed with a cardiac-specific Pkp2 cKO (αMHC-Cre ERT ) mouse to generate a tamoxifen inducible model (KIxKO). Cardiac function was assessed by echocardiography and arrhythmia burden by EKG. The KIxKO animals received AAV:PKP2 via retro-orbital injection. Results: Pkp2 KI het animals with normal chow had slow and mild ARVC development, and 50% decrease in PKP2 protein expression, with right ventricle (RV) dilation not occurring until animals were 9 months old. Induction with HFD from 8 weeks hastened and worsened the RV dilation. In contrast, the KIxKO mice exhibited &gt;90% decrease in PKP2 protein expression and a correspondingly severe ARVC phenotype starting from 3 weeks after Tamoxifen induction. This included a high arrhythmia burden and both RV area dilation and decreased ejection fraction, indicating the mice eventually progressed to biventricular heart failure. This resulted in 100% mortality in KIxKO animals by 9 weeks post-tamoxifen induction. A single dose of AAV:PKP2 gene therapy (6E13 vg/kg) maintained ejection fraction, prevented ARVC development and improved survival in the KIxKO mice after 9 weeks of treatment. Conclusion: The current results demonstrated that AAV:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations resulting in haploinsufficiency.

Abstract P3207: Mitoregulin Microprotein Influences Mitochondrial Membrane Integrity And Myocardial Ischemia-Reperfusion Injury

Microproteins have emerged as a class of proteins often found to be encoded by misannotated long noncoding RNAs (lncRNAs). We and others discovered that a ubiquitously-expressed “lncRNA” ( LINC00116 ) encodes for a highly-conserved mitochondrial transmembrane microprotein that regulates beta-oxidation; we named this protein Mitoregulin (Mtln). In cells and mice, we found that Mtln increases mitochondrial respiratory efficiencies and Ca 2+ retention capacities, while reducing ROS. To date, the molecular function of Mtln remains unclear, with instances of conflicting data across papers. Recently, we found that mitochondria from Mtln-knockout (KO) mice are susceptible to membrane freeze-damage, leading to matrix protein leak during mitochondrial isolation. This appears not to be a distal downstream consequence of chronic Mtln loss, as we have confirmed these findings in cells after acute Mtln knockdown and in a mouse model of inducible cardiac-specific KO of Mtln (AAV-based CRISPR in aMHC-Cas9 mice; ~90% reduction in Mtln). Furthermore, acute re-expression of Mtln using AAV in Mtln-KO mice rescues the membrane deficit. Transmission electron microscopy revealed that acute Mtln knockdown in cells disrupts mitochondrial cristae integrity / density. Given that we previously found that Mtln strongly binds cardiolipin, we assessed the effects of synthetic Mtln peptide on membrane dynamics in mitochondrial-simulated lipid monolayers and found that Mtln modulates lipid packing and mixing and increases monolayer elasticity. Whether these potential direct effects mediate Mltn’s broad positive impact on mitochondria remain unknown. To further explore a role for Mtln in cardiac disease, we subjected Mtln-KO and AAV-Mtln overexpression mice to myocardial ischemia-reperfusion (IR), given Mtln’s influence on mitochondrial Ca 2+ buffering and ROS. Mtln-KO mice showed significantly worse outcomes (increased infarct size, cardiac dilation, and decreased ejection fraction) at 72 h post-IR, whereas AAV-Mtln mice were protected (decreased infarct size and increased ejection fraction), each compared to control littermates. Overall, this work points to new molecular functions for Mtln and highlights its protective (therapeutic) role in IR injury.

Abstract P2048: New Insights Into The Role Of The Glycocalyx Components In Heart Failure Induced By Pressure Overload.

Heart failure (HF) is a complex disease with multifactorial etiology. The degradation of the glycocalyx is a process thought to contribute to the progression of HF. The relative individual contribution of glycocalyx components to HF progression is unclear. Previous studies have shown that the expression of glypican 1 (Gpc1), a glycocalyx component, is reduced after aortic banding. Herein, we sought to determine if Gpc1 participates in the progression of HF induced by pressure overload and the associated mechanisms. Methods: Male, 5-8 weeks old, WT and Gpc1 knockout mice (Gpc1KO) were submitted to transaortic constriction (TAC) or sham procedure. Heart function was assessed by echocardiography; heart remodeling was assessed by histological analysis; heparan sulfate and glypican 1 content was assessed by immunofluorescence; the expression of ANP and myosin was assessed by immunoblotting. Results: Gpc1KO showed preserved heparan sulfate content in heart sections. Gpc1KO showed cardiac hypertrophy as evidenced by increased left ventricle mass (173.75mg vs. 123.96 mg in WT; p=0.004; n=10), left ventricle wall thickness (1.43mm vs . 1.13mm in WT; p=0.033; n=10), intraventricular septal end-diastolic thickness (1.83mm vs. 1.62mm in WT; p=0.001; n=11) and decreased cardiomyocyte cross-sectional area (203.86μm2 vs. 248.44μm2; p&lt;0.0001; n=5). This was associated with increased stroke volume (52.89±2.1μL vs 46.42±2.0 μL; p=0.038, n=10), cardiac output (26.39 mL/min vs. 20.32 mL/min in WT), calcium deposits, ANP (0.86±0.02 vs. 0.57± 0.03; p&lt;0.0001; n=5) and myosin (0.71±0.1 vs. 0.50±0.01 in WT; p=0.03; n=5) content in the heart. Gpc1KO were prone to TAC-induced HF as shown by decreased ejection fraction (34.37% vs . 58.41% in WT; p=0.047; n=3) and stroke volume (35.24μL vs. 44.60 μL in WT; p=0.05, n=3) 3 weeks after TAC. Moreover, Gpc1KO showed increased mortality rate, not surviving 5 weeks post-TAC. Conclusions: Gpc1KO shows basal cardiac remodeling associated with changes in calcium dynamics and increased contractility. The increased susceptibility of Gpc1KO to TAC-induced HF seems to be independent of glycocalyx degradation. Further studies are required to understand the mechanisms whereby Gpc1 regulates the progression of TAC-induced HF.

Abstract P1137: Novel Transcriptomic Interactions In Human Cardiomyopathic Heart Failure

Noncoding regions span ~98% of the human genome and are emerging as key players in cardiovascular pathologies. However, the role of human noncoding RNAs and their interactions with other RNAs and protein-coding genes in ischemic (ICM) and nonischemic cardiomyopathic (NICM) heart failure is not clear. Twenty-eight patients (53±11 years; mix of gender and race) were studied using Tukey’s analysis of variance and post-hoc analyses. Significantly increased left ventricular (LV) internal diameter (diastole and systole; p&lt;0.01) and decreased ejection fraction (EF:p&lt;1E-10) were observed in both ICM (EF:17.5%±3.5) and NICM (EF:20.6%±3.2) compared to organ donor controls (EF:56.6%±6). End-systolic volume was increased in ICM, and QTc and QRS duration were prolonged in NICM (p&lt;0.05). Following blinded quality control validation of both LV RNA and data, blinded whole transcriptomics (n=4/group) revealed differential expression of numerous long noncoding (lnc)RNAs, micro(mi)RNAs, and mRNAs (p-corrected/adjusted; padj&lt;0.05). We uncovered 251 novel lncRNAs, 137 novel mature miRNAs, and 286 novel mRNAs (padj&lt;0.05). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and Disease Ontology enrichment analyses revealed several significant (padj&lt;0.05) pathways in cancer, neuro/macular degeneration, neuroembryological development, endocrine, inflammation, bone remodeling, vein disease, etc. Seven lncRNA-associated protein-protein interaction networks were identified in ICM (&gt;700 confidence score). Co-expression analysis revealed highly significant lncRNA-mRNA interactions with Pearson Correlation Coefficient of &lt;0.95 and &gt;0.95 with p&lt;0.00001. GO/KEGG also revealed miRNA-mRNA interactions related to bacterial/viral, parathyroid, cancer, mTOR, etc. (padj&lt;0.05). Importantly, several genes and interactions in all the above RNA species and multiple enrichment pathways distinguished ICM versus NICM (padj&lt;0.05). We also observed several lncRNA alternative splicing events (padj&lt;0.0004; false discovery rate&lt;0.05), numerous missense and silent mutations, and minimal nonsense mutations. Together, this study offers novel transcriptomic and interactomic understanding in human ICM and NICM heart failure.

Abstract P2046: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation. While mutations in sarcomere genes can account for a substantial proportion of familial cases, 40-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of homozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased maximal elastance, reduced diastolic function and are more susceptible to ventricular tachycardia with programmed stimulation. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Studies on isolated adult cardiomyocytes reveal altered fractional shortening, calcium dyshomeostasis, prolonged action potential duration, and T-wave alternans. Crossing of CRYAB R123W mice with a mybpc3 knock-in model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in this model are independent of the sarcomere. Thus, our data establish the Cryab R123W allele as a novel genetic model of HCM that potentially unveils additional sarcomere-independent mechanisms of cardiac pathological hypertrophy and sudden cardiac death.

Prognostic value of changes in coronary blood flow in patients with preserved ejection fraction

BACKGROUND: The measurement of the left ventricular ejection fraction during at echocardiographic study evaluates global contractility. A decrease in this parameter indicates a poor prognosis. However, in the range of normal values, the left ventricular ejection fraction loses prognostic significance. This category of patients requires the development of other prognostic methods.&#x0D; AIM: To explore the effect of changes in coronary blood flow parameters measured using dopplerography in patients with preserved left ventricular ejection fraction in predicting adverse outcomes over the next year.&#x0D; MATERIALS AND METHODS: The prospective study included patients referred for echocardiography in 20192020 followed up at the Saint Petersburg Research Center of Cardiology Medika. The inclusion criterion was age over 18 years. A decrease in left ventricular ejection fraction of less than 53% was an exclusion critrion. In addition to standard echocardiography, dopplerography has been used to study the velocity parameters of blood flow in the coronary arteries. The observation period was 1 year.&#x0D; RESULTS: The control group included 453 patients. During the year of observation, 89 cases of spontaneous adverse events (death / myocardial infarction / progressive heart failure) occurred, including 19 deaths. The patients who died were older (76.6 8.6 vs. 59.3 15.5 years; р 0.000001), with lower global longitudinal function (13.8 4.3% vs. 18.3 3.6%, р 0.000001), with a large volume index of the left atrium (54.6 15.5 vs. 36.5 13.1 ml/m2; р 0.000000), high pressure in the pulmonary artery (39 14.7 vs. 29.5 8.1 mmHg; р 0.000000), high left ventricular myocardial mass index (108.7 37.2 vs. 88,1 24.1 g/m2, р 0.000000) and impaired diastolic function [the ratio of blood flow velocity through the mitral valve in the first (early) phase of left ventricular filling and the average velocity of the mitral valve fibrous ring 13.6 7.1 vs. 9.4 4.4; р 0.000000]. The blood flow velocity in the anterior interventricular artery was significantly higher (78.0 39.0 vs. 50.0 25.4 cm/s, р 0.000007). Only age and flow velocity in anterior interventricular artery were independent predictors of death / myocardial infarction (р 0.004).&#x0D; CONCLUSIONS: Velocity parameters in the anterior interventricular artery are a significant predictor of short-term spontaneous events, including death, in patients with preserved ejection fraction.

Is balance a marker of health status in patients with reduced left ventricular ejection fraction

Abstract Funding Acknowledgements Type of funding sources: None. A significant percentage of patients hospitalized for the coronary disease have a decrease in left ventricular ejection fraction (LVEF), limiting their ability to perform their daily activities and increasing their dependence. Mobility is one of the most affected factors, namely postural balance, walking, transfers, hygiene care, among others. This fact can hinder the resolution of the underlying pathology, delay its resolution, facilitate the appearance of comorbidities, and cause prolonged hospitalization, causing a greater state of fragility. The implementation of measures that improve this dependence and fragility will hypothetically have effects on quality of life and prognosis. Exercise inertia is a well-defined cardiovascular (CV) risk factor, that causes greater physical dependence, greater frailty, and less responsiveness to disease. The authors consider that any improvement in this aspect will lead to a better CV prognosis. Purpose To assess the physical fitness of patients undergoing a phase I rehabilitation program to improve their cardiac condition Methods Longitudinal, prospective, and experimental study hospitalized for coronary disease. Physical fitness was evaluated: 1) dynamic balance and mobility (Fullerton test battery that already includes the 6-minute walk test and body composition), 2) upper body strength (handgrip strength test), 3) cardiorespiratory fitness, and 4) body composition. Morisky Medication Adherence Scale and STOP-Bang scale (Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender) were also applied. The descriptive and inferential analysis was performed using the R version 4.2.2 program, all test results with p&amp;lt;0.05 are considered statistically significant. Results 65 patients were evaluated, with a median age of 63 and interquartile range (57, 72), of which 23% had LVEF≤40%; 86% had high blood pressure, 80% have dyslipidemia, 73% drank alcohol daily and only 23% practice regular physical exercise. When applying the Fullerton balance test, we found that: 74% cannot safely turn 360º, needing four or more steps in both directions; 92% cannot walk independently and without interruptions on a straight line on the ground; 74% cannot balance on one leg autonomously and maintain the position for 20 seconds. We also found that 68% had a high risk of sleep apnea (STOP-Bang scale). LVEF data were divided into classes (LVEF ≤40; LVEF 41-50; LVEF &amp;gt;50) and the association was evaluated using Fisher's exact test and Kruskal-Wallis test, and it was verified that there is a positive association between balance and LVEF (p-value = 0.2) and 6mTM and LVEF (p-value = 0.07). Conclusion The positive associations found between balance and mobility limitations in this sample suggest that specific programs may improve balance and, consequently, the patient's general state of health.

Increased NT-proBNP levels and cardiac ventricular function during aortic valve replacement (pilot study)

The objective was to study the relationship between the increased preoperative N-terminal segment of B-type natriuretic peptide precursor (NT-proBNP) blood levels and the parameters of the heart ventricles function, as well as the conditions for coronary perfusion of their myocardium before and after on-pump aortic valve replacement.Materials and methods. The study involved 27 patients aged 57.7±2.5 years who underwent aortic valve replacement. NT-proBNP blood level was determined before surgery. The level of NT-proBNP &gt; 1000 pg/ml was considered increased. Invasive hemodynamics, including the data of the right ventricle thermodilution volumetry, and transesophageal echocardiography data were analyzed at the stages: the 1st – after anesthesia induction, the 2nd – at the end of surgery. Logistic regression and ROC analysis were used for data processing.Results. Preoperative blood levels of NT-proBNP &gt; 1000 (3163.0[2507.25–7319]) pg/ml were recorded in 55.6% of patients. At the 1st stage, the biomarker increased level was associated with increased index of left ventricular end-systolic volume (OR 1.0955, 95% CI 1.0097–1.1885, p = 0.028, AUC 0.903), decreased left ventricular ejection fraction (OR 0, 9447, 95% CI 0.8949–0.9973, p = 0.040, AUC 0.753) and area contraction fraction (OR 0.8868, 95% CI 0.8086–0.9726, p = 0.011, AUC 0.890), increased mean pulmonary artery pressure (OR 1.1824, 95% CI 1.0020–1.3952, p = 0.047, AUC 0.722), and increased transpulmonary gradient (OR 1.4497, 95% CI 1.0103–2.0802, p = 0.044, AUC 0.810), increased right ventricular stroke work index (OR 1.5151, 95% CI 1.0319–2.2246, p = 0.034, AUC 0.761), and decreased coronary perfusion gradients of the left (OR 0.8961–0.9241, 95% CI 0.8229–0.9459 – 0.8630–0.9896, p = 0.012–0.024, AUC 0.793–0.861) and right (OR 0.9519, 95% CI 0.9136–0.9918, p = 0.019, AUC 0.847) ventricles. At the 2nd stage, NT-proBNP blood values &gt; 1000 pg/ml were associated with impaired left ventricular function, decreased mean arterial pressure (OR 0.9066, 95% CI 0.8264–0.9946, p = 0.038, AUC 0.761), and the vasopressor and inotropic support (OR 8.4000, 95% CI 1.2584–56.0694, p = 0.028, AUC 0.710).Conclusions. Prior to aortic valve replacement, the blood level of NT-proBNP &gt; 1000 pg/ml is associated with a moderate decrease in the left ventricular ejection fraction and area contraction fraction, an increased left ventricular end-systolic volume with a normal end-diastolic volume, an increased index of right ventricular stroke work in combination with moderately increased mean pulmonary artery pressure and increased transpulmonary gradient, as well as a decreased coronary perfusion gradients. At the end of operations, increased NT-proBNP blood level is associated with signs of impaired left ventricular contractility, a tendency to arterial hypotension, and the vasopressor and inotropic support. Increased preoperative NT-proBNP blood level are not associated with right ventricular volumes and ejection fraction both before and after on-pump aortic valve replacement.

Ekhokardiohrafichni predyktory vynyknennia riznykh uskladnen systemy krovoobihu u khvorykh iz hostrym koronarnym syndromom (ohliad literatury; rezultaty vlasnykh doslidzhen)

Introduction. A big number of publications are reporting results obtained while using echocardiography (EchoCG) in heart diseases. However, so far, applicability of EchoCG data to predict possible complications in cardiovascular system have not been studied sufficiently. The aim of the study. Using available literature and own research results to analyze EchoCG predictors of the development of various complications of the blood circulatory system during acute coronary syndrome. Materials and methods. Literature review covered 41 analyzed articles, results of which were compared with our own observations. Results. Two years after the myocardial infarction there exist several variants of further disease development: favorable, with the preserved left ventricle dysfunction; conditionally preserved and moderately preserved, with pronounced dilatation and compensatory left ventricle hypertrophy; and unfavorable, with reduced left ventricle systolic function accompanied by the increased end systolic and end diastolic volumes. Repeated myocardial infarction is more often supplemented with the secondary myocardial necrosis in the perifocal zone and dilatation of the left ventricular cavities. Our observations revealed that violation of myocardial contractility is manifested in those cases, when the myocardial damage exceeds 20.0 % of the thickness of the left ventricular wall; in those cases, when the damage covers from 20.0 to 50.0 % – a Q wave is registered on the electrocardiography. Prognostic predictors and criteria for the development of unfavorable cardiovascular events after being subjected to ST elevation of myocardial infarction include: increased angina attacks, progression of congestive heart failure, age over 60 years, increased heart rate more than 90 beats/min, ventricular extrasystole 3-5 grades according to B. Laun, elevation of the ST segment more is equal 1 mm, left ventricle hypertrophy, alteration of two or more coronary arteries. Conclusions. Unfavorable prognostic predictors according to EchoCG data are as follows: increased end diastolic and end systolic volumes, decreased left ventricular ejection fraction is less than 40.0 % on the background of early or late remodeling, concentric type of remodeling. Eccentric left ventricular ejection fraction, being initially compensatory in nature, due to its increased severity and cardiomegaly accompanied by a decrease in left ventricular ejection fraction is less than 40.0 % – decompensated. Predictors of the right cardiac cusp are: ventricular extrasystoly of 3-5 gradations, ventricular tachicardia of the “pirouette” type, prolongation of Q-T interval, decrease in left ventricular ejection fraction is less than 40.0 %, increased anginal attacks and progression of congestive heart failure. Keywords: echocardiographic predictors, acute coronary syndrome, myocardial infarction, ventricular extrasystole.

A screening method for predicting left ventricular dysfunction based on spectral analysis of a single-channel electrocardiogram using machine learning algorithms

BackgroundAnalysis of a single-channel electrocardiogram can potentially be used as a screening method to detect systolic and diastolic dysfunction of the left ventricle. The purpose of our study was to develop a new screening method for detecting a decrease in systolic and/or diastolic function of the left ventricle based on single-channel ECG and pulse wave recording using machine learning methods. Materials and methodsThe study prospectively included 375 patients aged 18 years and above. Every participant underwent a transthoracic echocardiographic study with the aim of determining the systolic (EF below 52% for male and 54% for female) and diastolic dysfunction of the left ventricle, as well as, registering the 3 min single channel electrocardiogram and pulse wave using a portative electrocardiogram device. Spectral analysis of the electrocardiogram was performed which was based on the Fourier transform. ResultsFor ejection fraction decrease: Lasso regression showed a sensitivity of 92,3%, specificity of 90,2% (AUC = 0.922); Random Forest Classifier sensitivity − 100%, specificity − 84,3% (AUC = 0.931). For diastolic dysfunction: Lasso regression sensitivity − 86,2%, specificity − 84,5% (AUC 0.878); random forest classifier sensitivity − 82,8%, specificity 89,3% (AUC 0.854). Algorithm approbation has shown diagnostic accuracy of 95,6% left ventricular diastolic dysfunction of 2–3 grade. ConclusionsMachine learning models, based on the single lead ECG and pulse wave parameters, as well as age and gender may simplify screening diagnostics of ejection fraction decrease and diastolic dysfunction prior to echocardiographic study for in time heart failure diagnostics with high accuracy.

Sacubitril/valsartan for cardioprotection in breast cancer (MAINSTREAM): design and rationale of the randomized trial.

In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment-related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin-angiotensin-aldosterone inhibitors, might reduce the risk of treatment-related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early-stage breast cancer, which is the aim of the trial. MAINSTREAM is a randomized, placebo-controlled, double-blind, multicentre, clinical trial. After the run-in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti-human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy-related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031).

PHB2 ameliorates Doxorubicin-induced cardiomyopathy through interaction with NDUFV2 and restoration of mitochondrial complex I function

BackgroundDoxorubicin (DOX) is among the most widely employed antitumor agents, although its clinical applications have been largely hindered by severe cardiotoxicity. Earlier studies described an essential role of mitochondrial injury in the pathogenesis of DOX cardiomyopathy. PHB2 (Prohibitin 2) is perceived as an essential regulator for mitochondrial dynamics and oxidative phosphorylation (OXPHOS) although its involvement in DOX cardiomyopathy remains elusive. MethodsTo decipher the possible role of PHB2 in DOX cardiomyopathy, tamoxifen-induced cardiac-specific PHB2 conditional knockout mice were generated and subjected to DOX challenge. Cardiac function and mitochondrial profiles were examined. Screening of downstream mediators of PHB2 was performed using proteomic profiling and bioinformatic analysis, and was further verified using co-immunoprecipitation and pulldown assays. ResultsOur data revealed significantly downregulated PHB2 expression in DOX-challenged mouse hearts. PHB2CKO mice were more susceptible to DOX cardiotoxicity compared with PHB2flox/flox mice, as evidenced by more pronounced cardiac atrophy, interstitial fibrosis and decrease in left ventricular ejection fraction and fractional shortening. Mechanistically, PHB2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that PHB2 interacted with NDUFV2 (NADH-ubiquinone oxidoreductase core subunit V2), a key subunit of mitochondrial respiratory Complex I to mediate regulatory property of PHB2 on mitochondrial metabolism. PHB2 governed the expression of NDUFV2 by promoting its stabilization, while PHB2 deficiency significantly downregulated NDUFV2 in DOX-challenged hearts. Cardiac overexpression of PHB2 alleviated mitochondrial defects in DOX cardiomyopathy both in vivo and in vitro. ConclusionsOur study defined a novel role for PHB2 in mitochondrial dynamics and energetic metabolism through interacting with NDUFV2 in DOX-challenged hearts. Forced overexpression of PHB2 may be considered a promising therapeutic approach for patients with DOX cardiomyopathy.