Ischemic Chronic Heart Failure Research Articles

P2614Comparison of global longitudinal strain and ejection fraction in correlation to NT-proBNP in ischemic and non-ischemic heart failure

Abstract Background In chronic heart failure (CHF) NT-proBNP and left ventricular ejection fraction (LVEF) by echocardiography are standard diagnostic as well as follow-up markers and are known to correlate with prognosis. Speckle-tracking echocardiography is a more recent technique to quantify myocardial deformation as a measurement of left ventricular function with potential benefits over LVEF. Purpose The purpose of this investigation was to analyse the cross-sectional relationship between 2D speckle tracking-derived global longitudinal strain (GLS) and NT-proBNP plasma levels in a prospective cohort of ischemic and non-ischemic CHF patients. Methods We enrolled 205 patients with chronic heart failure. Major inclusion criteria were age over 18 years, stable disease with absence of unplanned hospitalization or change in medication or device therapy in the previous month or major surgery in the previous 3 months. CHF treatment had to be according to the recommendations of the ESC CHF guidelines 2016 and LVEF had to be below 50%. Patient history, physical examination and an extensive echocardiography exam were performed. Lab results included NT-proBNP. Manual longitudinal strain was calculated using EchoPAC (General Electric Medical Systems, Horten, Norway) by a single and blinded examiner. LVEF was measured using Simpson's biplane method. Results 205 patients included in the study. The baseline characteristics included mean age 65.0 years and 75% male. Mean GLS was −9.6% (SD ±4.5%) and median NT-proBNP 1269.5 (IQR 379.5–2759.5) ng/ml. The CHF aetiology was 70.0% ischemic vs 30.0% non-ischemic. There was a significant negative correlation between GLS and NT-proBNP (Pearson r=0.239, p=0.029), this was not significant for LVEF and NT-proBNP (Pearson r=0.149, p=0.228).In a multivariate regression analysis adjusted for age, sex, NYHA classification and HF aetiology, GLS remained significantly correlated with NT-proBNP (adjusted beta-coefficient= 0.289, p=0.011). Furthermore, in contrast to LVEF, GLS showed a significant correlation to NT-proBNP in patients with ischemic (Pearson r=0.266, p=0.049) as well as non-ischemic aetiology of heart failure (Pearson r=0.434, p=0.034). Conclusion Global longitudinal strain, not LVEF, was significantly correlated with NT-proBNP in patients with CHF, independently of age, sex, symptoms or heart failure aetiology. This shows that speckle-tracking might be superior to LVEF for the assessment of left ventricular function in CHF.

P774Transcoronary transfer of Wharton's jelly mesenchymal pluripotent stem cells in patients with chronic ischaemic heart failure shows safety and unprecedented high-grade myocardial uptake

Abstract Background Chronic ischaemic heart failure (CIHF) remains an important health problem on the patient/family- and society level. In animal models, Wharton's jelly (umbilical cord matrix) multipotent stem cells (WJMSCs) effectively promote angiogenesis, can differentiate to cardiomyocytes, and drive functional myocardial regeneration. Effective uptake of regenerative cells in ischaemic-impaired tissue is fundamental for any therapeutic effect. Purpose To evaluate safety and myocardial uptake of WJMSCs transcoronary transfer in CIHF applied as a novel myocardial regeneration strategy employing allogenic yet hypo-immunogenic, off-the-shelf “unlimited” source of therapeutic cells (NCT03418233 pilot cohort). Material and methods In ten consecutive patients (age 62.6±2.5), with stable CIHF and no current need for revascularization (LVEF 29.3±3% by echo and 26.3±6% by SPECT; NT-proBNP 1746±329pg/mL; myocardial scar tissue 39.9±3.9% by SPECT) and patency of at least two major native coronary arteries or by-pass graft(s), the CardioCell Investigational Medical Product, based on 30x106 WJMSCs, was administered to viable yet hypokinetic segments using a novel algorithm including a dedicated catheter for transcoronary delivery of cellular therapies. The cells were labeled with 99mTc-extametazime to routinely evaluate their myocardial uptake magnitude. Results No symptoms or signs of novel myocardial ischaemia occurred with cell delivery and no patient showed any adverse periprocedural events. One hour after administration, myocardial WJMSCs uptake (SPECT) was 40.3±6%; see Fig for a typical raw data image. By 6 months there were no adverse events in the study cohort. Figure 1 Conclusions This work indicates safety and unprecedented high-grade myocardial uptake of WJMSCs in CIHF patients. Together with animal data, this provides basis for continued assessment of this strategy in an endpoint-powered randomized controlled clinical trial employing CardioCell as an “unlimited” off-the-shelf cellular therapy strategy. Acknowledgement/Funding K/ZDS/005644 and 265761 (National Centre for Research and Development STRATEGMED)

Cardiorenal syndrome in patients with rheumatoid arthritis

In 2008, the term cardiorenal syndrome (CRS) was proposed by the Acute Dialysis Quality Initiative (ADQI) Group to denote pathological reciprocal conditions involving the heart and kidneys, which develop due to acute or chronic dysfunction of one of the organs, followed by acute or chronic dysfunction of the other one. The problem of CRS in patients with rheumatoid arthritis (RA) has not been studied. Of the greatest interest is CRS type 5 or secondary CRS that occurs in patients with systemic diseases, including in those with RA. Currently, there is no doubt that the risk of developing cardiovascular diseases in RA patients and the prevalence of non-ischemic and ischemic chronic heart failure (CHF) are higher than those in the general population. There is evidence that the prevalence of chronic kidney disease (CKD) and renal pathology-associated cardiovascular risk factors (RF) is high in patients with RA. In addition to traditional RFs for cardiovascular and kidney diseases, autoimmune inflammation is an independent predictor for CHF and CKD. The characteristics of CRS in RA should be investigated to develop an effective treatment strategy for this category of patients.

Positive effect of if-channel’s blocker ivabradine therapy in a patient with ischemic chronic heart failure with preserved left ventricle ejection fraction and hereditary thrombophilia (clinical case)

Chronic heart failure is one of the leading causes of mortality among patients with cardiovascular diseases. Current therapeutic methods for treating patients with chronic heart failure do not always provide a significant improvement in main intermediate and final outcomes. According to the neurohumoral theory of chronic heart failure development, an antagonism of the sympathoadrenal system with b-blockers is pathogenetically substantiated, and the drugs of this group are one of the first-line treatment for chronic heart failure. The selection of heart rate-reducing therapy in patients with chronic heart failure caused by ischemia, can often be difficult due to development of b-blockers side effects, b-blockers intolerance and/or due to the presence of contraindications at severe comorbid pathology. This article presents a clinical case of an effective administration of ivabradine, a drug of if-channel inhibitors group, in combination with b-blockers to a patient with chronic heart failure with a preserved ejection fraction.

A network pharmacology approach to discover action mechanisms of Yangxinshi Tablet for improving energy metabolism in chronic ischemic heart failure.

Most cardiovascular diseases ultimately result in heart failure, an intractable problem in modern medicine. Yangxinshi tablet (YXS) is a Chinese medicine formula that is used clinically to treat coronary heart disease. However, the active compounds, potential targets, and pharmacological and molecular mechanism of its anti-heart failure activity remain unclear. Therefore, further investigation is required. Active ingredients and potential targets of YXS for treating heart failure have been reported previously. However, the molecular functions or biological processes of YXS in energy metabolism have not been discovered. To date, no experimental study to validate the potential anti-heart failure mechanism of YXS. The aim of this study was to study the therapeutic effect of YXS on rats with chronic ischemic heart failure by evaluating rat cardiac function and exercise tolerance, and to explore its potential mechanism by network pharmacology, western blotting, quantitative RT-PCR and histological analysis. In this investigation, chronic ischemic heart failure rats were randomly assigned to five groups: control group (sham operation), model group (0.5% CMC-Na), trimetazidine group (positive control) and two YXS groups (low- and high-dose groups). Experimental rats were treated by gavage with 10 mg/kg/d (clinical equivalent dose) trimetazidine (TMZ), 500 mg/kg/d (clinical equivalent dose) YXS and 1000 mg/kg/d YXS, respectively, for 5 weeks. The cardiac functions of rats were detected by High-Resolution In Vivo Imaging System. We elucidated novel understanding of the active compounds of YXS in rat plasma and predicted the energy metabolism related targets and processes for heart failure. Then, we validated experimentally the targets and mechanism of YXS on these pathological processes in vivo. It was found that YXS was able to effectively improve cardiac LVIDs, LVEDV, LVESV and EF, decrease myocardial oxygen consumption and reduce myocardial infarct size in rats with chronic ischemic heart failure was similar to that of TMZ. We identified 63 major candidate targets for YXS that are closely to heart failure progression. Enrichment analysis revealed key targets for YXS associated to oxygen delivery, glucose utilization, and mitochondrial biogenesis. Meanwhile, we validated that YXS could promote the expression of downstream HIF-1α, PGC1α and GLUT4 by increasing phosphorylation of PI3K, Akt, mTOR, rpS6 and AMPK. The results show that YXS could activate related PI3K/Akt/mTOR/rpS6/HIF-1α and AMPK/PGC1α/GLUT4 signaling pathways in chronic ischemic heart failure rats. Further experiments demonstrated that YXS increased mitochondrial biogenesis in chronic ischemic heart failure rats and improved exercise tolerance CONCLUSION: YXS treated chronic ischemic heart failure through activating its targets which play pivotal roles in oxygen delivery, glucose utilization and mitochondrial biogenesis to improve energy metabolism through a multi-component, multi-level, multi-target, multi-pathway and multi-mechanism approaches.

Characteristics of chronic ischemic heart failure clinical course against the background of anemic syndrome according to retrospective analysis

Objective. To study the anemia relative frequency in hospitalized patients with chronic ischemic heart failure (CIHF), to assess its impact on the clinical course of the disease, to identify the frequency of risk factors and comorbid background that are associated with the presence of anemia.Material and methods. A retrospective analysis of 986 medical charts of inpatients with CIHF, who underwent inpatient treatment during the period from January 2016 to March 2019, has been carried out. The median age of the patients is 76 (53; 94) years. General clinical data, the results of laboratory and instrumental research methods have been evaluated. The statistical processing of the results has been performed using the software package “Statistica 13.0” according to modern requirements.Results. Among patients with CIHF, concomitant anemic syndrome occurred in 10.75% of cases, among which 57% were the ones with mild and moderate iron deficiency anemia. The distribution of patients with iron deficiency by the stage and functional class (FC) of CIHF has revealed that the majority of patients had CIHF stage IIA, FC II-III. More than half of the patients had a reduced left ventricular ejection fraction (LVEF). The severity of anemia affected the development of systolic dysfunction of the left ventricle, which was confirmed by the direct correlations of moderate strength between LVEF and hemoglobin and serum iron levels (rs = 0,51, rs = 0,36, respectively; p <0,05). The presence of concomitant iron deficiency in patients with CIHF increased verifiably the incidence of extrasystole ventriculaire almost by 1,4 times, atrial fibrillation by 1,6 times. Conclusion. The increase in the relative frequency of anemic syndrome among patients with CIHF is observed, while mild-to-moderate iron deficiency anemia is prevailing in its structure. Among patients with iron deficiency anemia, CHF IIA stage FC III with reduced LVEF prevails. A decrease in hemoglobin and serum iron levels is associated with a decrease in LVEF. Concomitant iron deficiency increases verifiably the incidence of arrhythmic disorders in patients with CHF.

Abstract 796: Dysfunctional Immune Cell Clock Contributes to Heart Failure Progression

Objective: Inappropriately sustained activation of monocytes/macrophages contributes to heart failure (HF) progression. Time-of-day greatly influences cardiovascular and immune systems, in part through cell autonomous circadian clocks. Here, we propose that disruption of monocyte/macrophage circadian clocks contributes to pathologic inflammation and HF progression following myocardial infarction (MI). Methods: MI-induced HF was achieved by permanent ligation of coronary artery in myeloid-specific Bmal1 knockout (MBK) mice and wild-type (WT) mice. Left ventricular (LV) function was assessed echocardiography. Flow cytometry was utilized for immune cell profiling. RNAseq and qRT-PCR was utilized for gene-expression studies. Tissue fibrosis was quantified using Masson-trichrome staining. Results: WT (C57Bl/6) HF mice exhibited altered Ly6C hi monocyte circadian clock gene expression as compared with sham-operated mice, with significantly reduced expression of the key clock effector Bmal1 . Genetic disruption of the monocyte clock in MBK mice had no effect on macrophage inflammatory markers during unstressed, baseline conditions. However, MBK-HF mice (4 w post-MI) exhibited increased infiltrating CCR2 + heart macrophages (2642±803 vs. 937±190 per heart, p<0.05), augmented cardiac fibrosis (22±1 vs. 14±3 %, p<0.05), greater LV dysfunction [ejection fraction 19.7±2 vs. 28.4±4 %, p<0.05), increased LV end-diastolic and end-systolic volume (EDV 140.4±10 vs. 100±8 μl, p<0.01; ESV 115±10 vs. 74±9 μl, p<0.01) and cardiac hypertrophy (heart weight/tibia length 12.1±0.6 vs. 10.5±0.4 mg/mm, p<0.05) as compared with WT HF littermate control mice. Moreover, circulating monocyte levels in MBK-HF mice were significantly increased at zeitgeber time 6 versus WT HF littermate controls (296±58 vs. 131±17 cells/μl, p<0.05). Conclusion/Broader Impact: Monocyte/macrophage circadian gene dysregulation resulting from Bmal1 loss-of-function exacerbates pathological LV remodeling, systemic and cardiac inflammation, and tissue fibrosis in chronic ischemic HF. Restoration of circadian clock function in innate immune cells may represent a potential therapeutic approach to immunomodulation in chronic HF.

Abstract 500: Progression of Chronic Ischemia-Mediated Arrhythmogenesis in a Rat Model of Heart Failure

Background: Worldwide, the prevalence of heart failure (HF) is increasing and HF patients are living longer. Chronic ischemic HF presents with increased vulnerability to ventricular tachycardia and fibrillation. However, the mechanism of these arrhythmias differ between the acute infarction phase and the chronic, namely via myocyte membrane potential instability in the acute phase versus substrate-mediated reentry in the chronic phase. We propose our chronic heart failure (CHF) model to recapitulate the potentially progressive nature of arrhythmogenesis in the chronic phase. Methods: Adult male Sprague Dawley rats underwent permanent left coronary artery ligation and were maintained for six or ten weeks; SHAM operations were also performed. At each respective endpoint, SHAM and CHF rats underwent transthoracic echocardiography and invasive hemodynamic evaluation. Finally, a median sternotomy was performed for epicardial electrophysiology (EP) assessment. Programmed electrical stimulation was utilized to assess susceptibility to induced ventricular tachycardia (VT) and also to determine effective refractory period (ERP). Results: Six-week CHF (n=50) induction proved successful as evidenced by the decrease in left ventricular ejection fraction (LVEF) (76±3% to 35±2%, p<0.0001) and the increase in left ventricular end-diastolic pressure (LVEDP) (6±1 mmHg to 20±2 mmHg, p=0.0008) compared to SHAM (n=15). Progression to ten-week CHF (n=18) also proved successful via LVEF and LVEDP maintenance (35±2% to 38±3%, p=0.3909) (20±2 mmHg to 15±3 mmHg, p=0.1578). EP studies revealed an increase in the incidence of induced VT between SHAM and six-week CHF (0% to 60%, p<0.0001) and a prolongation of the ERP (54±4 milliseconds to 69±3 ms, p=0.0228). The incidence of induced VT and ERP did not continue to increase between six- and ten-week CHF (60% to 50%, p=0.5804), (69±3 ms to 68±3 ms, p=0.8221). Conclusion: Myocardial infarction-mediated arrhythmogenesis is known to exist in an acute and a chronic phase. Here, we examine the chronic phase of ischemic HF and show evidence to support that once the adverse remodeling-mediated substrate stabilizes, proarrhythmic deterioration ceases.

THE ASSOCIATION OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL WITH CHRONIC ISCHEMIC HEART FAILURE

Cardiovascular diseases (CVD) are one of the leading causes of death. Beside established risk factors, clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of CVD. CHIP is defined as the expansion of a blood cell clone by somatic mutations in individuals without hematologic diseases. Our studies focused on the questions, whether there is a different disease progression in chronic ischemic heart failure (CHF) patients with CHIP and what the consequences on blood cell lineages and hematopoietic stem and progenitor cells (HSPC) are. Therefore, we investigated a clinically well-characterized cohort of CHF patients and correlated disease progression with CHIP-mutations and investigated alterations of peripheral blood (PB) and bone marrow (BM) cells. The most recurrent mutations occurred in DNMT3A and TET2, which both epigenetically control gene expression and regulate inflammation. We demonstrated a significant association of poor prognosis in CHF and CHIP-mutations in these genes. They may causally contribute to disease progression since there was a striking dose-response between the variant allele fraction and clinical outcome. By analyzing PB and BM in CHF patients, we detected an increase of HSPCs and BM leukocyte numbers without a bias in the distribution of leukocyte lineages in the BM of CHIP carriers. In patients harboring TET2 mutations. Surprisingly, we did not determine any alterations in HSPCs in patients with a DNMT3A mutation, which contrasts the results in knock-out mouse models, showing an increased stem cell self-renewal. Whether non-mutated HSPCs are also affected in individuals with TET2 mutations in a paracrine, cell-extrinsic fashion, caused by an inflammatory milieu due to altered cytokine production, requires further investigation.

Effect of long-term remote ischemic conditioning on inflammation and cardiac remodeling

Background. Remote ischemic conditioning (RIC) protects against acute ischemia-reperfusion injury and may have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischemic heart failure (CIHF). Methods. Prespecified post-hoc analysis of a prospective, exploratory and outcome-assessor blinded study. Twenty-one patients with compensated CIHF and 21 matched controls without heart failure or ischemic heart disease were treated with RIC once daily for 28 ± 4 days. RIC was conducted as 4 cycles of 5 minutes upper arm ischemia followed by 5 minutes of reperfusion. We evaluated circulating markers of inflammation and cardiac remodeling at baseline and following long-term RIC. Results. RIC reduced C-reactive protein from 1.5 (0.6–2.5) to 1.3 (0.6–2.1) mg/l following long-term RIC treatment (p = .02) and calprotectin from 477 (95% CI 380 to 600) to 434 (95% CI 354 to 533) ng/ml (p = .03) in patients with CIHF, but not in matched controls. Overall, RIC did not affect circulating markers related to adaptive or innate immunology or cardiac remodeling in patients with CIHF. Among patients with CIHF and N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels above the geometric mean of 372 ng/l, long-term RIC treatment reduced soluble ST2 (n = 9) from 22.0 ± 3.7 to 20.3 ± 3.9 ng/ml following long-term RIC treatment (p = .01). Conclusion. Our findings suggest that long-term RIC treatment has mild anti-inflammatory effects in patients with compensated CIHF and anti-remodeling effects in those with increased NT-proBNP levels. This should be further investigated in a randomized sham-controlled trial.

T-cell recruitment to the heart: friendly guests or unwelcome visitors?

Myocardial inflammation can lead to lethal acute or chronic heart failure (HF). T lymphocytes (T cells), have been reported in the inflamed heart in different etiologies of HF, and more recent studies support that different T-cell subsets play distinct roles in the heart depending on the inflammation-triggering event. T cells follow sequential steps to extravasate into tissues, but their specific recruitment to the heart is determined by several factors. These include differences in T-cell responsiveness to specific chemokines in the heart environment, as well as differences in the expression of adhesion molecules in response to distinct stimuli, which regulate T-cell recruitment to the heart and have consequences in cardiac remodeling and function. This review focuses on recent advances in our understanding of the role T cells play in the heart, including its critical role for host defense to virus and myocardial healing postischemia, and its pathogenic role in chronic ischemic and nonischemic HF. We discuss a variety of mechanisms that contribute to the inflammatory damage to the heart, as well as regulatory mechanisms that limit the magnitude of T-cell-mediated inflammation. We also highlight areas in which further research is needed to understand the role T cells play in the heart and distinguish the findings reported in experimental animal models and how they may translate to clinical observations in the human heart.

SUN-066 Circulating Irisin and Correlation with Antioxidant Systems in Different Models of Heart Failure

Irisin is a recently discovered myokine, derived from a proteolytic cleavage of the transmembrane protein Fibronectin type III-domain containing 5 (FNDC5), whose expression is induced by physical exercise. This myokine is involved in the browning of white adipose tissue, enhancing energy expenditure, granting a protection against insulin-resistance. Moreover, irisin has been considered a prognostic factor in Chronic Ischemic Cardiomyopathy and Acute Heart Failure. Nevertheless, no data are available on irisin levels in Chronic Heart Failure (CHF), both with preserved (HFpEF) or reduced (HFrEF) ejection fraction. We have evaluated circulating irisin levels, in these two subtypes of Heart Failure (HFpEF: n=22, age range 59-88 ys, mean±SEM BMI 28.9±1.3 kg/m2, NYHA class 2-3; HFrEF: n=18, age range 42-88 ys, mean±SEM BMI 27.8±1.28 kg/m2, NYHA class 2-3) and correlated them with echocardiographic features, metabolic parameters (HOMA-index) and Total Antioxidant Capacity (TAC), measured by spectrophotometric method, using the system H2O2-metmyoglobin, and expressed as LAG, latency time before the appearance of the radical species of the chromogen ABTS. Irisin was significantly higher in HFpEF patients (mean±SEM: 7.72±0.65 ng/ml vs 2.77±0.77 ng/ml), while TAC was higher in HFpEF, but not significantly (77.6±7.3 sec vs 69.6±4.5 sec). An inverse correlation between irisin and TAC was found in the same group (p<0.05). mean±SEM HOMA-index was 2.8±0.54 in HFpEF and 2.4±0.42 HFrEF; no correlation between irisin and HOMA was detected. No correlation between echocardiographic parameters and irisin was found both in HFpEF and HFrEF group. These data may suggest a different pathophysiological mechanism in these two subtypes of CHF, and a possible role of Oxidative Stress in modulation of irisin levels.

Influence of beta-blockers on mechanical dyssynchrony and cardiac remodeling in patients with ischemic chronic heart failure in the setting of revascularization

Introduction: Diastolic dysfunction (DD) and cardiac dyssynchrony (DS) are involved in the progression of chronic heart failure (CHF). A comparative analysis was conducted of the effect of a 6-month course of nebivolol and bisopr­olol on DD, DS and metalloproteinase-9 (MMP-9) level in patients with ischemic chronic heart failure with preserved ejection fraction (HFpEF) and with midrange ejection fraction (HFmrEF), as well as in patients with comorbid type 2 diabetes mellitus (T2DM) in the setting of coronary artery bypass grafting (CABG) after 6 months of therapy.&#x0D; Materials and methods: The study included 308 patients with CHF FC I-II, left ventricular ejection fraction (LVEF) &gt;40%, who had undergone CABG. The average dose of nebivolol in patients with DS 6 months later was 5.1±2.6 mg/day, and bisoprolol – 4.9±2.4 mg/day. Echocardiography (EchoCG) and evaluation of MMP-9 in blood plasma were performed. Mechanical myocardial asynchrony was determined by calculating the standard deviation of time to peak systolic myocardial velocity (TS-SD) and maximum segment delay (TS12) using a 6-basal and-midsegment model.&#x0D; Results and discussion: MMP-9 level in patients with CHF before CABG was 4.7 times higher (p&lt;0.001). MMP-9 correlated with LVEF (r=-0.60, p&lt;0.001), E/A (r=-0.49, p&lt;0.001), DT (r=0.43, p&lt;0.001), E` (r=-0.58, p&lt;0.001) and DS: TS12 (r=0.54, p&lt;0.001), TS-SD (r=0.49, p&lt;0.001). The six-month course of nebivolol improved the values of DS: TS12 – by 30% (p&lt;0.001), TS-SD – by 32% (p&lt;0.01) and reduced the MMP-9 level by 11% (p&lt;0.001). In patients with HFmrEF without DS nebivolol increased E/A by 19% (p&lt;0.01), E` – by 16% (P&lt;0.05), and decreased E/E’ by 9% (p&lt;0.05), DT – by 12% (p&lt;0.05). In patients with HFpEF and DM2, nebivolol reduced TS12 by 37% (p&lt;0.01), TS-SD – by 29% (p&lt;0.05) and MMP-9 – by 13% (p&lt;0.05).&#x0D; Conclusion: The positive effect of nebivolol on the DS, DD of the LV in patients with HFpEF, HFmrEF and with comorbid type 2 diabetes mellitus. The six-month course of nebivolol decreased the MMP-9 level in patients with ischemic CHF after CABG, including patients with T2DM.

Cause-specific mortality in osteoarthritis of peripheral joints

To estimate cause-specific mortality in osteoarthritis patients compared to the general population. We identified all residents in southern Sweden aged 45-84 years in 2003. Through the Skåne Healthcare Register (SHR) we identified those diagnosed with osteoarthritis in peripheral joints between 1998 and 2003. We followed all residents from 2004 until relocation outside of the region, death, or end of 2014. We classified the underlying cause of death from death certificates into: cardiovascular and neoplasms, diabetes, infections, dementia, diseases of digestive system, or other causes. For estimation, we used multi-state adjusted Cox proportional hazards models. We identified 15,901 patients (mean age [SD] 67 years [10], 41% men) with prevalent doctor-diagnosed osteoarthritis in knee, 9347 in hip, 4004 in hand and 5447 in other peripheral joints among 469,177 residents. For most causes of death in osteoarthritis patients, we found no increased mortality, with hazard ratios (HRs) close to 1, similar for men and women. However, for knee and hip osteoarthritis and cardiovascular death, HRs were non proportional and increased to 1.19 (95%CI 1.10, 1.28) and 1.13 (1.03, 1.24) during 9-11 years of follow-up, mostly due to excess mortality from chronic ischemic heart diseases and heart failure. The risk of cardiovascular excess deaths increases with duration of knee and hip osteoarthritis. The major contributors are chronic ischemic heart diseases and heart failure. Our results call for improved implementation of osteoarthritis treatment guidelines, with major focus on interventions to address mobility limitations and maintaining or increase physical activity level.

Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy.

Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and they promote immune activation and left ventricular (LV) remodeling. Adult male wild-type C57BL/6 mice, Foxp3-diphtheria toxin receptor transgenic mice, and tumor necrosis factor (TNF) α receptor-1 (TNFR1)-/- mice underwent nonreperfused myocardial infarction to induce HF or sham operation. LV remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays. Compared with wild-type sham mice, CD4+Foxp3+ Tregs in wild-type HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after myocardial infarction, beyond the early phase of wound healing, and exhibited proinflammatory T helper 1-type features with interferon-γ, TNFα, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated antiangiogenic and profibrotic properties. Selective Treg ablation in Foxp3-diphtheria toxin receptor mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T cells and systemic inflammation and enhancing tissue neovascularization. Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a C-C chemokine ligand 5/C-C chemokine receptor 5-dependent manner. Anti-CD25-mediated Treg depletion in wild-type mice imparted similar benefits on LV remodeling, circulating angiogenic cells, and tissue neovascularization. Proinflammatory and antiangiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

BackgroundIt has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia.Methods and resultsThis multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3‑month and P = 0.15 at 12-month follow-up).ConclusionIntramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia.Clinical Trial Registration: NTR2516Electronic supplementary materialThe online version of this article (10.1007/s12471-018-1213-2) contains supplementary material, which is available to authorized users.

Complex Sleep Apnea

The term complex sleep apnea syndrome (Comp-SAS) refers to a specific variant of respiratory impairment during sleep characterized by the appearance or significant increases in the number of episodes of central apnea and hypopnea after starting CPAP therapy for obstructive sleep apnea syndrome (OSAS). The mechanisms producing Comp-SAS are not fully understood. It is possible that respiration with positive pressure and elimination of pharyngeal obstruction in some patients lead to increases in pulmonary ventilation and decreases in PaCO2 to below the individual threshold required for stimulating respiration. The prevalence of Comp-SAS is 5–20% of patients with OSAS receiving CPAP therapy. Significant clinical predictors for Comp-SAS have not been established, though this respiratory disorder is known to occur more frequently in male patients, older patients, those with severe OSAS, and those with cardiovascular diseases such as ischemic heart diseases, atrial fibrillation, or chronic heart failure (CHF). In most cases, Comp-SAS settles spontaneously after 1–2 months of regular CPAP therapy. If positive pressure treatment has no effect, other contemporary treatment methods can be used, such as adaptive servo ventilation or BPAP treatment with controlled respiratory frequency, though these are contraindicated in systolic heart failure. The question of whether treatment of patients with Comp-SAS is obligatory when the course of illness is straightforward and symptom-free remains open.

STRATIFICATION OF NEPHROCEREBRAL AND CARDIOVASCULAR RISK IN CHRONIC GLOMERULONEPHRITIS (LITERATURE REVIEW)

This article analyzes the literature data concerning the origin and progression of cerebrovascular and cardiac diseases in renal dysfunction. Cardiovascular diseases and chronic kidney disease have common “traditional” risk factors, while the population growth in patients with renal impairment is currently mainly due to secondary renal damage in socially important diseases such as obesity, hypertension, atherosclerosis, type 2 diabetes, ischemic heart disease and chronic heart failure. The presented data of scientific researches testify to the direct correlation correlation between the decrease of the renal function and the increased risk of cardioand cerebrovascular diseases and death, irrespective of other risk factors. Obesity and associated biological substrates are independent risk factors for persistent impairment of kidney function and an increase in the body mass index causes direct damage to the kidneys, due to the disrupted synthesis of fat cytokines by various cytokines with nephrotoxic action, and also mediated — by inducing the development of diabetes mellitus 2 type and arterial hypertension, which are the most frequent risk factors for chronic kidney disease and cardiovascular diseases. The presented data on the role of endothelial dysfunction in impaired renal function, which contributes to the formation of atherosclerosis, and the increase in the severity of the atherosclerotic process contributes to an increase in the sever ity of renal failure. Literature data on the value of the heart rate are also presented. The increase in the heart rate can lead to atherosclerotic densification of the arteries, which is associated with an increase in the rate of spread of the pulse wave with a violation of the mechanisms of autoregulation of the blood flow in the brain and kidneys.

Abstract 16945: Identification of Peripheral Blood Mononuclear Cell Subpopulations in Chronic Left Ventricular Dysfunction Patients With Improved Functional Outcomes: A Biorepository Evaluation From the CCTRN FOCUS Trial

Background: Although cell therapy could potentially slow or reverse progression of chronic ischemic heart failure (HF), clinical trials of bone marrow-derived mononuclear cells (BM-MNC) have met with minimal success. It is unknown why some patients improve (i.e. improvers) and others do not (i.e. non-improvers). B cell numbers, in fact, have been associated with improvement after acute myocardial infarction (MI). We hypothesized that improvers have a higher percentage of B cells in peripheral blood (PB) vs. non-improvers after study treatment. Methods: We used flow cytometry to evaluate temporal changes in the frequency of PB subpopulations after BM-MNC or placebo therapy in HF patients enrolled in the FOCUS-CCTRN trial. PB was collected at day 0 (baseline) and days 1, 30, 90, and 180 from consented participants. Cohort 1 (n=17) patients, who improved in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (ESV), and maximal oxygen consumption (VO 2 max) during the 6-month course, were compared to patients who declined in the above three outcomes, cohort 2 (n=11). Linear mixed model was used to determine the changes over time in each cell population. The difference between each time point to day 0 was calculated as linear contrast. Results: Cohort 1 had a higher frequency of B cells (CD45+CD19+) at day 0 (15.24±7.55 vs. 8.95±3.49, p=0.002), day 1 (14.67±5.53 vs. 8.78±4.51, p=0.003), day 90 (14.98±6.64 vs. 8.49±4.33, p=0.006) and day 180 (13.44±7.85 vs. 8.07±4.34, p=0.033) and regulatory B cells (CD19+CD11B+) at day 0 (2.06±1.20 vs. 1.09±0.58, p=0.011) and day 90 (2.49±1.50 vs. 1.32±0.62, p=0.016) when compared to cohort 2. Both cohorts had an increase in CD11B+ at day 1 when compared to baseline (91.53±3.43 vs. 93.09±3.69, p=0.020) (92.01±3.63 vs. 94.60±8.70, p=0.005), which remained higher in cohort 2 until day 30 (92.01±3.63 vs. 93.92±1.91, p=0.020). Conclusion: A higher frequency of B cells and subsets was observed in PB of patients who improved independent of treatment. These data support prior findings of the importance of B cells in recovery after MI and suggest an important relationship between the humoral immune system and HF.

CABG in patients with left ventricular dysfunction: indications, techniques and outcomes.

Ischemic chronic heart failure (CHF) represents one of the cardiovascular diseases with the worst degree of morbidity and mortality in the western world, and with the highest health care costs. Despite several studies demonstrated that surgical revascularization (CABG), especially in the presence of viable myocardium, improve heart function, and therefore, survival, the matter remains unclear and controversial. In the late 1970s, the Coronary Artery Surgery Study showed that a subgroup of patients with coronary artery disease, angina, and reduce LV function had a significant survival benefit after CABG compared to those treated medically. The key concept behind this observation was the presence of viable myocardium, which can resume function following revascularization. In contrary, the surgical treatment for ischemic heart failure (STICH) trial, which randomized patients with CAD and LV dysfunction to evidence-based medical therapy or CABG plus medical therapy, failed to demonstrate at a median follow-up of 56months a significant difference between the CABG group and the medical therapy group in the rate of death from any cause. However, the results of the STICH extension study (STICHES) at 10years follow-up demonstrated that CABG is associated with a significant reduction in all-cause mortality, cardiovascular mortality, and readmission for heart compared to optimal medical therapy (OMT) in patients with severe ischemic LV dysfunction. Therefore, this review discusses the available evidences in literature, from observational studies to randomized trials, including operative techniques and controversial issues, in order to better clarify the role of CABG in the current management of ischemic patients with LVD.