Intracellular magnesium in elderly patients with heart failure: Effects of diabetes and renal dysfunction

Hypomagnesemia is frequent in diabetes mellitus (DM), while renal dysfunction (RD) may be associated with hypermagnesemia. Severe cardiac arrhythmias and other adverse clinical manifestations are frequent in heart failure (HF), in DM and in RD. Depletion of intracellular magnesium (icMg), which may coexist with normal serum Mg, might contribute to these deleterious effects. However, icMg content in normomagnesemic HF patients with RD or DM has not been studied. We assessed total icMg in peripheral blood mononuclear cells (PBMC) from 80 normomagnesemic furosemide-treated HF patients who were divided as follows: subgroups A (DM), B (RD), C (DM and RD), and D (free of DM or RD). PBMC from 18 healthy volunteers served as controls. IcMg content (μg/mg cell protein) in HF was lower compared to controls (1.68±0.2 vs. 2.4±0.39, p<0.001). In the entire HF group, a significant inverse correlation was evident between icMg and serum creatinine (r=−0.37) and daily furosemide dosages (r=−0.121). IcMg in the HF subgroups A, B, C, and D was 1.79±0.23, 1.57±0.23, 1.61±0.25, and 1.79±0.39, respectively (p=0.04 between A and B, p=0.08 between B and D, and non-significant in the remaining comparisons). Serum Mg, potassium, calcium, furosemide dosages and left ventricular ejection fraction were comparable in all subgroups. In conclusion, icMg depletion was demonstrable in PBMC, which may be responsible for some of the adverse clinical manifestations in HF patients. In particular, icMg depletion in RD might contribute to cardiac arrhythmias in this patient group. Mg supplementation to normomagnesemic HF patients might therefore prove beneficial.     

Autophagic vacuoles in cardiomyocytes of dilated cardiomyopathy with initially decompensated heart failure predict improved prognosis

Autophagy is a process of bulk protein degradation and organelle turnover, and is a current therapeutic target in several diseases. The present study aimed to clarify the significance of myocardial autophagy of patients with dilated cardiomyopathy (DCM). Left ventricular endomyocardial biopsy was performed in 250 consecutive patients with DCM (54.9±13.9 years; male, 79%), initially presenting with decompensated heart failure (HF). The association of these findings with HF mortality or recurrence was examined. Myofilament changes, which are apparent in the degenerated cardiomyocytes of DCM, were recognized in 164 patients (66%), and autophagic vacuoles in cardiomyocytes were identified in or near the area of myofilament changes in 86 patients (34%). Morphometrically, fibrosis (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93 to 0.99) and mitochondrial abnormality (OR, 2.24; 95% CI, 1.23 to 4.08) were independently related with autophagic vacuoles. During the follow-up period of 4.9±3.9 y, 24 patients (10%) died, including 10 (4%) who died of HF, and 67 (27%) were readmitted for HF recurrence. Multivariate analysis identified a family history of DCM (hazard ratio [HR], 2.117; 95% CI, 1.199 to 3.738), hemoglobin level (HR, 0.845; 95% CI, 0.749 to 0.953), myofilament changes (HR, 13.525; 95% CI, 5.340 to 34.255), and autophagic vacuoles (HR, 0.214; 95% CI, 0.114 to 0.400) as independent predictors of death or readmission due to HF recurrence. In conclusion, autophagic vacuoles in cardiomyocytes are associated with a better HF prognosis in patients with DCM, suggesting autophagy may play a role in the prevention of myocardial degeneration.     

应用C-反应蛋白区别急性失代偿性心力衰竭与肺炎

目的研究通过测定入院时C-反应蛋白（CRP）水平和CRP速度来鉴别急性失代偿性心力衰竭（ADHF）与肺炎的功效。方法回顾性研究三级医院两年的ADHF与肺炎患者的病例资料。住院时已经用抗生素治疗的患者除外。CRP作为诊断标志物的有效性通过ROC来评估。结果 72例ADHF和50例肺炎患者被纳入研究。ADHF患者入院时平均CRP水平为（13.5±13.5）mg/L,而肺炎患者为（127±84）mg/L（P〈0.001）。CRP增加大于等于0.56 mg/（L·h）时诊断肺炎。入院时CRP水平和CRP升高作为区别肺炎与ADHF的标记物时的敏感度是0.96,特异性为0.972。结论本研究强调生物标志物的动态特性,证实了急性期反复测量CRP的有效性,它将为临床医生提供有价值的工具来建立正确的诊断及减少不必要的抗生素使用。     

The GALA study: relationship between galectin-3 serum levels and short- and long-term outcomes of patients with acute heart failure

Objective: We tested the hypothesis that early measurement of galectin-3 at the emergency department (ED) during an episode of acute heart failure (AHF) allows predicting short- and long-term outcomes.

Methods: We performed an exploratory study including 115 patients consecutively diagnosed with AHF in a single ED. Clinical and analytical variables were recorded. The primary endpoint was 30-day all-cause mortality, and secondary endpoints were 30-day composite outcome (death, rehospitalization or ED reconsultation, whichever first) and 1-year mortality.

Results: Seven patients (6.1%) died within 30?days and 43 (37.4%) within 1?year. The 30-day composite endpoint was observed in 21.1% of patients. Galectin-3 was correlated with NT-proBNP and the glomerular filtration rate but not with age and s-cTnI. Measured at time of ED arrival, galectin-3 showed good discriminatory capacity for 30-day mortality (AUC ROC: 0.732; 95% CI 0.512–0.953; p?=?0.041) but not for 1-year mortality (0.521; 0.408–0.633; p?=?0.722). Patients with galectin-3 concentrations?>42?μg/L had an OR?=?7.67(95%CI?=?1.57-37.53; p?=?0.012) for 30-day mortality. Conversely, NT-proBNP only showed predictive capacity for 1-year mortality (0.642; 0.537–0.748; p?=?0.014). Patients with NT-proBNP concentrations?>5400?ng/L had an OR?=?4.34 (95%CI?=?1.93-9.77; p?<?0.001) for 1-year mortality. These increased short- (galectin-3) and long-term (NT-proBNP) risks remained significant after adjustment for age or renal function. s-cTnI failed in both short- and long term death prediction. No biomarker predicted the short-term composite endpoint.

Conclusion: These results suggest that galectin-3 could help to monitor the risk of short-term mortality in unselected patients with AHF attended in the ED.     

Redox-sensitive mechanisms underlying vascular dysfunction in heart failure

Abstract

Regardless of the progress in therapeutic drugs and devices to treat heart failure (HF) during the last few years, the clinical outcome of this disease remains deleterious. Impaired left ventricular function leads to neurohumoral activation, altered local shear forces, and hypoxia, which might give rise to inflammatory processes within the vasculature. Among those, the imbalance of the redox equilibrium toward increased concentrations of reactive oxygen species (ROS) is particularly important, as it affects the integrity of vascular function. Apart from injured or dysfunctional cardiomyocytes, vascular dysfunction has been demonstrated to play a crucial role in the development and progression of HF, which makes it an interesting target for new HF therapies. The mechanisms that initiate vascular dysfunction in HF pathogenesis and the processes leading to oxidative stress are not yet fully elucidated. However, oxidative stress promotes a variety of redox-sensitive mechanisms contributing to vascular dysfunction in HF. Here, we will summarize the sources of ROS in the vasculature, elucidate the impact of oxidative stress on functional and structural vascular remodeling, and consider the link to vascular dysfunction. Furthermore, we will point out the importance of vascular dysfunction in HF and discuss therapeutic options.     

Regulation of circulating chromogranin B levels in heart failure

Background: Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF.

Methods and results: We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair.

Conclusion: CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.     

Association of serum total bilirubin levels with diastolic dysfunction in heart failure with preserved ejection fraction

Background

Left ventricular diastolic dysfunction is one of the main characteristics of heart failure patients with a preserved left ventricular ejection fraction. As bilirubin is regarded as an important endogenous antioxidant molecule, serum total bilirubin levels were compared between heart failure patients with a preserved left ventricular ejection fraction and normal controls in this study. We recruited 327 heart failure patients with a preserved left ventricular ejection fraction and 200 healthy controls. Patients were divided into 4 subgroups by their comprehensive echocardiographic manifestations, 1-mild, 2-moderate, 3-severe (reversible restrictive), 4-severe (fixed restrictive). Total bilirubin levels were compared using stepwise multiple regressions adjusted for selected factors.

Results

After adjusting for gender, age, smoking, systolic blood pressure, diastolic blood pressure, total cholesterol and triglyceride, serum total bilirubin levels were significantly lower in the heart failure group compared with the control group (P < 0.01). Patients in the subgroup (4-severe) showed significantly (P < 0.05) lower levels of total bilirubin when compared with the subgroup (1-mild).

Conclusions

TB level was negatively correlated with left ventricular diastolic dysfunction in heart failure patients with a preserved left ventricular ejection fraction, which might provide a new insight into the complicated mechanisms of heart failure with a preserved left ventricular ejection fraction.     

Genetic risk scores to predict the prognosis of chronic heart failure patients in Chinese Han

Chronic heart failure (CHF) has poor prognosis and polygenic heritability, and the genetic risk score (GRS) to predict CHF outcome has not yet been researched comprehensively. In this study, we sought to establish GRS to predict the outcomes of CHF. We re‐analysed the proteomics data of failing human heart and combined them to filter the data of high‐throughput sequencing in 1000 Chinese CHF cohort. Cox hazards models were used based on single nucleotide polymorphisms (SNPs) to estimate the association of GRS with the prognosis of CHF, and to analyse the difference between individual SNPs and tertiles of genetic risk. In the cohort study, GRS encompassing eight SNPs harboured in seven genes were significantly associated with the prognosis of CHF (P = 2.19 × 10^?10 after adjustment). GRS was used in stratifying individuals into significantly different CHF risk, with those in the top tertiles of GRS distribution having HR of 3.68 (95% CI: 2.40‐5.65 P = 2.47 × 10^?10) compared with those in the bottom. We developed GRS and demonstrated its association with first event of heart failure endpoint. GRS might be used to stratify individuals for CHF prognostic risk and to predict the outcomes of genomic screening as a complement to conventional risk and NT‐proBNP.     

Usefulness of parathyroid hormone as a predictor of heart failure with preserved ejection fraction

Objective: To investigate the relation between parathyroid hormone (PTH) and heart failure with preserved ejection fraction (HF-PEF) in outpatients.

Methods: One hundred consecutive patients who had preserved left ventricular (LV) ejection fraction and heart failure (HF) symptoms, were enrolled. Echocardiography, assessing the diastolic functions was performed. Blood samples were collected for intact PTH and brain natriuretic peptide (BNP).

Results: Significant correlations between PTH level and predictors of advanced HF-PEF were found (p < 0.05). PTH level and left atrium diameter were found to be independent predictors of DHF.

Conclusion: Measurement of serum PTH provides complementary information for the diagnosis and prognosis of HF-PEF.     

Deleterious cardiovascular effect of exosome in digitalis‐treated decompensated congestive heart failure

Heart failure (HF) is a medical condition inability of the heart to pump sufficient blood to meet the metabolic demand of the body to take place. The number of hospitalized patients with cardiovascular diseases is estimated to be more than 1 million each year, of which 80% to 90% of patients ultimately progress to decompensated HF. Digitalis glycosides exert modest inotropic actions when administered to patients with decompensated HF. Although its efficacy in patients with HF and atrial fibrillation is clear, its value in patients with HF and sinus rhythm has often been questioned. A series of recent studies have cast serious doubt on the benefit of digoxin when added to contemporary HF treatment. We are hypothesizing the role and mechanism of exosome and its biological constituents responsible for worsening the disease state and mortality in decompensated HF patients on digitalis.     

Role of nitric oxide synthase activity in experimental ischemic acute renal failure in rats

To determine the role of nitric oxide (NO) in acute renal failure (ARF), we have studied the time course change activities to activity of nitric oxide synthase (NOS) isoform activities, both calcium dependent and independent NOS, in experimental ischemic ARF. We have also analyzed change activities to activity of the NOS activities in both renal cortex and medulla. Male SD rats (n = 5) were inducted to ARF by ischemia-reperfusion injury and divided into the following groups; Control group (sham operation), Day 0 group, (measurement performed on that day of operation), Day 1 group, (measurement performed one day after induction of ARF), Day 3 group and Day 7 group. Measurement of NOS activity was based on the following principles; NO is synthesized from arginine by nitric oxide synthase (NOS) and NO is converted to NO₂ ^–/NO₃ ^– (NOx) by oxidation. Detection of the final metabolite of NO, NOx was done using flow injection method (Griess reaction). The results were, (1) calcium dependent NOS activity in the cortex and medulla decreased, however it increased in the recovery period in the renal cortex (Cortex; Control, 0.941 ± 0.765, D0, 0.382 ± 0.271, D1, 0.118 ± 0.353, D3, 2.030 ± 0.235, D7, 3.588 ± 2.706, Medulla; Control, 1.469 ± 0.531, D0, 0.766 ± 0.156, D1, 0.828 ± 0.187, D3, 2.078 ± 0.094, D7, 1.289 ± 0.313 mol NOx produced/mg protein/30 min). (2) On the other hand, iNOS activity increased in the early phase of ARF, both in the cortex and medulla, but returned to control values during the recovery phase in cortex and was maintained at higher levels in the medulla (Cortex; Control, 0.333 ± 0.250, D0, 0.583 ± 0.428, D1, 1.167 ± 0.262, D3, 0.250 ± 0.077, D7, 0.452 ± 0.292, Medulla; Control, 0.139 ± 0.169, D0, 0.279 ± 0.070, D1, 1.140 ± 0.226, D3, 0.452 ± 0.048, D7, 0.625 ± 0.048 mol NOx produced/mg protein/30 min). These findings suggest that the role of NOS in ARF are different for the different NOS isoforms and have anatomic heterogeneity.     

Galectin 3 complements BNP in risk stratification in acute heart failure

Background: Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure.

Methods: Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial.

Results: Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide.

Conclusion: In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.     

Role of apoptosis of renal tubular cells in acute renal failure: Therapeutic implications

Acute renal failure (ARF) can be defined as a sudden loss of renal function and is a common and serious clinical problem. There are many causes of ARF but the most common cause results from injury to the renal tubular epi-thelial cells (RTECs). RTECs can be injured by schemia or by cytotoxic agents and, once injured, can die by necrosis or apotosis. In general, necrosis occurs in response to any severe injury, which leads to the biochemical collapse of the cell. Milder forms of the same types of injury cause apoptosis. At the cellular level there are fundamental differences between necrosis and apoptosis. Necrosis results from the additive effect of a number of independent biochemical events that are activated by severe depletion of cell energy stores. By contrast, apoptosis occurs via a coordinated, predictable and pre-determined pathway. These biochemical differences between apoptosis and necrosis have important therapeutic implications. Once a cell has been severely injured, necrosis is difficult to prevent. By contrast, the apoptotic pathway can potentially be modulated to maintain cell viability. The components of the apoptotic pathway that are potentially amenable to therapeutic modulation are discussed in detail in this review.     

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure

The thiazolidinedione (TZD) class of Peroxisome proliferator‐activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt‐retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H₂O retention or up‐regulation of Na⁺ transport‐linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto‐caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S‐Nitroso‐N‐acetylpenicillamine (SNAP‐NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF‐related genes and ANP signalling in the kidney were determined. RGZ‐treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This ‘sensitization’ to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down‐regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up‐regulation of ACE2, Agtrla, Mme and Cftr along down‐regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This ‘sensitization’ to ANP is independent of cGMP signalling, yet may involve post‐cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations.     

Changes and significance of serum angiopoietin-2 levels in patients with coronary heart disease

Coronary heart disease (CHD) is characterized by inflammatory process and endothelial dysfunction. To investigate angiopoietin-2 (Ang-2) profiles, we evaluated serum Ang-2 levels in different types of CHD in 166 subjects. Ang-2 was measured by enzyme-linked immunosorbent assay. Serum Ang-2 levels were significantly elevated in patients with CHD and gradually increased with advance of CHD. Ang-2 was positively correlated with Gensini scores and hs-CRP. Ang-2 might have potential implication in detecting and monitoring the progression of CHD.     

Differential expression of microRNA in serum fractions and association of Argonaute 1 microRNAs with heart failure

The serum or plasma microRNA (miRNA) molecules have been suggested as diagnostic and prognostic biomarkers, in various pathological conditions. However, these molecules are also found in different serum fractions, such as exosomes and Argonaute (Ago) protein complexes. Ago1 is the predominant Ago protein expressed in heart tissue. The objective of the study was to examine the hypothesis that Ago1‐associated miRNAs may be more relevant to cardiac disease and heart failure compared with the serum. In total, 84 miRNA molecules were screened for their expression in the whole serum, exosomes and Ago1, and Ago2 complexes. Ago1‐bound miR‐222‐3p, miR‐497‐5p and miR‐21‐5p were significantly higher, and let‐7a‐5p was significantly lower in HF patients compared with healthy controls, whereas no such difference was observed for those markers in the serum samples among the groups. A combination of these 4 miRNAs into an Ago1‐HF score provided a ROC curve with an AUC of 1, demonstrating clear discrimination between heart failure patients and healthy individuals. Ago1 fraction might be a better and more specific platform for identifying HF‐related miRNAs compared with the whole serum.     

Circulating LIPCAR is a potential biomarker of heart failure in patients post-acute myocardial infarction

In heart failure (HF) patients with reduced ejection fraction, LIPCAR, a long noncoding RNA is elevated and is associated with left ventricular remodeling and poor prognosis. We studied the role of LIPCAR in patients with HF post-acute myocardial infarction (AMI) to find biomarkers for early detection of HF. We conducted a study of 127 patients with AMI, of which 59 were patients with HF post-AMI. LIPCAR levels were higher in HF patients post-AMI than patients without HF, and LIPCAR had a high predictive value for diagnosis of HF, which was estimated by receiver operating characteristic curves (AUC: 0.985). The results indicate that LIPCAR may be a marker of early HF after AMI.