Function In Heart Failure Research Articles

(426) Response in Kidney Function in Heart Failure after Milrinone Loading

(426) Response in Kidney Function in Heart Failure after Milrinone Loading

Minimally Invasive Fully Implantable Cardiac Support System to Restore Left Ventricular Function in Heart Failure

Minimally Invasive Fully Implantable Cardiac Support System to Restore Left Ventricular Function in Heart Failure

Sildenafil and Kidney Function in Heart Failure with Preserved Ejection Fraction.

Chronic kidney disease (CKD) worsens the prognosis for people with heart failure with preserved ejection fraction (HFpEF). In the RELAX trial, sildenafil decreased estimated glomerular filtration rate (eGFR) compared to placebo despite favorable kidney effects in preclinical models. Since acute eGFR decline precedes long-term kidney benefits for select medications, we assessed the influence of sildenafil on acute and chronic eGFR slopes. The RELAX trial randomized 216 participants to placebo or sildenafil and assessed 24-week changes in cardiopulmonary exercise testing, cardiovascular imaging, and laboratory data. We applied linear mixed modeling to calculate the total, acute (0-12 weeks), and chronic (3-24 weeks) eGFR slopes by treatment. Using regression modeling, we assessed respective associations between eGFR slope and baseline data and clinical endpoints. We repeated the analyses using a binary outcome based on a substantial (≥20%) decline in eGFR. The mean baseline eGFR was 60.8 ml/min/1.73 m2, and the mean eGFR slope during follow-up was -3.21 ml/min/1.73 m2/year. Sildenafil did not alter total eGFR slope compared to placebo (difference +0.47 ml/min/1.73 m2/year, 95% CI -6.63 - 7.57 ml/min/1.73 m2/year). Sildenafil users tended to experience a more negative acute eGFR slope (difference -3.15 ml/min/1.73 m2/year) and more positive chronic slope (+2.06 ml/min/1.73 m2/year) compared to placebo, but neither difference reached statistical significance. Baseline NT-proBNP and loop diuretic use were associated with worse eGFR trajectory regardless of treatment. Substantial eGFR decline was associated with increase in endothelin-1 and a greater risk of hospitalization or death (HR 2.34, 95% CI 1.21-4.53, p=0.01). Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in a HFpEF cohort, suggesting lack of long-term risk related to early reduction in eGFR after initiating treatment. Long-term studies are needed to determine the effect of sildenafil on kidney function in HFpEF.

Autonomic regulation therapy in chronic heart failure with preserved/mildly reduced ejection fraction: ANTHEM-HFpEF study results

BackgroundAutonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) appeared to be safe and to improve autonomic tone, symptoms, and cardiac mechanical function in patients with symptomatic heart failure and reduced ejection fraction in the ANTHEM-HF Study. The ANTHEM-HFpEF Study is the first investigation to evaluate the safety and feasibility of ART in patients with symptomatic heart failure and preserved or mildly reduced ejection fraction (HFpEF, HFmrEF). MethodsThis open-label interventional study enrolled 52 patients with HFpEF or HFmrEF, NYHA Class II-III, and LVEF ≥40%, who received stable guideline-directed medical therapy. All patients were successfully implanted with LivaNova VNS Therapy® system with an electrical lead surrounding the right cervical vagus nerve. ResultsAdverse event incidence was low. At 12 months, NYHA class (p <0.0001), 6-min walk distance (p <0.05), and quality of life (p <0.0001) were improved. Cardiac mechanical function measures were normal at baseline, except for left ventricular mass index in women and E/e' ratio in all patients, which were elevated at baseline, and were unchanged by ART. Autonomic tone and reflexes improved, indicated by 29% decrease in low-frequency/high-frequency heart rate variability to normal levels (p = 0.028) and by increased heart rate turbulence slope (p = 0.047). T-wave alternans (p = 0.001) and T-wave heterogeneity (p = 0.001) were reduced from abnormal to normal ranges. Nonsustained ventricular tachycardia incidence decreased (p = 0.027). ConclusionsART appeared well-tolerated and safe in patients with HFpEF or HFmrEF. Chronic ART did not alter mechanical function measures but was associated with improved heart failure symptoms, exercise tolerance, autonomic tone, and cardiac electrical stability. Clinical trial registryAutonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure with Preserved Ejection Fraction [ClinicalTrials.gov #NCT03163030, registered 05/22/2017].

Respiratory patterns and baroreflex function in heart failure

Little is known on the effects of respiratory patterns on baroreflex function in heart failure (HF). Patients with HF (n = 30, age 61.6 ± 10 years, mean ± SD) and healthy controls (CNT, n = 10, age 58.9 ± 5.6 years) having their R–R interval (RRI, EKG), systolic arterial blood pressure (SBP, Finapres) and respiratory signal (RSP, Respitrace) monitored, were subjected to three recording sessions: free-breathing, fast- (≥ 12 bpm) and slow- (6 bpm) paced breathing. Baroreflex sensitivity (BRS) and power spectra of RRI, SBP, and RSP signals were calculated. During free-breathing, compared to CNT, HF patients showed a significantly greater modulation of respiratory volumes in the very-low-frequency (< 0.04 Hz) range and their BRS was not significantly different from that of CNT. During fast-paced breathing, when very-low-frequency modulations of respiration were reduced, BRS of HF patients was significantly lower than that of CNT and lower than during free breathing. During slow-paced breathing, BRS became again significantly higher than during fast breathing. In conclusion: (1) in free-breathing HF patients is present a greater modulation of respiratory volumes in the very-low-frequency range; (2) in HF patients modulation of respiration in the very-low and low frequency (around 0.1 Hz) ranges contributes to preserve baroreflex-mediated control of heart rate.

Left Atrial Strain in the Assessment of Diastolic Function in Heart Failure: A Machine Learning Approach.

Diastolic dysfunction (DD) assessment in heart failure is still challenging. Peak atrial longitudinal strain (PALS) is strongly related to end-diastolic pressure and prognosis, but it is still not part of standard DD assessment. We tested the hypothesis that a machine learning approach would be useful to include PALS in DD classification and refine prognostic stratification. In a derivation cohort of 864 heart failure patients in sinus rhythm (age, 66.6±12 years; heart failure with reduced ejection fraction, n=541; heart failure with mildly reduced ejection fraction, n=129; heart failure with preserved ejection fraction, n=194), machine learning techniques were retrospectively applied to PALS and guideline-recommended diastolic variables. Outcome (death/heart failure rehospitalization) of the identified DD-clusters was compared with that by guidelines-based classification. To identify the best combination of variables able to classify patients in one of the identified DD-clusters, classification and regression tree analysis was applied (with DD-clusters as dependent variable and PALS plus guidelines-recommended diastolic variables as explanatory variables). The algorithm was subsequently validated in a prospective cohort of 189 heart failure outpatients (age, 65±13 years). Three distinct echocardiographic DD-clusters were identified (cluster-1, n=212; cluster-2, n=376; cluster-3 DD, n=276), with modest agreement with guidelines-recommended classification (kappa=0.40; P<0.001). DD-clusters were predicted by a simple algorithm including E/A ratio, left atrial volume index, E/e' ratio, and PALS. After 36.5±29.4 months follow-up, 318 events occurred. Compared to guideline-based classification, DD-clusters showed a better association with events in multivariable models (C-index 0.720 versus 0.733, P=0.033; net reclassification improvement 0.166 [95% CI, 0.035-0.276], P=0.013), without interaction with ejection fraction category. In the validation cohort (median follow-up: 18.5 months), cluster-based classification better predicted outcome than guideline-based classification (C-index 0.80 versus 0.78, P=0.093). Integrating PALS by machine learning algorithm in DD classification improves risk stratification over recommended current criteria, regardless of ejection fraction status. This proof of concept study needs further validation of the proposed algorithm to assess generalizability to other populations.

Comparative effect of different physical exercise training on exercise capacity and cardiac function in heart failure with preserved ejection fraction: a network meta-analysis-ExIC-FEp Study.

This network meta-analysis aimed to compare the effect of different types of physical exercise [endurance training, endurance/resistance training, and high-intensity interval training (HIIT)] on exercise capacity and cardiac function parameters in patients with heart failure with preserved ejection fraction. A systematic search of the MEDLINE (via PubMed), Scopus, and Web of Science databases was conducted to identify experimental studies addressing the effect of different physical exercise training programmes on exercise capacity and cardiac function in heart failure with preserved ejection fraction. Comparative evaluation of the effect of exercise training type was performed by conducting a standard pairwise meta-analysis and a network meta-analysis for direct and indirect comparisons between exercise training types and controls/non-interventions. Eleven studies were included in the analysis showing that endurance training improves the main exercise capacity parameters (VO2peak, workload, exercise time, peak heart rate, VO2, and 6 min walk distance). Additionally, endurance/resistance training showed a significant effect on VO2peak, workload, early mitral annulus velocity, and early mitral/mitral annulus velocity ratio. Finally, HIIT showed a significant effect on VO2peak, VO2, and the early mitral/mitral annulus velocity ratio. Our findings support the effect of three different types of physical exercise on exercise capacity, mainly VO2peak. Additionally, endurance/resistance training and HIIT could reverse left ventricular remodelling in patients with heart failure with preserved ejection fraction. PROSPERO: CRD42021276111.

Does the Measurement of Ejection Fraction Still Make Sense in the HFpEF Framework? What Recent Trials Suggest.

Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber's real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy

BackgroundCirculating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. Methods and ResultsHigh-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14–1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. Conclusionshs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

PS-BPC07-4: RENOPROTECTIVE EFFECTS OF SGLT2 INHIBITORS AND RELATED FACTORS IN CHRONIC HEART FAILURE PATIENTS WITH DIABETES

Objective: Large-scale clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on not only cardiovascular and renal outcomes but also the preservation of renal function in patients with diabetes mellitus and/or chronic kidney disease. However, the effect of SGLT2 inhibitors on renal function in heart failure remains to be fully elucidated. The present study investigated whether SGLT2 inhibitors exert renoprotective effects in chronic heart failure patients with diabetes, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after SGLT2 inhibitor administration. In addition, if SGLT2 inhibitors had a favorable effect on renal function, we examined what cardiac/hemodynamic and noncardiac factors were involved in its effect. Design and method: Methods: From 83 outpatients with chronic heart failure and type-2 diabetes mellitus taking both SGLT2 inhibitors and loop diuretics, 50 patients whose eGFR levels were continuously measured for more than 6 months both before and after administration of SGLT2 inhibitors were selected. In this longitudinal observational study, eligible patients were retrospectively followed up before and after SGLT2 inhibitor administration. Clinical data such as body weight, blood pressure, heart rate, blood (hematological and biochemical) parameters, echocardiographic parameters, and medical treatment were collected at respective ends of the follow-up periods before and after SGLT2 inhibitor administration. All eGFR values were separately plotted before and after the initiation of treatment with SGLT2 inhibitors along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. Results: The mean follow-up periods before and after SGLT2 inhibitor administration were 2.6 and 1.9 years, respectively. Changing rates of eGFR per year were significantly improved after treatment with SGLT2 inhibitors (mean ± SD, -5.78 ± 7.67 to -0.43 ± 10.81 mL/min/1.73m2/year, p = 0.006). The daily doses of loop diuretics were not altered after SGLT2 inhibitor administration. Body weight decreased and hematocrit and hemoglobin increased by SGLT2 inhibitor administration, but neither change was not associated with the change in eGFR slope before and after SGLT2 inhibitor administration. While, the decrease in inferior vena cava diameter was significantly correlated with the improvement of eGFR decline slope after SGLT2 inhibitor administration (r = -0.428, p = 0.004). Conclusions: This study demonstrated that long-term treatment with SGLT2 inhibitors ameliorated annual decline in eGFR in Japanese patients with chronic heart failure. The observed renoprotective effect may have been mediated by improved venous congestion.

Impact of Diet on Gut Microbiota Composition and Microbiota-Associated Functions in Heart Failure: A Systematic Review of In Vivo Animal Studies.

Heart failure (HF) represents a cardiovascular disease with high mortality and morbidity. The latest evidence shows that changes in the composition of the gut microbiota might play a pivotal role in the prevention and management of HF. This systematic review aims at assessing the potential associations between the diet, gut microbiota, and derived metabolites with the outcomes of HF. A systematic literature search was performed up to July 2022 on the PubMed, Web of Science, and Scopus databases. The PRISMA guidelines were followed when possible. The risk of bias was assessed with the SYRCLE and ARRIVE tools. A total of nine pre-clinical studies on animal models, with considerable heterogeneity in dietary interventions, were included. High-fiber/prebiotic diets (n = 4) and a diet rich in polyphenols (n = 1) modified the gut microbiota composition and increased microbial metabolites' activities, linked with an improvement in HF outcomes, such as a reduction in systolic blood pressure, cardiac hypertrophy, and left ventricular thickness. A high-fat diet (n = 2) or a diet rich in choline (n = 2) induced an increase in TMAO and indole derivative production associated with a decrease in cardiac function, systemic endotoxemia, and inflammation and an increase in cardiac fibrosis and cardiac remodeling. Although results are retrieved from animal studies, this systematic review shows the key role of the diet-especially a high-fiber and prebiotic diet-on gut microbial metabolites in improving HF outcomes. Further studies on human cohorts are needed to identify personalized therapeutic dietary interventions to improve cardiometabolic health.

1098 CHARACTERIZATION OF DIFFERENT TYPES OF LV REMODELING USING QUANTITATIVE INTRACARDIAC FLUID-DYNAMICS

Abstract Background Hyperdoppler is a novel advanced echocardiographic technique for the quantitative assessment of intracardiac fluid-dynamics. Recently, its use has been proven useful to complement traditional echocardiographic evaluation of cardiac function in Heart Failure. However, no specific data are available on its application to differentiate between different types of LV remodeling. Thus, our aim was to investigate whether quantitative changes in fluid dynamics might be able to characterize patients with different ventricular geometry. Methods We enrolled 100 consecutive patients with one of the following: LV concentric hypertrophy (CH), eccentric hypertrophy (EH), concentric remodeling, normal LV geometry (CTRL). They underwent a complete echocardiographic examination with intracardiac fluid-dynamic analysis by Color Vector Flow Mapping (Hyperdoppler, Esaote, Genova, Italy). The following parameters were obtained: vortex area (VA); vortex length (VL); vortex depth (VD). Bland Altman Plot has been used to assess intra and inter-observer variability. Results Mean Vortex Depth was significantly higher in CR (p=0.011), CH (p=0.001) and EH (p=0.025) compared to CTRL (p=0.013, p=0.001 and p=0.022, respectively). In addition, CH had significantly higher Vortex Length (p= 0.008) and larger VA (p=0.012) compared to CTRL. No significative differences in vortices parameters have been observed between CH and EH. Conclusion(s) Quantitative fluid-dynamic assessment was feasible and reliable in the whole population and is a promising tool to complement standard echocardiography for the early characterization of different types of LV remodeling.

POST – CARDIOTOMY EXTRACORPOREAL LIFE SUPPORT IN OCTOGENARIANS: SINGLE CENTER EXPERIENCE

<h3>Background</h3> Recently extracorporeal membrane oxygenation (ECMO) is becoming the first line treatment option for post-cardiotomy cardiac failure. The age limit for the use of support is yet to be defined. The aim of our study was to evaluate outcomes of octogenarians supported with ECMO following cardiac surgery in our institution. <h3>Methods</h3> Retrospective review of consecutive elderly patients (age ≥ 70 years) supported with ECMO following surgery during 13 years period in a tertiary care center. Patient's demographic variables, comorbidities, pre-existing medical conditions, perioperative data and outcomes were collected from patient medical records. Data of octogenarian patients were compared with the septuagenarian patient group. The primary endpoint of the study was in-hospital mortality. <h3>Results</h3> Sixty patients in our study were ≥ 70 years old and were included in the final analysis as "elderly group". Eleven patients (18,3 %) in the elderly group were octogenarians (aged 80 years or above) and forty nine (81,7 %) were septuagenarians (aged 70 – 79 years). There was no difference except age in all demographic and preoperative variables between groups. In the majority of cases VA ECMO was initiated in the intensive care unit after surgery (n=37, 61,7 %) and 23 cases (38,3 %) were initiated in the operating room. Central cannulation was more common in septuagenarian group than octogenarian group (83,7 % vs 54,5 %, p = 0,034 respectively). The median duration of ECMO support was 148 (71 – 288) hours and was longer in septuagenarian group (178 (92 – 300) hours vs 70 (46 – 93) hours in octogenarian group, p = 0,007). Pre ECMO Save, SOFA, SAPS – II and inotropic scores were significantly higher in septuagenarians than octogenarians. Pre ECMO data are shown in Table 1. Thirty one patient (52 %) were successfully weaned form ECMO and 13 (22 %) patients survived to hospital discharge. There was no statistically significant difference in hospital mortality between groups (7 (64%) octogenarian group vs. 40 (82%) septuagenarian group, p = 0,19). <h3>Conclusion</h3> ECMO could be successfully used in selected octogenarian patients undergoing cardiac surgery to support failing heart function with acceptable survival rate. Further studies needed to evaluate long term outcomes.

InsP3R-RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle.

Dysregulated intracellular Ca2+ handling involving altered Ca2+ release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP3 receptor Ca2+ channels (InsP3R) in pathological alterations in cardiomyocyte Ca2+ handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined. Using electrophysiological and Ca2+ recordings in human ventricular cardiomyocytes, we uncovered that Ca2+ release via InsP3Rs facilitated Ca2+ release from RyR and induced arrhythmogenic delayed after depolarisations and action potentials. InsP3R-RyR crosstalk was particularly increased in HF at RyR clusters isolated from the T-tubular network. Reduced SERCA activity in HF further facilitated the action of InsP3. Nanoscale imaging revealed co-localisation of InsP3Rs with RyRs in the dyad, which was increased in HF, providing a mechanism for augmented Ca2+ channel crosstalk. Notably, arrhythmogenic activity dependent on InsP3Rs was increased in tissue wedges from failing hearts perfused with AngII to promote InsP3 generation. These data indicate a central role for InsP3R-RyR Ca2+ signalling crosstalk in the pro-arrhythmic action of GPCR agonists elevated in HF and the potential for their therapeutic targeting.

Reducing brain TACE activity improves neuroinflammation and cardiac function in heart failure rats.

Tumor necrosis factor (TNF)-α converting enzyme (TACE) is a key metalloprotease mediating ectodomain shedding of a variety of inflammatory mediators, substrates, and growth factors. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to sympathetic excitation in heart failure (HF). Here, we sought to determine whether central interventions in TACE activity attenuate neuroinflammation and improve cardiac function in heart failure. Myocardial infarction-induced HF or sham-operated (SHAM) rats were treated with bilateral paraventricular nucleus microinjection of a TACE siRNA or a 4-week intracerebroventricular (ICV) infusion of the TACE inhibitor TAPI-0. Compared with SHAM rats, scrambled siRNA-treated HF rats had higher TACE levels in the PVN along with increased mRNA levels of TNF-α, TNF-α receptor 1 and cyclooxygenase-2. The protein levels of TNF-α in cerebrospinal fluid and phosphorylated (p-) NF-κB p65 and extracellular signal-regulated protein kinase (ERK)1/2 in the PVN were also elevated in HF rats treated with scrambled siRNA. The expression of these inflammatory mediators and signaling molecules in the PVN of HF rats were significantly attenuated by TACE siRNA. Interestingly, the mRNA level of TNF-α receptor 2 in the PVN was increased in HF treated with TACE siRNA. Moreover, sympathetic excitation, left ventricular end-diastolic pressure, pulmonary congestion, and cardiac hypertrophy and fibrosis were reduced by PVN microinjection of TACE siRNA. A 4-week treatment with intracerebroventricular TAPI-0 had similar effects to ameliorate these variables in HF rats. These data indicate that interventions suppressing TACE activity in the brain mitigate neuroinflammation, sympathetic activation and cardiac dysfunction in HF rats.

Abstract 11262: Effect of Active Cancer/Cachexia on the Development of Cardiac Dysfunction in Mice

Introduction: Cancer is independently associated with the alteration of cardiac function prior to cardiotoxic chemotherapy (CCT) exposure. Similar to cancer associated cachexia (CAC), the elevation and the deleterious role of IL-6 in plasma was associated with a reduced cardiac function in heart failure (HF) patients subpopulation. Cancer cells manipulate BCL-2-associated athanogene 3 (BAG3)-HSP70-regulated pathways in tumor cells, which is a key regulator of protein turnover and contractility in cardiomyocyte. Hypothesis: Here, we aimed to characterize the progression of cardiac dysfunction and the expression of BAG3 and HSP70 in tumor-bearing mice. Methods: Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously adult male BALB/c mice. Control mice were injected with PBS (n=13). Echocardiographic examinations and invasive hemodynamic measurements ( in vivo and ex vivo using isolated working hearts system) were performed at 10 (early) and 20 (late) days post injection, respectively. The expression of BAG3 and Hsp70 were determined by Western blot. Results: The tumor size was comparable between the cancer groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p&lt;0.05, respectively), confirming cachectic condition. Echocardiography results show a tendency to decline of ejection fraction at the early phase (p~0.08 vs Control), and turned significance lower at late stage (p&lt;0.05 vs Control) in tumor-bearing mice. In line with that, invasive hemodynamic and isolated working heart measurements confirmed LV systolic and diastolic dysfunction (late stage, p&lt;0.05 vs Control, respectively). Interestingly, heart rate and aortic flow were predominantly declined in cachectic animals (p&lt;0.05 vs Control). Importantly, cardiac dysfunction was associated with a significant reduction in both BAG3 and Hsp70 in the myocardium independently of cachexia. Conclusions: Cancer rather than CAC is a main driver for the development of cardiac contractile dysfunction prior to CCT exposure. In addition, our data suggest that targeting BAG3-Hsp70 complex in the cardiomyocytes may provide a novel strategy to improve the cancer associated cardiac dysfunction.

Effect of Ivabradine on Left Ventricular Diastolic Function of Patients With Preserved Ejection Fraction - Results of the IVA-PEF Study.

Background: The association between heart rate (HR) reductions caused by ivabradine and left ventricular (LV) diastolic function in heart failure with preserved ejection fraction (HFpEF) remains uncertain because of off-label use. Thus, the present study investigated the effect of HR reductions by ivabradine on LV diastolic function in HFpEF patients.Methods and Results: This study enrolled 16 HFpEF patients with HR ≥75 beats/min. After 3 months administration of ivabradine, no significant changes were observed in mitral inflow E and mitral e’ annular velocities, B-type natriuretic peptide, or left atrial volume index, but there were significant improvements in global longitudinal strain.Conclusions: Ivabradine did not improve LV diastolic function for HFpEF patients with HR ≥75 beats/min. Because this may be due to some study limitations, further studies should be conducted.

Proenkephalin as a novel prognostic marker in heart failure patients: a meta-analysis

Abstract Background Proenkephalin (PENK), a novel biomarker, sequentially activates delta-opioid receptors in heart tissue causing reduced myocardial contractility, blood pressure, and heart rate. PENK has several prognostic abilities for patients with myocardial infarction, stroke, and impaired renal function. However, its prognostic value in heart failure patients is still inconclusive. Purpose To evaluate the association between plasma PENK level at the time of admission and all-cause mortality in patients with heart failure. Methods We collected studies from MEDLINE and EMBASE databases until January 2022 to perform a meta-analysis. High level of PENK is defined as plasma PENK level more than 99th percentile of the general population. Separated pooling hazard ratio (HR) for all-cause mortality among high and normal levels of PENK was performed using a random-effect model, generic inverse variance method of DerSimonian and Laird. Sources of heterogeneity including clinical and methodological variations were explored using a meta regression and subsequent subgroup analysis. Results A total of six observational studies composed of 6,929 patients with either acute heart failure or chronic heart failure were included in this analysis. There are five studies involving heart failure patients with both reduced ejection fraction and preserved ejection fraction and another one concerning those with only preserved ejection fraction. High level of PENK was found in 70.9% of patients. The high level of PENK compared with normal levels was associated with a higher prevalence of all-cause mortality with pooled HRs of 1.72 (95% CI, 1.62–1.84; I2=84%). The analyzed data were shown in the Figure 1. Conclusions This study demonstrates the association between high levels of PENK and all-cause mortality in heart failure patients. These findings suggest that the opioid system might be involved in deteriorating cardiovascular function in heart failure. Funding Acknowledgement Type of funding sources: None.

Global warming, renal function and heart failure: a 20-year follow-up study

Abstract Background There is a growing concern about the possible effects of global warming on human health. In HF outpatients, renal function significantly worsens during summer. More specific analyses on the impact of increasing temperatures on body homeostasis are lacking. Purpose We investigated the relationship between the trend of temperatures from 2002 to 2021 and renal function in heart failure (HF) outpatients. Methods All creatinine and estimated glomerular filtration rate (eGFR) values of HF outpatients followed at one tertiary hospital in a Mediterranean area of Spain were retrieved from electronic health records. eGFR was calculated through the CKD-EPI formula. Temperature data from the local municipality were derived from the Meteocat service; as temperatures from the years 2004–2005 were not available, these years were not analysed. Summer was defined as the timespan from June to September included. We calculated average values of creatinine and eGFR during summer and the rest of the same year, considering each patient and each year. Similarly, we averaged temperature values during summer and the rest of the same year. Results We derived 6,307 couples of average creatinine/eGFR values in summer and in the rest of the year from 2,194 patients. Across all the years (2002–2003 and 2006–2021), creatinine was slightly higher in summer than in the rest of the year (1.26 vs. 1.21 mg/dL, p&amp;lt;0.001), and eGFR was lower (65 vs. 67 mL/min/1.73 m2, p&amp;lt;0.001). Temperatures in summer and the rest of the year increased gradually, albeit not linearly, from 2002 to 2021 (Figure 1). The absolute (Δ) and percent changes (Δ%) in median temperatures between summer and the rest of the year increased across years (r=0.149, p=0.001 and r=0.144, p=0.002, respectively), as well as Δ and Δ% of the monthly median of maximal temperatures (r=0.119, p&amp;lt;0.001 and r=0.052, p&amp;lt;0.001, respectively) (Figure 1). The Δ and Δ% temperatures between summer and the rest of the year displayed several significant correlations with Δ and Δ% creatinine and eGFR after adjusting for several variables including age, sex, HF therapies, and creatinine outside of summer (Figure 2). Conclusions Over a 20-year timespan there has been an increase in 1) temperatures in summer and in the rest of the year, and 2) the temperature excursion between summer and the rest of the year. Changes in temperatures between summer and the rest of the year correlated with the magnitude of the decrease in renal function during summer, likely because of worse dehydration with higher temperatures. Therefore, the progressive rise in temperature may have detrimental effects on renal function during summer in HF outpatients. Funding Acknowledgement Type of funding sources: None.

The relation among myocardial iron load and the severity of heart failure

Abstract Heart failure (HF) symptoms are related to reduced circulatory perfusion, peripheral congestion, also impaired peripheral muscle strength &amp; oxygen utilization due to iron deficiency. Despite many premises, the correlation between myocardial iron load and failing heart function was not proved. The purpose of this study was to assess iron itself and iron-related proteins in human failing (FH) vs non-failing (NFH) myocardium. The study group consisted of 58 explanted FHs vs the control consisted of 31 NFHs unsuitable for transplantation. HF study group presented with LV dilatation (LVDD 67±8 mm; LVSD 59±13 mm), reduced contraction (LVEF 20±7.5%), RV enlargement (RVD 42±6.5 mm), pulmonary hypertension (2.21±0.93 Wu) and elevated NTproBNP (3955.5±2250.5pg/ml). We assessed iron serum markers: ferritin (FR), transferrin/saturation (TSAT), transferrin receptor (soluble sTfR), sTFR/log FR; myocardial iron homeostasis assessment: M-Iron (Instrumental Neutron Activation Analysis, μg/g) and iron gathering proteins (by ELISA): divalent metal transporter (DMT-1); L-type calcium channel (L-CH), TfR-1/TfR-2; ferritins: heavy (FT-H), light (FT-L) chain, mitochondrial (FT-MT); ferroportin (FPN) and oxidative stress marker: 4-hydroxynonenal (4-HNE). In FH vs NFH, M-Iron was reduced (164.6±25.2 vs 182.3±23.9; p=0.0358) however, did not apply to the entire group. Therefore we divvied the FH group into two subgroups (based on M-Iron concentration in NFH controls). Average iron concertation in non-iron-deficient (NIDM) subgroup was 172.5±19.1 (n=35) and in iron-deficient (IDM) subgroup wad 127.0±16.5; (n=23, p=0.0001). Regardless M-Iron load in FH vs NFH myocardial proteins expressions were reduced: L-CH (NIDM vs IDM vs NFH: 49.2±9.2; 42.5±4.2; 67.3±23.0, p=0.0022); FT-L (16.4±7.3; 11.6±4.8; 26.3±7.5, p= &amp;lt;0.0001, respectively); FT-MT (41.2±7.6; 38.7±4.1; 59.3±10.4 p≤0,0001, respectively). With regard to M-Iron load, only in DMT-1 expression was changed (NIDM vs IDM vs NFH 4.8±0.7; 4.0±0.5; 5.8±0.8; p≤0.0001). 4-HNE levels in FH vs NFH were increased, regardless M-Iron load (NIDM-Iron vs IDM-Iron vs NFH; 55.7±29.2; 57.2±47.8; 9.9±8.1 p≤0.0001). Interestingly, the iron load (NIDM-Iron vs IDM-Iron) did not modify the assessed clinical parameters. With regard to commonly used systemic iron markers only sTFR/log FR proved M-Iron load difference (NIDM-Iron vs IDM-Iron 0.6±0.2; 0.7±0.3; p=0.047910) In FH, we observed, the subgroup with the reduced M-Iron load. The observed reduction of iron gathering proteins were independent on M-Iron load, except DMT-1 the main iron transportation protein into the cell. The results showed that the HF degree and concertation of iron proteins are unlikely to be affected by the M-Iron load, except DMT-1 protein. The oxidative stress was also regardless from M-Iron load, and increased in the whole FH group. Commonly used systemic iron markers except sTFR/log FR did not define M-Iron load. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Cardinal Stefan Wyszyński National Institute of Cardiology