Dysfunction In Chronic Heart Failure Research Articles

Right ventricular dysfunction in chronic heart failure: clinical laboratory and echocardiographic characteristics. (the RIVED-CHF registry).

Right ventricular dysfunction (RVD) and pulmonary hypertension have been recognized as two important prognostic features in patients with left side heart failure. Current literature does not distinguish between right heart failure (RHF) and RVD, and the two terms are used indiscriminately to describe pulmonary hypertension and RVD as well as clinical sign of RHF. Therefore, the right ventricle (RV) adaptation across the whole spectrum of left ventricular ejection fraction (LVEF) values has been poorly investigated. This is a multicenter observational prospective study endorsed by the Italian Society of Cardiology aiming to analyze the concordance between the signs and symptoms of RHF and echocardiographic features of RVD. The protocol will assess patients affected by chronic heart failure in stable condition regardless of the LVEF threshold by clinical, laboratory, and detailed echocardiographic study. During the follow-up period, patients will be observed by direct check-up visit and/or virtual visits every 6 months for a mean period of 3 years. All clinical laboratory and echocardiographic data will be recorded in a web platform system accessible for all centers included in the study. The main study goals are: to investigate the concordance and discordance between clinical signs of RHF and RVD measured by ultrasonographic examination; to evaluate prognostic impact (in terms of cardiovascular mortality and heart failure hospitalization) of RVD and RHF during a mean follow-up period of 3 years; to investigate the prevalence of different right ventricular maladaptation (isolated right ventricular dilatation, isolated pulmonary hypertension, combined pattern) and the related prognostic impact. With this protocol, we would investigate the three main RVD patterns according to heart failure types and stages; we would clarify different RVD and pulmonary hypertension severity according to the heart failure types. Additionally, by a serial multiparametric analysis of RV, we would provide a better definition of RVD stage and how much is it related with clinical signs of RHF (ClinicalTrials.gov Identifier: NCT06002321).

Chymase-independent vascular Ang-(1–12)/Ang II pathway and TXA2 generation are involved in endothelial dysfunction in the murine model of heart failure

The angiotensin (Ang)-(1–12)/Ang II pathway contributes to cardiac pathology. However, its involvement in the development of peripheral endothelial dysfunction associated with heart failure (HF) remains unknown. Therefore, this study aimed to characterise the effect of exogenous Ang-(1–12) and its conversion to Ang II on endothelial function using the murine model of HF (Tgαq*44 mice), focusing on the role of chymase and vascular-derived thromboxane A2 (TXA2).Ex vivo myographic assessments of isolated aorta showed impaired endothelium-dependent vasodilation in late-stage HF in 12-month-old Tgαq*44 mice. However, endothelium-dependent vasodilation was fully preserved in the early stage of HF in 4-month-old Tgαq*44 mice and 4- and 12-month-old FVB control mice. Ang-(1–12) impaired endothelium-dependent vasodilation in 4- and 12-month-old Tgαq*44 mice, that was associated with increased Ang II production. The chymase inhibitor chymostatin did not inhibit this response. Interestingly, TXA2 production reflected by TXB2 measurement was upregulated in response to Ang-(1–12) and Ang II in aortic rings isolated from 12-month-old Tgαq*44 mice but not from 4-month-old Tgαq*44 mice or age-matched FVB mice. Furthermore, in vivo magnetic resonance imaging showed that Ang-(1–12) impaired endothelium-dependent vasodilation in the aorta of Tgαq*44 mice and FVB mice. However, this response was inhibited by angiotensin I converting enzyme (ACE) inhibitor; perindopril, angiotensin II receptor type 1 (AT1) antagonist; losartan and TXA2 receptor (TP) antagonist-picotamide in 12-month-old-Tgαq*44 mice only.In conclusion, the chymase-independent vascular Ang-(1–12)/Ang II pathway and subsequent TXA2 overactivity contribute to systemic endothelial dysfunction in the late stage of HF in Tgαq*44 mice. Therefore, the vascular TXA2 receptor represents a pharmacotherapeutic target to improve peripheral endothelial dysfunction in chronic HF.

Systemic mapping of organ plasma extravasation at multiple stages of chronic heart failure.

Introduction: Chronic Heart failure (CHF) is a highly prevalent disease that leads to significant morbidity and mortality. Diffuse vasculopathy is a commonmorbidity associated with CHF. Increased vascular permeability leading to plasma extravasation (PEx) occurs in surrounding tissues following endothelial dysfunction. Such micro- and macrovascular complications develop over time and lead to edema, inflammation, and multi-organ dysfunction in CHF. However, a systemic examination of PEx in vital organs among different time windows of CHF has never been performed. In the present study, we investigated time-dependent PEx in several major visceral organs including heart, lung, liver, spleen, kidney, duodenum, ileum, cecum, and pancreas between sham-operated and CHF rats induced by myocardial infarction (MI). Methods: Plasma extravasation was determined by colorimetric evaluation of Evans Blue (EB) concentrations at 3days, ∼10weeks and 4months following MI. Results: Data show that cardiac PEx was initially high at day 3 post MI and then gradually decreased but remained at a moderately high level at ∼10weeks and 4months post MI. Lung PEx began at day 3 and remained significantly elevated at both ∼10weeks and 4months post MI. Spleen PExwas significantly increased at ∼10weeks and 4months but not on day 3 post MI. Liver PEx occurred early at day 3 and remain significantly increased at ∼10weeks and 4months post MI. For the gastrointestinal (GI) organs including duodenum, ileum and cecum, there was a general trend that PEx level gradually increased following MI and reached statistical significance at either 10weeks or 4months post MI. Similar to GI PEx, renal PEx was significantly elevated at 4months post MI. Discussion: In summary, we found that MI generally incites a timedependent PEx of multiple visceral organs. However, the PEx time window for individual organs in response to the MI challenge was different, suggesting that different mechanisms are involved in the pathogenesis of PEx in these vital organs during the development of CHF.

Systemic Mapping of Organ Plasma Extravasation Post Myocardial Infarction

Chronic Heart failure (CHF) is a highly prevalent disease that leads to significant morbidity and mortality. Diffuse vasculopathy is a common feature of the morbidity associated with CHF. Increased vascular permeability leading to plasma extravasation (PEx) occurs in surrounding tissues following endothelial dysfunction. Such micro- and macro-vascular complications develop over time and lead to edema, inflammation, and multi-organ dysfunction in CHF. However, a systemic examination of PEx in vital organs among different time windows of CHF has never been performed before. In the present study, we investigated time-dependent PEx in several major visceral organs including heart, lung, liver, spleen, kidney, duodenum, ileum, cecum and pancreas between sham-operated and CHF rats induced by myocardial infarction (MI). Plasma extravasation was determined by evaluating Evans Blue concentrations calorimetrically at fluorescence excitation wavelength of 620 nm (bandwidth 10 nm) and an emission wavelength of 680 nm (bandwidth 40 nm) at 3 days, 8-10 weeks and 4 months following MI. Data show that heart PEx level was initially high at day 3 post MI and then gradually decreased but still remained at a moderately high level at 8-10 weeks and 4 months post MI. Lung PEx began at day 3 and remained significantly high at both 8-10 weeks and 4 months post MI. Spleen PEx level was significantly high at 8-10 weeks and 4 months but not day 3 post MI. Liver PEx occurs early at day 3 and remain significantly high at 8-10 weeks and 4 months post MI. For the gastrointestinal (GI) organs including Duodenum, ileum and cecum, there was a general trend that PEx level gradually increased following MI and reached a statistical significance at 4 months post MI. Different with GI PEx, renal PEx level was initially high at day 3 but back to normal level at 8-10 weeks post MI. However, renal PEx was significantly elevated again at 4 months post MI. In summary, we found that MI generally incites a time-dependent PEx of multiple visceral organs. However, the PEx time window for individual organ in response to the MI challenge was different, suggesting that different mechanisms might be involved in the pathogenesis of PEx in these vital organs during CHF. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Accelerated ageing and coronary microvascular dysfunction in chronic heart failure in Tgαq*44 mice

Age represents a major risk factor in heart failure (HF). However, the mechanisms linking ageing and HF are not clear. We aimed to identify the functional, morphological and transcriptomic changes that could be attributed to cardiac ageing in a model of slowly progressing HF in Tgαq*44 mice in reference to the cardiac ageing process in FVB mice. In FVB mice, ageing resulted in the impairment of diastolic cardiac function and in basal coronary flow (CF), perivascular and interstitial fibrosis without changes in the cardiac activity of angiotensin-converting enzyme (ACE) or aldosterone plasma concentration. In Tgαq*44 mice, HF progression was featured by the impairment of systolic and diastolic cardiac function and in basal CF that was associated with a distinct rearrangement of the capillary architecture, pronounced perivascular and interstitial fibrosis, progressive activation of cardiac ACE and systemic angiotensin-aldosterone-dependent pathways. Interestingly, cardiac ageing genes and processes were represented in Tgαq*44 mice not only in late but also in early phases of HF, as evidenced by cardiac transcriptome analysis. Thirty-four genes and 8 biological processes, identified as being ageing related, occurred early and persisted along HF progression in Tgαq*44 mice and were mostly associated with extracellular matrix remodelling and fibrosis compatible with perivascular fibrosis resulting in coronary microvascular dysfunction (CMD) in Tgαq*44 mice. In conclusion, accelerated and persistent cardiac ageing contributes to the pathophysiology of chronic HF in Tgαq*44 mice. In particular, prominent perivascular fibrosis of microcirculation resulting in CMD represents an accelerated cardiac ageing phenotype that requires targeted treatment in chronic HF.

Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure

Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.

Prevalence of Chronic Heart Failure, Associated Factors, and Therapeutic Management in Primary Care Patients in Spain, IBERICAN Study.

Background: The prevalence of chronic heart failure (CHF) in patients assisted in primary care is not well known. We investigated the prevalence of CHF, its associated factors, and its therapeutic management. Methods and findings: This was a cross-sectional, multicenter study conducted in primary care (PC) in baseline patients of the IBERICAN study (Identification of the Spanish Population at Cardiovascular and Renal Risk). CHF was defined as the presence of this condition in the medical history, classifying patients according to the type of ventricular dysfunction in CHF with preserved ejection fraction (pEF), or CHF with reduced ejection fraction (rEF). Clinical characteristics, relationship between CHF and main cardiovascular risk factors (CVRF), and drug treatments used according to ejection fraction (EF) were analyzed. Results: A total of 8066 patients were included (54.5% women), average age (SD) was 57.9 (14.8) years, of which 3.1% (95% CI: 2.3–3.7) presented CHF, without differences between men and women. CHF with pEF (61.8%; 95% CI: 55.5–67.6) was more frequent in women, and CHF with rEF (38.1%; 95% CI: 33.2–45.5) (p = 0.028) was similar in both genders (65.9%; 95% CI: 57.1–73.4 vs. 57.3%; 95% CI: 47.7–65.8) (p = 0.188). A progressive increase of the prevalence with age (15.2% in ≥80 years) and with the aggregation of CVRF was observed. The most prescribed treatments were beta-blockers (54.7%) followed by angiotensin converting enzyme inhibitors (42.8%) and angiotensin II receptor antagonists (41.3%), without differences between pEF and rEF. The variables that are most associated with the probability of suffering CHF were a personal history of left ventricular hypertrophy (OR: 5.968; p < 0.001), of atrial fibrillation (OR: 3.494; p < 0.001), and of peripheral vascular disease (OR: 2.029; p < 0.001). Conclusions: Three in every 100 patients included in the IBERICAN study presented CHF, of which two thirds had pEF. The condition increased exponentially with age and aggregation of CVRF. We did not find any differences in drug treatment according to the type of ventricular dysfunction. The treatment of HF with rEF has much room for improvement.

Contracting Skeletal Muscle Oxygen Pressures in Rats with Heart Failure: Impact of Soluble Guanylyl Cyclase Activator

Introduction Heart failure with reduced ejection fraction (HFrEF) causes impaired convective and diffusive oxygen (O2) transport, in part, by nitric oxide -soluble guanylyl cyclase (sGC)- cyclic guanosine monophosphate pathway dysfunction. sGC activators were developed to selectively target oxidized, heme-free sGC and promote vasodilation, thereby demonstrating potential for improving skeletal muscle oxygenation in HFrEF. We tested the hypotheses that 5 days of administration of sGC activator BAY 60-2770 would increase the O2 delivery (Q̇O2)-to-V̇O2 ratio in the skeletal muscle interstitial space (PO2is, pressure driving O2 into the contracting myocyte) of HFrEF rats at rest and during twitch contractions. Methods HFrEF was induced in adult male Sprague-Dawley (3-4 mo. old) rats via myocardial infarction (MI) and the development of HFrEF was monitored via transthoracic echocardiography. Following 3 weeks of HFrEF progression, rats were treated with 0.3 mg/kg of BAY 60-2770 via oral gavage twice per day (HFrEF + BAY; n =10) for 5 days prior to the contraction protocol. The control heart failure group (HFrEF; n = 9) received vehicle only. Phosphorescence quenching protocols determined the partial pressure of O2 in the spinotrapezius muscle interstitial space at rest and during twitch contractions. Results The degree of HFrEF was not different between groups as evidenced by ejection fraction (44.7 ± 5.1 vs. 46.3 ± 4.8%), left ventricular end-diastolic pressure (16 ± 1 vs. 14 ± 1 mmHg), and MI size (29 ± 2 vs. 28 ± 3%) (all P > 0.05) . Despite no difference either at rest or during the contracting steady-state, across the on transient (14-22 seconds of contractions) there was a ~30% increase in PO2is in HFrEF + BAY vs HFrEF (P ≤ 0.05), demonstrating a greater pressure head driving oxygen to the contracting myocyte. There was also a decrease in arterial blood lactate in HFrEF + BAY vs HFrEF (P < 0.05). Conclusions These data support that during the rest-contraction transient, BAY 60-2770 increases PO2is in rats with moderate HFrEF at the transition from rest to exercise, which may speed V̇O2 kinetics, thereby reducing lactate accumulation. This supports sGC activators as a therapeutic targeting vasomotor dysfunction in chronic heart failure which has the potential to increase exercise capacity and quality of life in this patient population.

Koenzim Q10 (ubikvinon) i bolesti mozga - veza sa okom i telom

Coenzyme Q10 (CoQ10; ubiquinone) is a vitamin-like substance that is involved in the respiratory chain in the mitochondria. Ubiquinone is synthesized in all tissues, but with age, the content decreases, as well as in some pathological conditions and with the use of statins. Ubiquinone is necessary for the growth and maintenance of cells in the human body, and with age, food intake is desirable, because endogenous synthesis is no longer sufficient. CoQ10 participates in oxidative phosphorylation and adenosine triphosphate (ATP) production and is a potent antioxidant. Primary CoQ10 deficiencies manifest as multisystem disease, encephalomyopathy, cerebellar ataxia, myopathy, and nephrotic syndrome. In the case of CoQ10 deficiency, reactive oxygen species occur first, and in the case of severe deficiency, the loss of ATP. CoQ10 deficiency also causes apoptosis which is found in the brain and retina of the elderly. CoQ10 deficiency contributes to heart muscle dysfunction in chronic heart failure. The effects of CoQ10 deficiency are inflammation and oxidative stress. An inverse relationship between serum CoQ10 and the risk of developing dementia has been shown. CoQ10 administration resulted in a reduction in depression in patients with metabolic syndrome as well as an improvement in concentration in schizophrenia and schizoaffective disorder. CoQ10 deficiency may be associated with the occurrence of static myopathy. In people with primary CoQ10 deficiencies, there is retinopathy, and in acquired macular degeneration and glaucoma, CoQ10 levels are reduced. High doses of CoQ10 help survive chronic heart failure and coronary heart disease. Beneficial effects of CoQ10 on the treatment of obesity, oxidative stress, metabolic syndrome, type II diabetes mellitus and non-alcoholic fatty liver have been shown. Fatigue applications are controversial. There has been some positive effect of CoQ10 in breast cancer. Studies indicate that the use of CoQ10 has beneficial effects in the early stages of sepsis. For therapeutic purposes, CoQ10 is administered in doses of 30-3000 mg. Doses of 22 mg daily to 400 mg/day are considered safe. Side effects are mostly mild and rare.

Identification of Cardiac Expression Pattern of Transient Receptor Potential Vanilloid Type 1 (TRPV1) Receptor using a Transgenic Reporter Mouse Model

Transient receptor potential vanilloid type 1 (TRPV1) channels are structurally related, non-selective cation channels that exhibit a high permeability to calcium. Sensory nerve endings expressing TRPV1 channels play a prominent role in regulating the cardiac sympathetic afferent reflex and contribute to cardiac remodeling and dysfunction in chronic heart failure. However, the precise expression of TRPV1 channels in cardiomyocytes vs. non-cardiomyocytes remains debated. Here we utilized a tdTomato-GFP reporter mouse crossed with a mouse line expressing Cre recombinase under the control of the TRPV1 promoter to map the TRPV1 expression pattern in heart. In this model, TRPV1-negative cells express tdTomato protein (red), whereas TRPV1-positive cells express GFP protein (green). As we expected, substantial GFP expression was found in many small and medium diameter dorsal root ganglia neurons in heterozygous TRPV1-Cre +/-, tdTomato flox/flox +/- male mice, suggesting that this heterozygous model is sufficient for labeling TRPV1-positive cells. Furthermore, these results showed that GFP green staining was not detectable in cardiomyocytes. Instead, we found strong GFP green staining in cardiac blood vessels—thought to be arterioles—in the heart. We also observed strong GFP signals on PGP9.5-positive cardiac nerve endings in the epicardium. In summary, this study does not support the concept that TRPV1 channels are strongly expressed in mouse cardiomyocytes. We conclude that TRPV1 channels in mouse heart are mostly expressed on non-cardiomyocyte cells including cardiac nerve endings and vessels. These data have important implications for the modulations of cardiogenic reflexes.

Биомаркеры миокардиальной и почечной дисфункции при хронической сердечной недостаточности

Биомаркеры миокардиальной и почечной дисфункции при хронической сердечной недостаточности

Clinical features and prognosis in heart failure patients with chronic obstructive pulmonary diseases

Multimorbidity is a specific characteristic of the modern patient with chronic heart failure (CHF) which significantly changes clinical course, prognosis of the syndrome, leads to socio‑economic losses and makes significant adjustments to treatment tactics. The goal is to study the clinical features and prognosis of patients with CHF in combination with chronic obstructive pulmonary disease (COPD). We studied 183 HF patients, including with stable CHF, including 105 with CHF combined with COPD. The clinical phenotype was assessed by its belonging to the functional class and the severity of COPD. A 6‑minute walk test (6‑MWT), spirometry, echocardioscopy, testing on a scale assessing the clinical condition, quality of life were studied. The end points during the year were: all‑cause mortality and cardiovascular mortality, myocardial infarction, stroke, pulmonary embolism, and hospitalization rates due to acute decompensation of CHF. The clinical phenotype of CHF combined with COPD was characterized by a high frequency of smoking, low quality of life and exercise tolerance. Respiratory dysfunction in CHF in combination with COPD was characterized by mixed disorders (68.4%), in CHF without lung disease, restrictive (25.6%). Cardiovascular mortality in comorbid pathology was 4.0%, in CHF without COPD - 4.6%; myocardial infarction was observed 1.7 times more often with lung disease than in patients with CHF only (16.8% and 10.8%); stroke was observed exclusively in comorbid pathology (8.9%). The combined endpoint (all cardiovascular events) with CHF in combination with COPD was achieved 2.3 times more often in comparison with patients with COPD only (29.7% and 15.4%). Hospitalization due to acute decompensation of CHF occurred 2 times more often with CHF in combination with COPD than without it (32.7% and 15.4%) with a tendency to increase as the left ventricular ejection fraction decreased. The results of the study demonstrate that COPD contributes to the formation of the clinical phenotype of CHF from the standpoint of the mutual influence of the characteristics of the cardiovascular and respiratory systems, and also aggravates the prognosis that requires an integrated approach to the differential diagnosis and individualization of pharmacotherapy.

Endothelial Dysfunction in Chronic Heart Failure: Assessment, Findings, Significance, and Potential Therapeutic Targets.

Chronic heart failure (CHF) is a complex syndrome that results from structural and functional disturbances that affect the ability of the heart to supply oxygen to tissues. It largely affects and reduces the patient’s quality of life, socio-economic status, and imposes great costs on health care systems worldwide. Endothelial dysfunction (ED) is a newly discovered phenomenon that contributes greatly to the pathophysiology of numerous cardiovascular conditions and commonly co-exists with chronic heart failure. However, the literature lacks clarity as to which heart failure patients might be affected, its significance in CHF patients, and its reversibility with pharmacological and non-pharmacological means. This review will emphasize all these points and summarize them for future researchers interested in vascular pathophysiology in this particular patient population. It will help to direct future studies for better characterization of these two phenomena for the potential discovery of therapeutic targets that might reduce future morbidity and mortality in this “at risk” population.

Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to β-adrenergic stimulation in adult rat cardiomyocytes.

Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early-response gene activated in the heart under β-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by increased NR4A2 expression in cardiomyocytes and their impact on the physiological response of those cells to sustained β-adrenergic stimulation. Treatment of adult rat ventricular myocytes with isoproterenol induced a rapid (<4 h) increase in NR4A2 levels that was accompanied by a transient (<24 h) increase in nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 to similar levels modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. Consistent with those findings, NR4A2 overexpression also blocked the phosphorylative activation of growth-related kinases ERK1/2, Akt, and p70 S6 kinase. Prominent among the transcriptional changes induced by NR4A2 was the upregulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pretreatment of NR4A2-overexpressing cardiomyocytes with the DUSP inhibitor BCI [(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one] prevented the inhibition of ERK1/2 following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the β-adrenergic receptor-mediated growth response in cardiomyocytes and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.

Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure.

BackgroundChronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of MuRF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function.MethodsMyocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described MuRF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed.ResultsChronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up‐regulation of the MuRF1 and MuRF2 was attenuated after infarct.ConclusionsOur murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.

SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3′ untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3′ UTR 158–165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel’s activity against chronic heart failure.

Impact of comorbidities on myocardial remodeling and dysfunction in heart failure with preserved ejection fraction.

Aim. The generalization of the modern data on the influence of comorbidities on cardiac remodeling and heart dysfunction in chronic heart failure (CHF) with preserved ejection fraction (EF). The objectives of the study included the analysis of the pathogenesis of CHF with preserved ejection fraction. Material and methods. Analyzed all Russian and English literature, submitted to the search engines. Results. Analysis of scientific literature showed that the increase in systemic vascular inflammation, endothelial dysfunction and oxidative stress lead to reduced bioavailability of nitric oxide , which leads to increased stiffness of the left ventricle and adverse remodeling of the heart in CHF with preserved ejection fraction. Comorbidities such as overweight /obesity, diabetes, hypertension, chronic obstructive pulmonary disease, anaemia and chronic renal dysfunction leads to coronary remodeling in microvascular endothelial inflammation. The negative contribution is also made by demographic factors such as older age and female gender. In the present review substantiates the crucial role of comorbidities in the pathophysiology of CHF with preserved ejection fraction. Conclusion. Summarizing the analysis of literature sources, devoted to the pathogenesis of CHF with comorbidity, the findings that, in addition to diastolic dysfunction of the left ventricle, there are other patofiziologiia mechanisms: the violation of backup functions, the violation of jeludochno-blood relationship, the energy deficit of the myocardium, pulmonary hypertension, chronotropic imbalance, inflammation, oxidative stress and endothelial dysfunction. With CHF with preserved ejection fraction comorbidities contribute to systemic inflammation which causes oxidative stress in the coronary microvascular endothelium. This reduces the bioavailability of nitric oxide in the myocardium and leads to reduced activity of protein kinase G in cardiomyocytes, which therefore become stiff and hypertrophied. In addition, with increasing age and postmenopausal hormonal changes may lead to additional structural and functional changes.

Associations Between Neutrophil Gelatinase Associated Lipocalin, Neutrophil-to-Lymphocyte Ratio, Atrial Fibrillation and Renal Dysfunction in Chronic Heart Failure.

BackgroundAtrial fibrillation (AF) and renal dysfunction are two common comorbidities in patients with chronic heart failure with reduced ejection fraction (HFrEF). This study evaluated the effect of permanent AF on renal function in HFrEF and investigated the associations of atrial fibrillation, neutrophil gelatinase-associated lipocalin (NGAL), and neutrophil-to-lymphocyte ratio (NLR) with adverse clinical outcome.Material/MethodsSerum NGAL levels measured by ELISA and NLR were compared between patients with sinus rhythm (HFrEF-SR, n=68), with permanent AF (HFrEF-AF, n=62), and a healthy control group (n=50).ResultsMean eGFR levels were significantly lower, and NLR and NGAL levels were significantly higher in the HFrEF patients than in the control patients but the difference between HFrEF-SR and HFrEF-AF was not statistically significant (NGAL: 95 ng/mL in HFrEF-SR, 113 ng/mL in HFrEF-AF and 84 ng/mL in the control group; p<0.001). Independent associates of baseline eGFR were age, hemoglobin, NLR, triiodothyronine, and pulmonary artery systolic pressure. In a mean 16 months follow-up, adverse clinical outcome defined as progression of kidney dysfunction and composite of all-cause mortality and re-hospitalization were not different between HFrEF-SR and HFrEF-AF patients. Although NGAL was associated with clinical endpoints in the univariate analysis, Cox regression analysis showed that independent predictors of increased events were the presence of signs right heart failure, C-reactive protein, NLR, triiodothyronine, and hemoglobin. In ROC analysis, a NLR >3 had a 68% sensitivity and 75% specificity to predict progression of kidney disease (AUC=0.72, 95% CI 0.58–0.85, p=0.001).ConclusionsPresence of AF in patients with HFrEF was not an independent contributor of adverse clinical outcome (i.e., all-cause death, re-hospitalization) or progression of renal dysfunction. Renal dysfunction in HFrEF was associated with both NLR and NGAL levels, but systemic inflammation reflected by NLR seemed to be a more important determinant of progression of kidney dysfunction.

Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches.

Mitochondria are cellular organelles responsible for energy production, calcium handling, controlled synthesis of reactive oxygen species (ROS), and regulation of apoptosis. All these functions are crucial for cardiac homeostasis, and may be impaired in chronic heart failure (CHF). Therefore, mitochondrial dysfunction might represent a crucial element in the onset and progression of CHF and, as such, a promising therapeutic target. Original articles and review on the treatment of mitochondrial dysfunction in CHF were searched on Medline and Scopus. The present review summarizes the current knowledge about mitochondrial modulation as a therapeutic strategy for CHF, and proposes some perspectives for future studies. Mitochondrial dysfunction can be ascribed to neuro-humoral activation and cardiac remodeling associated with CHF. Conceptually, the correction of mitochondrial dysfunction could provide an additive benefit to optimal CHF treatment. Increasing glucose metabolism and reducing oxidative stress within mitochondria are the two most promising approaches, even though further studies are required before implementing new treatments in the setting of CHF. On the other hand, inhibition of apoptosis, and normalization of calcium and mitochondrial dynamics have been assessed almost exclusively in ex vivo models, and mostly in settings other than CHF. Mitochondrial modulation in CHF is an intriguing example of translational research and a potentially rewarding field.

C-Jun N-terminal Kinase mediates prostaglandin-induced sympathoexcitation in rats with chronic heart failure by reducing GAD1 and GABRA1 expression.

Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of this study was to investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signalling in PVN in CHF rats. Chronic heart failure was induced by left coronary ligation in Wistar rats. Renal sympathetic nerve discharge (RSND) and mean arterial pressure (MAP) responses to the PVN infusion were determined in anaesthetized rats. Osmotic minipumps were used for chronic PVN infusion. PTGER3 expression was examined with immunofluorescence staining, quantitative real-time PCR and Western blot. Chronic heart failure rats had increased JNK activation and decreased glutamate decarboxylase 1 (GAD1) and GABAA receptor alpha 1 subunit (GABRA1) expression in the PVN. PVN infusion of the PTGER3 agonist SC-46275 caused sympathoexcitation in sham-operated control (Sham) rats and increased it further in CHF. The PTGER3 antagonist L798106 reduced sympathoexcitation and cardiac dysfunction in CHF. PVN infusion of EP1 receptor antagonist SC-19220, EP2 receptor antagonist AH6809 or EP4 receptor antagonist L-161982 had no effect on sympathoexcitation. The JNK inhibitor SP600125 normalized sympathoexcitation and GAD1 and GABRA1 expression in PVN in CHF rats. Both the p44/42 and p38 mitogen-activated protein kinase inhibitors PD98059 and SB203580 could not prevent the downregulation of GAD1 and GABRA1 expression in PVN in CHF. PTGER3 agonist activated JNK but downregulated GAD1 and GABRA1 expression in NG108 neuronal cells. Prostaglandin signalling through upregulated PTGER3 activates JNK which reduces GAD1 and GABRA1 expression in the PVN, and contributes to sympathoexcitation in CHF.