Pathogenesis Of Congestive Heart Failure Research Articles

Preclinical models of congestive heart failure, advantages, and limitations for application in clinical practice.

Congestive heart failure (CHF) has increased over the years, in part because of recent progress in the management of chronic diseases, thus contributing to the maintenance of an increasingly aging population. CHF represents an unresolved health problem and therefore the establishment of animal models that recapitulates the complexity of CHF will become a critical element to be addressed, representing a serious challenge given the complexity of the pathogenesis of CHF itself, which is further compounded by methodological biases that depend on the animal species in use. Animal models of CHF have been developed in many different species, with different surgical procedures, all with promising results but, for the moment, unable to fully recapitulate the human disease. Large animal models often provide a more promising reality, with all the difficulties that their use entails, and which limit their performance to fewer laboratories, the costly of animal housing, animal handling, specialized facilities, skilled methodological training, and reproducibility as another important limiting factor when considering a valid animal model versus potentially better performing alternatives. In this review we will discuss the different animal models of CHF, their advantages and, above all, the limitations of each procedure with respect to effectiveness of results in terms of clinical application.

Improving Diuretic Response in Heart Failure by Implementing a Patient-Tailored Variability and Chronotherapy-Guided Algorithm.

Heart failure is a major public health problem, which is associated with significant mortality, morbidity, and healthcare expenditures. A substantial amount of the morbidity is attributed to volume overload, for which loop diuretics are a mandatory treatment. However, the variability in response to diuretics and development of diuretic resistance adversely affect the clinical outcomes. Morevoer, there exists a marked intra- and inter-patient variability in response to diuretics that affects the clinical course and related adverse outcomes. In the present article, we review the mechanisms underlying the development of diuretic resistance. The role of the autonomic nervous system and chronobiology in the pathogenesis of congestive heart failure and response to therapy are also discussed. Establishing a novel model for overcoming diuretic resistance is presented based on a patient-tailored variability and chronotherapy-guided machine learning algorithm that comprises clinical, laboratory, and sensor-derived inputs, including inputs from pulmonary artery measurements. Inter- and intra-patient signatures of variabilities, alterations of biological clock, and autonomic nervous system responses are embedded into the algorithm; thus, it may enable a tailored dose regimen in a continuous manner that accommodates the highly dynamic complex system.

Peripheral blood lymphocyte subtypes in dogs with different stages of myxomatous mitral valve disease.

BackgroundData on alterations in peripheral blood lymphocyte (PBL) subtypes in dogs with myxomatous mitral valve disease (MMVD) is lacking.ObjectivesTo investigate PBL subtypes and their correlation with parameters of inflammation and MMVD progression markers in dogs with different stages of MMVD.AnimalsSeventy‐eight client‐owned dogs: 65 with MMVD (American College of Veterinary Internal Medicine [ACVIM] classification stages B2, C, and D) and 13 healthy controls.MethodsProspective cross‐sectional study. Complete cardiac assessment, flow cytometry (T lymphocytes [CD3+], their subtypes [CD3+CD4+, CD3+CD8+, CD3+CD4+CD8+, CD3+CD4−CD8−], and B lymphocytes [CD45+CD21+]) and measurement of N‐terminal pro B‐type natriuretic peptide, cardiac troponin I, and C‐reactive protein concentrations were performed.ResultsThe percentage of CD3+CD4+ lymphocytes was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .003), the percentage of CD3+CD8+ lymphocytes was significantly higher in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01), CD3+CD8+ lymphocyte concentration was significantly higher in unstable ACVIM C and D patients (P = .05), and the CD3+CD4+/CD3+CD8+ ratio was significantly lower in stable ACVIM C patients (P = .01) and unstable ACVIM C and D patients (P = .01) compared with healthy controls.Conclusions and Clinical ImportanceThe percentages of CD3+CD4+ and CD3+CD8+ PBL and CD4+/CD8+ ratio were altered in MMVD dogs with congestive heart failure (ACVIM C, D), but not in ACVIM B2, suggesting involvement of these PBL subtypes in the pathogenesis of congestive heart failure in dogs with MMVD.

Angiotensin II-induced muscle atrophy via PPARγ suppression is mediated by miR-29b

The activation of the renin-angiotensin system (RAS) induced by increased angiotensin II (AngII) levels has been implicated in muscle atrophy, which is involved in the pathogenesis of congestive heart failure. Although peroxisome proliferator-activated receptor gamma (PPARγ) activation can suppress RAS, the exact role of PPARγ in AngII-induced muscle atrophy is unclear. Here we identified PPARγ as a negative regulator of miR-29b, a microRNA that is able to promote multiple types of muscle atrophy. Suppression of miR-29b could prevent AngII-induced muscle atrophy both in vitro and in vivo. IGF1, PI3K(p85α), and Yin Yang 1 (YY1) were identified as target genes of miR-29b, and overexpression of these targets could rescue AngII-induced muscle atrophy. Importantly, inhibition of PPARγ was sufficient to induce muscle atrophy, while PPARγ overexpression could attenuate that. These data indicate that the PPARγ/miR-29b axis mediates AngII-induced muscle atrophy, and increasing PPARγ or inhibiting miR-29b represents a promising approach to counteract AngII-induced muscle atrophy.

β-Adrenergic receptor signaling in cardiac function and heart failure

N/A

Prevalence and Patterns of Obstructive Sleep Apnea in Asian Indians With Congestive Heart Failure.

BackgroundSleep-disordered breathing (SDB) has a potential association with the pathogenesis of congestive heart failure (CHF). We assessed the prevalence and patterns of obstructive sleep apnea (OSA) in patients presenting with CHF.MethodThis was a prospective, observational, all-comers study of consecutive 77 confirmed cases of CHF. All these patients were clinically assessed and evaluated for OSA with sleep study after routine blood testing, electrocardiogram (ECG), chest X-ray, and echocardiography.ResultsOf 77 patients with CHF 38 (49.4%) had apnea-hypopnea index (AHI) <5 while 39 (50.6%) had AHI >5. Of these 39, 37 (94.8%) patients showed the clinical features of OSA. The majority (64.9%) of them were males. The majority of OSA (64.9%) had coronary artery disease (CAD) (p<0.05) as the etiology of CHF, followed by dilated cardiomyopathy (32.4%) and valvular heart disease (2.7%). The prevalence of OSA was higher amongst New York Heart Association (NYHA) class 2 (51.4%) as compared to NYHA class 3 (37.8%) and NYHA class 4 (10.8%). There were 12 (32.8%) patients, each having OSA with a heart rate between 71 and 80 bpm and 81 and 90 bpm. Twenty-two (59.5%) had systolic blood pressure (BP) more than 120 mmHg and 20 (54.1%) had diastolic BP more than 80 mmHg. The majority (64.9%) patients had the lowest O2 saturation between 80% and 90%. A significantly large number of patients (62.2%) had ejection fraction 21%-30% (p<0.05). The majority (62.16%) of patients with OSA had AHI between 5 and 15. With 5-15 AHI, 20 (87%) patients with OSA had a snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and male gender (STOP-Bang) score between 3 and 7 with AHI 5-15 (p<0.05).ConclusionsIn our cohort, the prevalence of OSA in CHF was 50.6%. Predictors of OSA in CHF were left ventricular ejection fraction (LVEF) 20%-30% and NYHA class 2. The majority had AHI between 5 and 15. Sleep apnea screening should be routinely implemented in the evaluation and follow-up of heart failure patients.

Cardiovascular-renal axis disorder and acute-phase proteins in cats with congestive heart failure caused by primary cardiomyopathy.

BackgroundCurrently, the pathogenesis of congestive heart failure (CHF) in cats is not fully understood.ObjectiveTo identify novel biomarkers for CHF in cats caused by primary cardiomyopathy, particularly related to cardiovascular‐renal axis disorder and systemic inflammatory response.AnimalsTwenty‐five cats in CHF caused by primary cardiomyopathy, 12 cats with preclinical cardiomyopathy, and 20 healthy controls.MethodsCase control and observational case series. The following serum biomarkers were compared among the 3 cat groups: a cardiorenal profile that included N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), symmetric dimethylarginine (SDMA), and creatinine and an inflammatory profile that included 7 acute‐phase proteins (APPs). Survival analyses and longitudinal studies were performed in CHF cats.ResultsAll cardiorenal biomarkers were positively correlated and higher in CHF cats, and high NT‐proBNP and SDMA were associated with poor clinical outcome. Cats with CHF had significantly higher leucine‐rich alpha‐2‐glycoprotein 1, serum amyloid A, and ceruloplasmin, and these APPs were positively correlated with NT‐proBNP and left atrial size. In a multivariable survival analysis, alpha‐1‐acid glycoprotein concentration (P = .01), body weight (P = .02) and left atrial‐to‐aortic root ratio (P = .01) were independent prognostic factors for CHF in these cats.Conclusions and Clinical ImportanceIn cats, CHF is an inflammatory disorder and outcome in CHF may be determined by the extent of inflammation and possibly the amount of residual renal function. These novel biomarkers have potential use for the clinical management, prognosis, and future research into CHF and cardiomyopathy in cats.

Evaluation of Serum Urocortin 2 Levels in Patients with Hypertension.

Urocortin 2 (UCN2), is an endogenous stress-related peptide belonging to the corticotropin-releasing factor (CRF) family, has a major role in the pathogenesis of congestive heart failure, ischemic heart disease, and hypertension. To investigate the role of UCN2 levels in patients with hypertension (HTN). Serum UCN2 levels measured by ELISA were compared between patients with HTN (n = 86) and nonHTN (n = 53). Eighty-six patients with HTN [median age 66 (45-76); 38 men] and 53 patients with non-HTN [median age 62 (40-80); 39 men] were included into this study. Serum UCN2 (5.17ng/ml; IQR, 1.26-11.68ng/ml vs 0.79ng/ml; IQR, 0.07-4.10ng/ml, p < 0.0005) levels were found significantly elevated in patients with HTN compared to nonHTN control group.Concentrations of serum UCN2 were positively correlated with left ventricle mass index to body surface area (LV mass index to BSA, r = 0.20, p = 0.03), LV mass index to height2.7 (r = 0.28, p = 0.002) and body mass index (r = 0.24, p = 0.008). Additionally, logistic regression analysis was performed to UCN2, uric acid, creatinine, glomerular filtration rate, age, body mass index, coronary artery disease and diabetes mellitus which are the potential confounders of hypertension. According to logistic regression analysis serum UCN2 values were found out as an independent predictor of HTN. UCN2 levels, correlated with LV mass index were increased in HTN patients compared to nonHTN patients. These data provide evidence that there could be a relationship between high concentrations of UCN2 and HTN. UCN2 may appear as a promising choice of HTN treatment in the future.

Natriuretic peptides system in the pulmonary tissue of rats with heart failure: potential involvement in lung edema and inflammation.

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention as evident by peripheral and lung edema. Although the pathogenesis of CHF remains largely unclarified, it is widely accepted that neurohormonal changes and inflammatory processes are profoundly involved in structural and functional deterioration of vital organs including, heart, kidney and lungs. Corin, a cardiac serine protease, is responsible for converting pro-ANP and pro-BNP to biologically active natriuretic peptides (NPs). Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and PCSK6, a key enzyme in the conversion of procorin to corin, have not been studied in the pulmonary tissue. Thus, this study aims at examining the status of PCSK6/Corin in the lung of rats with CHF induced by the creation of aorto-caval fistula (ACF) between the abdominal aorta and vena cava in SD rats. Rats with ACF were divided into 2 subgroups based on the pattern of their daily sodium excretion, compensated and decompensated CHF. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more severe in the decompensated subgroup, despite remarkable elevation of circulatory ANP and BNP levels. Corin mRNA and immunoreactive peptide were detected in pulmonary tissue of all experimental groups. However, the expression and abundance of pulmonary corin significantly increased in the decompensated animals, but not in the compensated ones. Noteworthy, the expression of PCSK6 and ANP/BNP in the pulmonary tissue followed a similar pattern as corin. The upregulation of pulmonary Corin/PCSK6 and NPs were accompanied by local activation of cathepsin L and certain cytokines including IL-6. In light of the anti-inflammatory role of NPs, we postulate that the obtained upregulation of pulmonary PCSK6/Corin along NPs in rats with decompensated CHF may represent a counterbalance response to the inflammatory milieu characterizing CHF especially in severe cases.

Association Between C1q/TNF-Related Protein-1 Levels in Human Plasma and Epicardial Adipose Tissues and Congestive Heart Failure

Background/Aims: C1q and tumour necrosis factor-related protein 1 (CTRP1) possesses anti-atherogenic and anti-inflammatory effects. This study investigated whether the CTRP1 levels in the plasma and epicardial adipose tissue (EAT) were associated with congestive heart failure (CHF) and to disclose possible molecular mechanisms. Methods: Plasma and tissue samples were obtained from subjects with or without CHF. Plasma levels of CTRP1 were measured by ELISA. The mRNA levels of CTRP1 and inflammatory cytokines were detected by RT-PCR. The protein levels of CTRP1, aldosterone synthase (CYP11B2) and mitogen-activated protein kinase were examined by Western blotting. Results: The levels of CTRP1 in the plasma and EAT were higher in the CHF patients than those in the controls. There were no differences in the CTRP1 levels in cardiomyocytes between the CHF group and the non-CHF group. An exploratory survival analysis showed that higher CTRP1 values at admission were associated with a worse prognosis after discharge. CTRP1 increased the IL-6 mRNA level in H295R cells. CTRP1 recruited ERK1/2 and Jak-2 for aldosterone release by modulating the CYP11B2 protein level, and brain natriuretic peptide repressed the CTRP1-induced aldosterone release through the JAK2-STAT3 signalling pathways. Conclusion: The CTRP1 levels in the plasma and EAT were increased in the CHF patients. CTRP1 is involved in the pathogenesis of CHF by modulating IL-6 levels and aldosterone release.

Cytokine expression in peripheral blood mononuclear cells of dogs with mitral valve disease

Inflammation plays an important role in the pathogenesis of congestive heart failure (CHF). In humans with CHF, increased production and high plasma concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1, IL-8 and transforming growth factor-β (TGF-β) have been associated with disease progression and a negative prognosis. The aim of this study was to investigate whether differences in cytokine blood mRNA expression exist between clinically healthy dogs and dogs with myxomatous mitral valve disease (MMVD); to determine if the expression was related to the severity of MMVD, and to detect any correlations with echocardiographic parameters of cardiac remodelling. Twenty-three dogs with MMVD of varying severity and six clinically healthy dogs were included in the study. Whole blood samples were obtained for measurement of mRNA expression of IL-1α, IL-1β, IL-6, IL-8, TGF-β1, TNF-α by reverse transcriptase-PCR (RT-PCR).There were statistically significant differences between clinically healthy dogs and dogs with MMVD for IL-8 and TGF-β1 gene expression. IL-8 expression increased with increasing MMVD severity and TGF-β1 expression was higher in asymptomatic dogs with echocardiographic signs of cardiac remodelling (American College Veterinary Internal Medicine class B2) than in all other groups. These results could suggest the involvement of these cytokines at different stages of the disease.

Reaktívoxigén-származékok szerepe a szívműködés szabályozásában

Increased production of reactive oxygen species has been implicated in the pathogenesis of congestive heart failure. However, emerging evidence suggests a role for reactive oxygen species in regulating various physiological cellular processes in the myocardium. The authors summarize the current understanding of involvement of reactive oxygen species in the regulation of cardiac contractility under physiological conditions.

Lung Natural Killer Cells Play a Major Counter-Regulatory Role in Pulmonary Vascular Hyperpermeability After Myocardial Infarction

Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1β-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. This study is the first to identify a critical role for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after myocardial infarction.

GW24-e0403 Autoantibodies against angiotensin II type 1 receptor-positive patients with heart failure have better clinical efficacy to perindopril treatment

ObjectivesPreviously, we reported that autoantibodies specific for the angiotensin II type 1 receptor (anti-AT1-AR) is implicated in the pathogenesis of congestive heart failure (CHF). We hypothesised that the presence of...

Role of genetic factors in the development of congestive heart failure

The article reviews studies of gene polymorphisms effects on the phenotype and the prognostic value of the genotype determination in patients with congestive heart failure. The results of studies analyzing the impact of angiotensinogen, angiotensin-converting enzyme, β2-adrenoreceptor genes polymorphism on the development of hypertension, myocardial and carotid arteries damage, and congestive heart failure prognosis are surveyed. However, despite the large number of studies addressing the association of polymorphic markers of candidate genes and phenotype, no consensus on the impact of candidate genes on the major systems involved in the pathogenesis of congestive heart failure has been achieved so far. Due to gene distribution variability in different populations, the studies of ethnic and geographical association of candidate genes with congestive heart failure development, as well as studies of phenotypic markers of the disease, are still relevant.

A Global Transcriptome Analysis of a Dog Model of Congestive Heart Failure With the Human Genome as a Reference

BackgroundThe global molecular changes in cardiac tissue during congestive heart failure (CHF) have not been fully examined. Transcriptome analysis with the use of next-generation sequencers is a useful tool for elucidating the pathogenesis of CHF. Although there are some advantages in a dog CHF model, transcriptome analyses in dogs are limited by the relative lack of genomic information. Methods and ResultsThe transcriptome analysis of hearts from dogs with CHF was conducted with the use of a genome analyzer and the Casava software. The mRNA sequence reads showed alignments with ∼800 of 1,019 genes from the dog reference database. On the other hand, the reads aligned with ∼15,000 of the 21,407 genes in the hg19 human reference database. The correlation of expressed genes was extremely high (r = 0.93; P < .0001) between the dog and human databases. A pathway analysis using the hg19 reference revealed increased expression of p53 pathway–related (P < 10−10) and inflammatory interleukin–related (P < 10−10) genes in the CHF model. ConclusionsThe use of the human genome as a reference in global transcriptome analyses of dogs is a useful approach for investigating diseases such as CHF. Such an approach would also be useful for analyzing disease models in other experimental animals.

Physiological regulation of cardiac contractility by endogenous reactive oxygen species

Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of congestive heart failure. However, emerging evidence suggests the involvement of ROS in the regulation of various physiological cellular processes in the myocardium. In this review, we summarize the latest findings regarding the role of ROS in the acute regulation of cardiac contractility. We discuss ROS-dependent modulation of the inotropic responses to G protein-coupled receptor agonists (e.g. β-adrenergic receptor agonists and endothelin-1), the potential cellular sources of ROS (e.g. NAD(P)H oxidases and mitochondria) and the proposed end-targets and signalling pathways by which ROS affect contractility. Accumulating new data supports the fundamental role of endogenously generated ROS to regulate cardiac function under physiological conditions.

Vitamin D Supplementation in Infants With Chronic Congestive Heart Failure

Increased circulating proinflammatory cytokines may contribute to the pathogenesis of congestive heart failure (CHF). In vitro studies have suggested that vitamin D suppresses proinflammatory cytokines and increases anti-inflammatory cytokines. The aim of this work was to evaluate the effect of vitamin D supplementation on renin-angiotensin system cytokines as well as different clinical, biochemical, and echocardiographic variables in infants with chronic CHF. This was a double-blind, placebo-controlled intervention study and included 80 infants with CHF. The intervention consisted of either giving Vitamin D(3) oral drops (group I) or placebo oral drops (group II). In both study groups, baseline 25-hydroxyvitamin D [25(OH)D] concentrations were below the lower end of the reference range. After 12 weeks of intervention, vitamin D supplementation for group I infants caused significant improvement of HF score, left-ventricular (LV) end-diastolic diameter, LV end-systolic diameter, LV ejection fraction%, and myocardial performance index together with markedly increased serum 25(OH)D and interleukin (IL)-10 and decreased PTH, IL-6, and TNF-α compared with the placebo group; these differences were statistically significant (p < 0.001). Vitamin D supplementation has great benefits as an anti-inflammatory agent in infants with CHF. It helps acceleration of the clinical improvement and cytokine profile balance.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

β2‐Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another ‘radical’ road to heart failure?

Persistent activation of the cardiac β-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both β₁- and β₂-adrenoceptors are known to mediate these noxious effects, yet the β₁-adrenoceptor-PKA axis has received greater attention with less information available on β₂-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that β₂-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that β₂-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4.