Ischemic Chronic Heart Failure Research Articles

Gene therapy encoding cell cycle factors to treat chronic ischemic heart failure in rats.

Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL-treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL-treated rats. This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.

Clinical efficacy and safety of adjunctive treatment of chronic ischemic heart failure with Qishen Yiqi dropping pills: a systematic review and meta-analysis.

Our study was to evaluate the effect of Qishen Yiqi Dropping Pills(QSYQ) on the prognosis of chronic ischemic heart failure(CIHF) and its safety. Databases including CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, The Cochrane Library and EMbase were searched from their inception to April 2023 to screen relevant randomized controlled trials (RCTs). Primary indicators included readmission rates, rates of major adverse cardiovascular events (MACE), and all-cause mortality rates. The quality of the literature was assessed according to the Cochrane Reviewers' Handbook 5.0 and the Modified Jadad Scale (with a score of 4-7 rated as high quality). Meta-analysis was performed using the meta-package created by R software version 4.2.3, continuous data were compared using SMDs, and dichotomous and ordered data were compared using ORs; and the I2 test was used to assess the heterogeneity. Fifty-nine studies out of 1,745 publications were finally included, totalling 6,248 patients. Most studies were poorly designed and had some publication bias, with only 26 high-quality papers (Jadad score ≥4). Meta-analysis showed that the combined application of QSYQ was able to reduce the readmission rate [OR = 0.42, 95% CI (0.33, 0.53), P < 0.001], all-cause mortality rate [OR = 0.43, 95% CI (0.27, 0.68), P < 0.001], and the incidence of MACE [OR = 0.42, 95% CI (0.31, 0.56), P < 0.001]. Also, the treatment method can improve clinical effectiveness [OR = 2.25, 95% CI (1.97, 2.58), P < 0.001], increase 6-min walking distance (6MWD) [SMD = 1.87, 95% CI (1.33, 2.41), P < 0.0001] and left ventricular ejection fraction (LVEF) [SMD = 1.08, 95% CI (0.83, 1.33), P < 0.0001], and decrease the Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores [SMD = -2.03, 95% CI (-3.0, -1.07), P < 0.0001], BNP levels [SMD = -2.07, 95% CI (-2.81, -1.33), P < 0.0001] and NT-ProBNP levels [SMD = -2.77, 95% CI (-4.90, -0.63), P < 0.05]. A total of 21 studies (n = 2,742) evaluated their adverse effects, of which 13 studies reported no adverse effects and 8 studies reported minor adverse effects. Our results suggest that the combined application of QSYQ can further improve patients' cardiac function and exercise tolerance, improve their quality of life, and ultimately improve patients' prognosis with a favorable safety profile. Nonetheless, limited by the quality and high heterogeneity of the literature, we must be conservative and cautious about the present results. PROSPERO (CRD42023449251).

Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure

Introduction: Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals. Hypothesis: The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state. Methods: Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation. Results: Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.

Right ventricular free wall and four-chamber longitudinal strain in relation to incident heart failure in the general population.

Right ventricular free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) are associated with adverse events in various patient populations including patients with heart failure (HF). We sought to investigate the prognostic value of RVFWLS and RV4CLS for the development of incident HF in participants from the general population. Participants from the 5th Copenhagen City Heart Study (2011-2015) without known chronic ischaemic heart disease or HF at baseline were included. RVFWLS and RV4CLS were obtained using two-dimensional speckle-tracking echocardiography from the right ventricular (RV)-focused apical four-chamber view. The primary endpoint was incident HF. Among 2740 participants (mean age 54 ± 17 years, 42% male), 43 (1.6%) developed HF during a median follow-up of 5.5 years (IQR 4.5-6.3). Both RVFWLS and RV4CLS were associated with an increased risk of incident HF during follow-up independent of age, sex, hypertension, diabetes, body mass index and tricuspid annular plane systolic excursion (TAPSE), (HR 1.06, 95%CI 1.00-1.11, P = 0.034, per 1% absolute decrease and HR 1.14, 95%CI 1.05-1.23, P = 0.001, per 1% absolute decrease, respectively). Left ventricular ejection fraction (LVEF) modified the association between RV4CLS and incident HF (P for interaction = 0.016) such that RV4CLS was only of prognostic importance among those with LVEF < 55% (HR 1.21, 95%CI 1.11-1.33, P < 0.001 vs. HR 0.94, 95%CI 0.80-1.10, P = 0.43 in patients with LVEF ≥ 55%). In participants from the general population, both RVFWLS and RV4CLS were associated with a greater risk of incident HF independent of important baseline characteristics and TAPSE, and LVEF modified the relationship between RV4CLS and incident HF.

Too Loud to Handle? Transportation Noise and Cardiovascular Disease.

The World Health Organization reported that more than 1.6 million healthy life-years are lost yearly from traffic-related noise in western Europe. In addition, the number of studies on health side effects in response to traffic noise is steadily growing, mainly cardiovascular disease, such as acute and chronic ischemic heart disease, heart failure, arrhythmia, and stroke. Pathophysiologically nighttime noise has been shown to cause sleep disturbances, including too short sleep periods and frequent interruption of sleep leading to an increase in the levels of circulating stress hormones and subsequently to a significant increase in the production of reactive oxygen species (oxidative stress) and inflammation in the vasculature and the brain. The consequence is arterial hypertension and vascular (endothelial) dysfunction, which might increase the risk of cardiovascular disease. With the present review, we give an overview of the "so-called" nonauditory cardiovascular health effects of noise, which have been proposed to be responsible for the future development of cardiovascular disease. We present epidemiological evidence but also evidence provided by translational human and experimental noise studies. Finally, we discuss manoeuvres to mitigate noise effectively.

Current Role of Myocardial Viability Imaging Using Positron Emission Tomography in Patients with Chronic Ischemic Heart Failure and Left Ventricular Dysfunction

Current Role of Myocardial Viability Imaging Using Positron Emission Tomography in Patients with Chronic Ischemic Heart Failure and Left Ventricular Dysfunction

Abstract P3084: Neutrophil Expansion And Netosis Are Essential For Adverse Left Ventricular Remodeling And Dysfunction In Chronic Ischemic Heart Failure

Chronic inflammation contributes significantly to disease progression in heart failure (HF) with the expansion and adverse activation of macrophages, dendritic cells, and T cells in the failing heart. Neutrophils play a well-known role in the initial acute immune response to myocardial infarction (MI), however, whether and how they contribute to inflammation and adverse LV function and remodeling in chronic ischemic HF is unknown. We tested the hypothesis that activated neutrophils are required for tissue remodeling and disease progression in HF in mice studied 4 and 8 weeks after MI during established ischemic HF (vs sham). CD11b + Ly6G + neutrophils were expanded in peripheral blood (PB), heart, spleen and bone marrow 8 w post-MI. Neutrophils in the failing heart were localized to the MI border zone and augmented in remote zone myocardium by immunofluorescent staining. CXCL1 and CXCL5 expression was increased in the failing heart, consistent with chemotactic signals for myocardial neutrophil recruitment. Plasma from HF mice elicited greater chemotaxis in naïve neutrophils (vs naïve plasma) by time-lapse video microscopy. Further, PB neutrophils from HF mice exhibited significantly increased neutrophil extracellular trap (NET) production, with concomitant increase in plasma NETs (histone-DNA complexes) in HF mice. The direct pathological impact of NETs was demonstrated by intramyocardial injection of isolated NETs into naïve hearts mimicking HF with decreased EF, LV dilation, and fibrosis. Finally, the in vivo role of neutrophils in chronic HF (4 and 8 w post-MI) was determined via depletion studies using genetic (Ly6G-diptheria toxin receptor mice) and antibody (1A8) based approaches. Neutrophil depletion significantly improved LV EF and reduced end systolic and diastolic volumes. 1A8 treated HF mice also exhibited reduced remote zone fibrosis. The necessity of NETosis in HF development was confirmed using neutrophil and myeloid – specific PAD4 deletion where the decline in LV EF and increase in volumes in HF were attenuated. In conclusion , neutrophil expansion and NETosis are important contributors to chronic inflammation in HF and play an obligatory role in the development of LV dysfunction and remodeling in ischemic cardiomyopathy.

Abstract P3068: Hematopoietic Loss Of Y-chromosome In Circulating Monocytes Derived From Heart Failure Patients Associates With Cardiac Fibrotic Signaling

Background: Hematopoietic mosaic loss of Y chromosome (LOY) correlates with age and associates with increased cardiovascular disease incidence. Moreover, new murine studies propose that LOY could promote cardiac fibrosis by stimulating cardiac infiltration and activation of circulating macrophages. Yet, specific profiles of hematopoietic LOY cells in patients with heart failure (HF) are missing. Methods and Results: To decipher the genetic profile of human circulating immune cells and assess the effects of LOY, we performed single-cell RNA-sequencing (scRNA-seq) with immune cells of 10 male patients having chronic ischemic HF (mean age 67.3 years, ejection fraction 34.4%). We bioinformatically sorted immune cells by presence or absence of Y-chromosome-associated genes. Relative distribution of LOY was assessed, with monocytes having the greatest absolute count of LOY cells with no significant change in distribution among cell types. Given the abundance of monocytic LOY cells, we examined LOY monocytic cells transcriptional profiles (29810 Y-carrier monocytes, 2205 LOY monocytes) in an unbiased manner. Using a patient-specific, paired analysis, LOY monocytes showed significantly diminished expression of TGF-ß inhibiting genes (SMAD7, TGIF2) in LOY cells versus Y-carrier cells. Opposingly, from 193 upregulated genes, LOY cells showed elevated markers associated with monocyte/macrophage-mediated tissue damage and pro-fibrotic cardiac remodelling (S100A8, CLEC4D, TLR2). Gene ontology terms derived from upregulated genes in LOY cells further supported a mechanistic link to cardiac fibrosis by calling terms associated with TLR signaling, which are known to enhance cardiac fibrosis. Conclusion: This is the first study to study the genetic signature of LOY monocytes in HF patients. Our results considerably extend very recent experimental results in mice that LOY sensitizes macrophages to enhanced signaling associated with cardiac fibrosis. Reduced TGF-ß inhibitory molecule expression and enhanced TLR signaling may contribute to the aggravation of heart failure by LOY in patients with HF.

Circulating H-FABP as a biomarker of frailty in patients with chronic heart failure.

Increased vulnerability to physiologic stressors, termed frailty, is a common occurrence in patients with chronic heart failure (CHF). However, the definite biomarkers to assess frailty in CHF patients are not known. Here, we assessed the frailty phenotype and its potential association with heart failure (HF) markers in CHF patients. We categorized controls (n = 59) and CHF patients (n = 80), the participants, into robust, pre-frail, and frail based on the cardiovascular health study (CHS) frailty index. The plasma levels of HF markers, including tumorigenicity 2 (s-ST2), galectin-3, and heart-type fatty acid binding protein (H-FABP), were measured and correlated with frailty phenotype and cardiac function. The levels of plasma s-ST2, galectin-3, and H-FABP were profoundly elevated in CHF patients. Conversely, the frailty index scores were significantly lower in ischemic and non-ischemic CHF patients versus controls. Of the assessed HF markers, only H-FABP was positively correlated (r2 = 0.07, P = 0.02) with the frailty score in CHF patients. Collectively, these observations suggest that circulating H-FABP may serve as a biomarker of frailty in CHF patients.

Metabolic Approaches for the Treatment of Dilated Cardiomyopathy.

In dilated cardiomyopathy (DCM), where the heart muscle becomes stretched and thin, heart failure (HF) occurs, and the cardiomyocytes suffer from an energetic inefficiency caused by an abnormal cardiac metabolism. Although underappreciated as a potential therapeutic target, the optimal metabolic milieu of a failing heart is still largely unknown and subject to debate. Because glucose naturally has a lower P/O ratio (the ATP yield per oxygen atom), the previous studies using this strategy to increase glucose oxidation have produced some intriguing findings. In reality, the vast majority of small-scale pilot trials using trimetazidine, ranolazine, perhexiline, and etomoxir have demonstrated enhanced left ventricular (LV) function and, in some circumstances, myocardial energetics in chronic ischemic and non-ischemic HF with a reduced ejection fraction (EF). However, for unidentified reasons, none of these drugs has ever been tested in a clinical trial of sufficient size. Other pilot studies came to the conclusion that because the heart in severe dilated cardiomyopathy appears to be metabolically flexible and not limited by oxygen, the current rationale for increasing glucose oxidation as a therapeutic target is contradicted and increasing fatty acid oxidation is supported. As a result, treating metabolic dysfunction in HF may benefit from raising ketone body levels. Interestingly, treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) improves cardiac function and outcomes in HF patients with or without type 2 diabetes mellitus (T2DM) through a variety of pleiotropic effects, such as elevated ketone body levels. The improvement in overall cardiac function seen in patients receiving SGLT2i could be explained by this increase, which appears to be a reflection of an adaptive process that optimizes cardiac energy metabolism. This review aims to identify the best metabolic therapeutic approach for DCM patients, to examine the drugs that directly affect cardiac metabolism, and to outline all the potential ancillary metabolic effects of the guideline-directed medical therapy. In addition, a special focus is placed on SGLT2i, which were first studied and prescribed to diabetic patients before being successfully incorporated into the pharmacological arsenal for HF patients.

The use of quadrotherapy of chronic heart failure in cancer patients (case series)

Background: Chronic heart failure (CHF) for a patient with cancer is complex, as it complicates antitumor treatment. In some cases, severe CHF is a contraindication to the chemotherapy or surgical treatment. Despite significant progress in CHF treatment, some groups of drugs, particularly mineralocorticoid receptor inhibitors, angiotensin receptor-neprilysin inhibitors, and sodium-glucose co-transporter type 2 inhibitors, have not been studied related to cancer patients. Clinical case description: In this report, we introduce two clinical cases in which, because of the invaluable contribution of the cardio-oncological team, we have managed to solve complex problems of treating patients with CHF and cancer. In patient 1 with severe CHF, it was possible to achieve regression of systolic dysfunction, despite the progression of bladder cancer T4N1M0. In patient 2 with severe ischemic cardiopathy and CHF, owing to the timely administration of quadruple therapy, we managed to significantly improve the cardiac status and increase the LV EF that the patient underwent gastrectomy and cholecystectomy for cancer of the cardiac part of the stomach cT2N0M0 without complications. Conclusion: The above clinical cases demonstrate the possibilities of a team, multidisciplinary approach in the treatment of complex category of patients with CHF and active oncological disease. Modern therapy of cancer patients with severe heart failure allows successful antitumor treatment.

BS-452758-2 RESCUE OF ISCHEMIC DILATED CARDIOMYOPATHY IN CANINES

Ischemic cardiomyopathy and resultant heart failure (HF) are significant causes of morbidity and mortality worldwide. Mainstay therapeutic options are limited to the blockade of neurohormonal stress pathways. An unmet need in HF therapy is the development of targeted myocardium-specific therapies. Cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein in transverse-tubule microdomains, organizes the calcium handling apparatus proteins in cardiomyocytes. cBIN1 is transcriptionally reduced in failing hearts, impairing calcium transients and systolic and diastolic function. This study explored cBIN1 as a gene therapy-based rescue of ischemic cardiomyopathy. To investigate whether cBIN1 gene therapy rescues failing myocardium in a preclinical canine model of chronic ischemic HF. Nine healthy adult mongrel dogs (30±3 kg) underwent a lateral thoracotomy followed by left anterior descending artery ligation to induce myocardial infarctions. Animals developed progressive dilated cardiomyopathy and chronic ischemic HF over 10 – 16 weeks. When their left ventricular ejection fraction (LVEF) decreased below 40%, animals received a single intramyocardial injection of either adeno-associated virus serotype 9 (AAV9)-cBIN1 gene (n=6) or AAV9-green fluorescent protein (GFP) (Control, n=3) in the LV. Weekly echocardiography, laboratory testing and daily clinical examinations were performed up to 7 weeks post-therapy. From therapy to post-injection week 5, LV function in the GFP-treated cohort continued to decline. By week 5, all control animals developed progressive dilated cardiomyopathy and had to be euthanized due to worsening prognostic factors. In contrast, the cBIN1-treated cohort never developed HF symptoms, and LVEF statistically improved by 4% gain (Figure, p=0.003 – reclassifying the animals from HF with reduced ejection fraction to HF with mildly reduced ejection fraction), whereas the control cohort lost an additional 7% in LV function. In cBIN1-treated animals, there was no significant further LV dilation and positive remodeling to smaller dimensions. Cardiac biomarkers of HF continued to increase in the control cohort and decreased in the cBIN1-treated cohort. In a canine model of chronic ischemic HF, cBIN1 gene therapy significantly rescued and improved LV function. This work suggests that recovery of transverse-tubule microdomains and normalizing excitation-contraction coupling by cBIN1 gene therapy can restore contractility in ischemic HF.

A canine model of chronic ischemic heart failure.

Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: group 1 (n = 4) (simple LAD: proximal and distal LAD ligation); group 2 (n = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and group 3 (n = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles). Dogs were followed until chronic severe HF developed defined as left ventricular ejection fraction (LVEF) < 40% and NH2-terminal-prohormone B-type natriuretic peptide (NT-proBNP) > 900 pmol/L. Overall early survival (48-h postligation) in 29 dogs was 83% and the survival rate at postligation 5 wk was 69%. Groups 1 and 2 had 100% and 71% early survival, respectively, yet only a 50% success rate of developing chronic HF. Group 3 had excellent survival at postligation 48 h (91%) and a 100% success in the development of chronic ischemic HF. The TLD approach, which limits full LAD and collateral flow to its perfusion bed, provides excellent early survival and reliable development of chronic ischemic HF in canine hearts.NEW & NOTEWORTHY The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.

Effect of Intravenous Lignocaine vs Placebo on Hemodynamic Responses during Direct Laryngoscopy

Aim: To determine the effect of placebo vs intravenous lignocaine pre-intubation on hemodynamic responses during direct laryngoscopy. Study design: Randomized control trial Place and duration of study: Department of Anaesthesia, Indus Hospital, Karachi from 1st March 2017 to 31st August 2017. Methodology: One hundred and twenty patients were included and divided into two groups. In one group, lignocaine arm (1.5mg/kg I/V lignocaine) was given while placebo arm was given (6ml normal saline pre-intubation) in group two. In both groups after arrival at the operation theatre, base-line parameters like the heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure was measured non-and later hemodynamic assessment was done before giving lignocaine, prior and post intubation and after 3,5 and 10 minutes of intubation. Results: Fifty six (46.15%) were male while 64 (53.85%) were females. No patients were found to have asthma, COPD, ischemic heart disease, TB, CHF, Cushing syndrome, phenochromcytoma, and drug allergy. No significant association was found between the two groups when comparing the gender, BMI, comorbids, ASA grade and Mallampati grade. The systolic blood pressure at 3,5 and 10 minutes was significant in the two groups, while diastolic was not significantly associated. The pulse rate at3 and 10 minutes was found to have a significant association while at 5 minutes was insignificant. MAP showed no significant association between the two groups. Conclusion: Hemodynamic stability is only affected in terms of systolic blood pressure, while other parameters are not significantly affected. Keywords: Lignocaine, Hymodynamic changes, Laryngoscopy

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction-the SCIENCE trial.

The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0ml, p=0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0ml, p=0.736) and LVEF (-1.6 ± 1.0%, p=0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups. The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.

68Ga]Ga-NODAGA-E[(cRGDyK)]2 and [64Cu]Cu-DOTATATE PET Predict Improvement in Ischemic Cardiomyopathy.

An increasing number of patients are living with chronic ischemic cardiomyopathy (ICM) and/or heart failure. Treatment options and prognostic tools are lacking for many of these patients. Our aim was to investigate the prognostic value of imaging angiogenesis and macrophage activation via positron emission tomography (PET) in terms of functional improvement after cell therapy. Myocardial infarction was induced in rats. Animals were scanned with [18F]FDG PET and echocardiography after four weeks and randomized to allogeneic adipose tissue-derived stromal cells (ASCs, n = 18) or saline (n = 9). Angiogenesis and macrophage activation were assessed before and after treatment by [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE. There was no overall effect of the treatment. Rats that improved left ventricular ejection fraction (LVEF) had higher uptake of both [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE at follow-up (p = 0.006 and p = 0.008, respectively). The uptake of the two tracers correlated with each other (r = 0.683, p = 0.003 pre-treatment and r = 0.666, p = 0.004 post-treatment). SUVmax at follow-up could predict improvement in LVEF (p = 0.016 for [68Ga]Ga-RGD and p = 0.045 for [64Cu]Cu-DOTATATE). High uptake of [68Ga]Ga-RGD and [64Cu]Cu-DOTATATE PET after injection of ASCs or saline preceded improvement in LVEF. The use of these tracers could improve the monitoring of heart failure patients in treatment.

Impact of heart failure on all-cause mortality in COVID-19: findings from the Eurasian International Registry.

To study all-cause mortality in patients hospitalized with COVID-19 with or without chronic heart failure (CHF) during hospitalization and at 3 and 6months of follow-up. The international registry Analysis of Comorbid Disease Dynamics in Patients with SARS-CoV-2 Infection (ACTIV) was conducted at 26 centres in seven countries: Armenia, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Russian Federation, and Uzbekistan. The primary endpoints were in-hospital all-cause mortality and all-cause mortality at 3 and 6months of follow-up. Of the 5616 patients hospitalized with COVID-19, 917 (16.3%) had CHF. Total in-hospital mortality was 7.6%. In-hospital mortality was higher in patients with CHF than in patients without a history of CHF [17.7% vs. 4.0%, P<0.001; odds ratio (OR) 4.614, 95% confidence interval (CI) 3.633-5.859; P<0.001]. The risk of in-hospital all-cause mortality correlated significantly with the severity of CHF; specifically, the risk of in-hospital all-cause mortality was greater for patients in New York Heart Association functional classes III and IV (OR 6.124, 95% CI 4.538-8.266; P<0.001 vs. patients without CHF) than for patients in functional classes I and II (OR 2.446, 95% CI 1.831-3.267, P<0.001 vs. patients without CHF). The risk of mortality in patients with ischemic CHF was 58% higher than in patients with non-ischaemic CHF [OR 1.58 (95% CI 1.05-2.45), P=0.030]. In the first 3months of follow-up, the all-cause mortality rate in patients with CHF was 10.32%, compared with 1.83% in patients without CHF (P<0.001). At 6months of follow-up, NYHA classes II-IV was a strong risk factor for all-cause mortality [OR 5.343 (95% CI 2.717-10.508); P<0.001]. Hospitalized COVID-19 patients with CHF have an increased risk of in-hospital all-cause mortality, which remains high 6months after discharge.

Chronic ischemic heart failure is defined by ongoing immune cell activation promoting inflammation and altered crosstalk with endothelial cells

Chronic ischemic heart failure is defined by ongoing immune cell activation promoting inflammation and altered crosstalk with endothelial cells

Contemporary Challenges of Regenerative Therapy in Patients with Ischemic and Non-Ischemic Heart Failure.

It has now been almost 20 years since first clinical trials of stem cell therapy for heart repair were initiated. While initial preclinical data were promising and suggested that stem cells may be able to directly restore a diseased myocardium, this was never unequivocally confirmed in the clinical setting. Clinical trials of cell therapy did show the process to be feasible and safe. However, the clinical benefits of this treatment modality in patients with ischemic and non-ischemic heart failure have not been consistently confirmed. What is more, in the rapidly developing field of stem cell therapy in patients with heart failure, relevant questions regarding clinical trials' protocol streamlining, optimal patient selection, stem cell type and dose, and the mode of cell delivery remain largely unanswered. Recently, novel approaches to myocardial regeneration, including the use of pluripotent and allogeneic stem cells and cell-free therapeutic approaches, have been proposed. Thus, in this review, we aim to outline current knowledge and highlight contemporary challenges and dilemmas in clinical aspects of stem cell and regenerative therapy in patients with chronic ischemic and non-ischemic heart failure.