Search

Enhancers regulate gene expressions in a tissue- and pathology-specific manner by altering its activities. Plasma levels of atrial and brain natriuretic peptides, encoded by the Nppa and Nppb, respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative Nppb enhancer at 22-kb upstream from the Nppb gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in Nppb expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and Nppb expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and Nppb expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and Nppa and Nppb expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell-specific response to mechanical loads than the -520-bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Accumulating evidence indicates that the brain natriuretic peptide (BNP) and its receptor (natriuretic peptide receptor, NPR) are widely distributed in a variety of tissues including trigeminal ganglion (TG). Furthermore, recent studies support the involvement of the BNP-NPR-A pathway in acute and chronic pain. To investigate the role of this pathway in chronic pain, an infraorbital nerve-chronic constriction injury (ION-CCI) model of trigeminal neuralgia (TN) was produced in the rat. The time course of changes in mechanical pain threshold was examined. We observed an upregulation of BNP and NPR-A and a downregulation of large-conductance Ca 2+ -activated K + (BKCa) mRNA and protein in rats subjected to ION-CCI. Patch clamping experiments in vitro found that BKCa currents were significantly reduced in rats subjected to ION-CCI. BNP increased BKCa currents in ION-CCI rats. These results suggest that BNP and NPR-A might serve as endogenous pain relievers in ION-CCI rats. Modulation of the BNP/NPR-A/BKCa channel pathway in TG may be a viable strategy for the treatment of TN. NEW & NOTEWORTHY BNP has been known to activate its receptor, NPR-A, to modulate inflammatory pain. However, the potential modulatory roles of BNP in TN have not been investigated in detail. We established an ION-CCI model of TN in the rat and observed an upregulation of BNP and NPR-A and a downregulation of BKCa in rats subjected to ION-CCI. Moreover, BNP can increase BKCa currents in ION-CCI rats. Thus, BNP and NPR-A might have inhibitory effects on trigeminal neuralgia through activating the BNP/NPR-A/BKCa channel pathway.

Mitochondrial dysfunction has been suggested to be the key factor in the development and progression of cardiac hypertrophy. The onset of mitochondrial dysfunction and the mechanisms underlying the development of cardiac hypertrophy (CH) are incompletely understood. The present study is based on the use of multiple bioinformatics analyses for the organization and analysis of scRNA-seq and microarray datasets from a transverse aortic constriction (TAC) model to examine the potential role of mitochondrial dysfunction in the pathophysiology of CH. The results showed that NADH:ubiquinone oxidoreductase core subunit S1- (Ndufs1-) dependent mitochondrial dysfunction plays a key role in pressure overload-induced CH. Furthermore, in vivo animal studies using a TAC mouse model of CH showed that Ndufs1 expression was significantly downregulated in hypertrophic heart tissue compared to that in normal controls. In an in vitro model of angiotensin II- (Ang II-) induced cardiomyocyte hypertrophy, Ang II treatment significantly downregulated the expression of Ndufs1 in cardiomyocytes. In vitro mechanistic studies showed that Ndufs1 knockdown induced CH; decreased the mitochondrial DNA content, mitochondrial membrane potential (MMP), and mitochondrial mass; and increased the production of mitochondrial reactive oxygen species (ROS) in cardiomyocytes. On the other hand, Ang II treatment upregulated the expression levels of atrial natriuretic peptide, brain natriuretic peptide, and myosin heavy chain beta; decreased the mitochondrial DNA content, MMP, and mitochondrial mass; and increased mitochondrial ROS production in cardiomyocytes. The Ang II-mediated effects were significantly attenuated by overexpression of Ndufs1 in rat cardiomyocytes. In conclusion, our results demonstrate downregulation of Ndufs1 in hypertrophic heart tissue, and the results of mechanistic studies suggest that Ndufs1 deficiency may cause mitochondrial dysfunction in cardiomyocytes, which may be associated with the development and progression of CH., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2021 Rongjun Zou et al.)

The heart is closely connected with the endocrine system. On the one hand, the heart is an endocrine organ itself and produces several hormones like atrial and brain natriuretic peptides. On the other hand, cardiac structures are targets of many hormones like catecholamines, thyroid hormones, and corticosteroids. Therefore, many endocrine diseases come with cardiac symptoms. In this article, we describe three instructive clinical cases of patients with hormonal disorders that mimicked cardiovascular disease. Furthermore, we shortly discuss useful diagnostic and treatment algorithms. All cases emphasize the value of interdisciplinary management of patients with cardiac symptoms., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

A four- and a half-month-old girl with severe dilated cardiomyopathy due to neonatal enterovirus myocarditis, treated with diuretics and milrinone for the past 4 months, was infected with SARS-CoV-2. The disease course was characterised by high fever and gastrointestinal symptoms. Cardiac function, as measured by echocardiography, remained stable. The treatment focused on maintaining a normal heart rate and a stable fluid balance. In children with severe underlying cardiac disease, even a mild SARS-CoV-2 infection can require close monitoring and compound treatment.

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and "in vitro." Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an "in vivo" heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2021 Orsolya Horvath et al.)

Background: High-output congestive heart failure secondary to high-flow arteriovenous fistula (AVF) has been reported in haemodialysis (HD) patients. As high-flow AVF (HFA) would be expected to result in fluid retention, we conducted an observational study to characterize the relationship between AVF flow (Qa) and extracellular water (ECW) in HD patients., Methods: We measured Qa by ultrasound dilution in prevalent HD outpatients with an AVF in two dialysis centres. The ECW:total body water (TBW) ratio was measured both pre- and post-dialysis by multifrequency bioimpedance analysis. Transthoracic echocardiograms (TTEs) were performed as part of routine clinical management., Results: We included 140 patients, mean age 62.7 ± 15.7 years, 60.7% male, 47.9% diabetic and 22.9% with coronary revascularization. Mean Qa was 1339 ± 761 mL/min and 22 (15.7%) patients had HFA defined as Qa >2.0 L/min. Qa was positively associated with an upper arm AVF (P = 0.005), body mass index (P = 0.012) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P = 0.047) and negatively associated with diabetes (P < 0.001) and coronary revascularization (P = 0.005). The ECW:TBW ratio was positively associated with age (P < 0.001), Davies comorbidity index (P = 0.034), peripheral vascular disease (P = 0.030) and NT-proBNP (P = 0.002) and negatively associated with serum albumin (P < 0.001). Qa was not associated with the ECW:TBW ratio (P = 0.744). TTE parameters were not associated with Qa., Conclusions: In our outpatient HD cohort, high AVF flow was not associated with ECW expansion, either pre- or post-dialysis when accounting for potential confounders. By controlling ECW, high access flow should not necessarily be perceived as a threat to cardiovascular physiology., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Despite the growing burden of heart failure (HF), there have been no recommendations for use of any of the primary prevention models in the existing guidelines. HF was also not included as an outcome in the American College of Cardiology/American Heart Association (ACC/AHA) risk score., Methods: Among 2743 men and 3646 women aged ≥ 55 years, free of HF, from the population-based Rotterdam Study cohort, 4 Cox models were fitted using the predictors of the ACC/AHA, ARIC and Health-ABC risk scores. Performance of the models for 10-year HF prediction was evaluated. Afterwards, performance and net reclassification improvement (NRI) for adding NT-proBNP to the ACC/AHA model were assessed., Results: During a median follow-up of 13 years, 429 men and 489 women developed HF. The ARIC model had the highest performance [c-statistic (95% confidence interval [CI]): 0.80 (0.78; 0.83) and 0.80 (0.78; 0.83) in men and women, respectively]. The c-statistic for the ACC/AHA model was 0.76 (0.74; 0.78) in men and 0.77 (0.75; 0.80) in women. Adding NT-proBNP to the ACC/AHA model increased the c-statistic to 0.80 (0.78 to 0.83) in men and 0.81 (0.79 to 0.84) in women. Sensitivity and specificity of the ACC/AHA model did not drastically change after addition of NT-proBNP. NRI(95%CI) was - 23.8% (- 19.2%; - 28.4%) in men and - 27.6% (- 30.7%; - 24.5%) in women for events and 57.9% (54.8%; 61.0%) in men and 52.8% (50.3%; 55.5%) in women for non-events., Conclusions: Acceptable performance of the model based on risk factors included in the ACC/AHA model advocates use of this model for prediction of HF risk in primary prevention setting. Addition of NT-proBNP modestly improved the model performance but did not lead to relevant discrimination improvement in clinical risk reclassification.

Background: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces cardiovascular death and worsening heart failure in patients with chronic heart failure and reduced ejection fraction. Early initiation during an acute heart failure (AHF) hospitalization may facilitate decongestion, improve natriuresis, and facilitate safe transition to a beneficial outpatient therapy for both diabetes and heart failure., Objective: The objective is to assess the efficacy and safety of initiating dapagliflozin within the first 24 hours of hospitalization in patients with AHF compared to usual care., Methods: DICTATE-AHF is a prospective, multicenter, open-label, randomized trial enrolling a planned 240 patients in the United States. Patients with type 2 diabetes hospitalized with hypervolemic AHF and an estimated glomerular filtration rate of at least 30 mL/min/1.73m 2 are eligible for participation. Patients are randomly assigned 1:1 to dapagliflozin 10 mg once daily or structured usual care until day 5 or hospital discharge. Both treatment arms receive protocolized diuretic and insulin therapies. The primary endpoint is diuretic response expressed as the cumulative change in weight per cumulative loop diuretic dose in 40 mg intravenous furosemide equivalents. Secondary and exploratory endpoints include inpatient worsening AHF, 30-day hospital readmission for AHF or diabetic reasons, change in NT-proBNP, and measures of natriuresis. Safety endpoints include the incidence of hyper/hypoglycemia, ketoacidosis, worsening kidney function, hypovolemic hypotension, and inpatient mortality., Conclusions: The DICTATE-AHF trial will establish the efficacy and safety of early initiation of dapagliflozin during AHF across both AHF and diabetic outcomes in patients with diabetes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Patients affected by heart failure with reduced ejection fraction (HFrEF) receive clinical and functional beneficial effects from treatment with sacubitril/valsartan. However previous studies have shown that patients with an implantable cardioverter defibrillator (ICD) could obtain even greater benefit, but only make up a only a small proportion of patients. In the current study we evaluated the effect of sacubitril/valsartan in patients with an ICD., Methods: Thirty-five outpatients with HFrEF (aged 60 ± 11 years, 28 were males), on optimal medical therapy were studied. All patients received an ICD at least 6 months before enrollment or were non-responders to ICD plus resynchronization (CRT-D). An open-label sacubitril/valsartan treatment was established at the maximum tolerated dose. Clinical assessment, 6-min walk test (6MWT) and echocardiography, were performed during follow-up at 90, 180, and 360 days. Quality of life score and perceived fatigue on exercise were assessed., Results: Clinical conditions dramatically improved in most patients, especially within the first 6 months of therapy (76 % were in NYHA-I and 24 % in NYHA-II at the end of study vs 71 % NYHA-II and 29 % NYHA III at enrollment, p < 0.001). Quality of life and exercise performance significantly improved according to N-terminal pro-brain natriuretic peptide (NT-proBNP) serum levels lowering. Walking distance at 6MWT increased from 274 ± 97 to 389 ± 53 m and walking speed from 0.74 ± 0.27 to 1.07 ± 0.15 m/s (p < 0.001), while oxygen saturation did not differ significantly (from 90 ± 1 % to 91 ± 2 %). More gradual was left ventricular reverse remodeling. Ejection fraction improved mildly (+ 5 points %, p < 0.001). Global longitudinal strain and diastolic function were also assessed over time., Conclusion: Sacubitril/valsartan therapy for HFrEF may lead to significant clinical and functional improvements even in patients with ICD at greater arrhythmic risk. Clinical improvement is obtained within the first 6 months of treatment while reverse remodeling needs more time.

Purpose: Acute decompensated heart failure (ADHF) caused by ischemic heart disease is associated with higher mortality and requires immediate diagnosis. Recently, novel methods to diagnose non-ST elevation myocardial infarction (NSTEMI) using high-sensitivity cardiac troponin have been applied. We compared the clinical utility of high-sensitivity troponin I (hS-TnI), delta troponin I, and other traditional methods to diagnose NSTEMI in patients with ADHF., Materials and Methods: This retrospective cross-sectional study was conducted to analyze patients with ADHF who underwent hS-TnI evaluation of 0-2-h protocol in our emergency department. Patients were grouped according to a diagnosis of NSTEMI., Results: A total of 524 ADHF [ADHF with NSTEMI, n=109 (20.8%)] patients were enrolled in this analysis. The mean values of hS-TnI (ng/mL) in the ADHF with and without NSTEMI groups were 2.44±5.60 and 0.25±0.91, respectively. Multivariable analysis revealed that regional wall-motion abnormality, T-wave inversion/hyperacute T wave, and initial and delta hS-TnI were predictive factors for NSTEMI. Laboratory values related to cardiac biomarkers, including hS-TnI [odds ratio (OR) (95% confidence interval, CI): 2.18], and the delta hS-TnI [OR (95% CI): 1.55] were significant predictors of NSTEMI. Moreover, receiver operating characteristic analysis showed that the areas under receiver operating characteristic curves for electrocardiographic abnormalities, initial hS-TnI, and delta hS-TnI were 0.794, 0.802, and 0.773, respectively., Conclusion: For diagnosis of suspected NSTEMI in patients with ADHF, initial hS-TnI assay has similar predictive value as ischemic changes on electrocardiogram and superior predictive value than delta hS-TnI calculated by the 0-2-h protocol., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2021.)

Aims/hypothesis: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D 3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes., Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D 3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years., Results: A total of 333 participants were randomised to vitamin D 3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D 3 , 370 to vitamin D 3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D 3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index., Conclusions/interpretation: Among adults with type 2 diabetes, supplementation with vitamin D 3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years., Trial Registration: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.

Aims: Natural products still serves as a hope for some illnesses which modern medicine fails to cure. Many people, either knowing their effects or not, are using these herbal products. Treatment of chronic heart failure (CHF) is yet a complicated clinical challenge and there is need to improve or make new therapeutic targets. Finding new agents for CHF is an important subject in cardiovascular drug research. In this study, we evaluated the effects of ten herbals on treatment of CHF on isoproterenol-induced model., Methods and Results: Ninety-six male Wistar rats (16 weeks old) were used in 12 groups. Transthoracic echocardiography was performed on the rats for confirmation of CHF model by decreasing ejection fraction. After 4 weeks' treatment, hearts were removed and blood samples were collected in tubes to measure plasma levels of laboratory findings. Our results showed that the mean of ejection fraction in model rats was 51.82 ± 3.49 percent and all of our used natural products could significantly increase the ejection fraction (P < 0.01). The most effective herbals in improving the ejection fraction were Allium sativum (30.69 %), Peganum harmala (26.08 %) and Apium graveolens (24.09 %). The best results in decreasing NT-ProBNP, was obtained from Allium sativum, Peganum harmala and Berberis vulgaris respectively. Our results showed that none of natural products had toxic effect on renal and liver tissues., Conclusion: Our results showed that Allium sativum, Peganum harmala and Berberis vulgaris could significantly improve cardiac function by improvement of left ventricular remodeling, lowering hs-CRP and NT-ProBNP and echocardiographic indexes without liver or renal side effects., (Copyright © 2020. Published by Elsevier Masson SAS.)

On March 11, 2020 the World Health Organization (WHO) declared the state of global pandemic caused by the new SARS-CoV-2 (COVID-19). To date, no antivirals directed against SARS-CoV-2 or effective vaccines to combat the viral infection are available. Severe acute respiratory syndrome caused by SARS-CoV-2 is treated empirically with antivirals, anti-inflammatory, anticoagulants. The approval of an effective vaccine still takes time. In this state, it may be useful to find new therapeutic solutions from drugs already on the market. Recent hypotheses suggest that the use of AT-1 receptor antagonists (ARB) in combination with neprilisin inhibitors (NEPi) could indirectly provide clinical benefits to patients with SARS-CoV-2 and cardiac involvement. In this article we investigate and describe a possible innovative pharmacological approach for the treatment of the most severe stages of COVID-19 infection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

BACKGROUND Serum lactate, troponin, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been proposed to be useful prognostic indicators in patients with sepsis and septic shock. This study aimed to evaluate the predictive ability of these biomarkers and assess how their prognostic utility may be improved by using them in combination. MATERIAL AND METHODS A retrospective review of the medical records of 1242 patients with sepsis and septic shock who were admitted to the Richmond University Medical Center between June 1, 2018, and June 1, 2019, was carried out; 427 patients met the study criteria and were included in the study. The primary outcome measures included 30-day mortality, APACHE II scores, length of hospital stay, and admission to the Medical Intensive Care Unit (MICU). RESULTS High levels of lactate (>4 mmol/L), troponin (>0.45 ng/mL), and NT-proBNP (>8000 pg/mL) were independent predictors of 30-day mortality, with an adjusted odds ratio of mortality being 3.19 times, 2.13 times, and 2.5 times higher, respectively, compared with corresponding reference groups, at 95% confidence intervals. Elevated levels of lactate, troponin, and NT-proBNP were associated with 9.12 points, 7.70 points, and 8.88 points in higher APACHE II scores, respectively. Only elevated troponin levels were predictive of a longer length of hospital stay. In contrast, elevated lactate and troponin were associated with an increased chance of admission to the MICU. CONCLUSIONS Elevated levels of serum lactate, troponin, and NT-proBNP are independent predictors of mortality and higher APACHE II scores in patients with sepsis and septic shock.

Background: L-carnitine mediates the utilization of fatty acids and glucose in the myocardium. The potential of L-carnitine in managing dilated cardiomyopathy (DCM) in patients has been extensively reported, with additional benefits., Objective: This meta-analysis purposed to explore the clinical efficacy of L-carnitine therapy on DCM patients., Methods: We searched publications up to May 2020 from several databases including PubMed, Embase, Cochrane Library, Chinese Biomedical (CBM) database, Chinese Science and Technology Periodicals database (VIP), Chinese National Knowledge Infrastructure (CNKI) database, and Wanfang database. Subsequently, publications that met the inclusion criteria were systematically evaluated by two independent reviewers., Results: A total of 23 RCTs conducted in China with 1455 DCM patients were included in this study. In the meta-analysis, L-carnitine therapy was associated with a considerable improvement in the overall efficacy (RR = 1.28, 95% CI (1.21-1.36), P < 0.0001), left ventricular ejection fraction (LVEF) (MD = 6.16%, 95% CI (4.50, 7.83), P < 0.0001), and cardiac output (CO) (MD = 0.88 L/min, 95% CI (0.51, 1.25), P < 0.0001) as compared to the control group. Moreover, L-carnitine therapy significantly decreased left ventricular end-diastolic dimension (LVEDD) (MD = -2.53, 95% CI (-3.95, -1.12), P = 0.0005), brain natriuretic peptide (BNP) (SMD = -1.71 ng/L, 95% CI (-3.02, -0.40), P = 0.01), and the transforming growth factor-beta (TGF- β 1) (MD = -56.78 ng/L, 95% CI (-66.02, -47.53), P < 0.0001)., Conclusions: L-carnitine potentially enhanced the therapeutic efficiency in DCM patients. Following weaknesses in the evidence due to low methodological quality and high clinical heterogeneity in the included studies, well-designed trials are recommended., Competing Interests: The authors declared no conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2021 Yayun Weng et al.)

Rationale: ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide), encoded by the clustered genes Nppa and Nppb , are important prognostic, diagnostic, and therapeutic proteins in cardiac disease. The spatiotemporal expression pattern and stress-induction of the Nppa and Nppb are tightly regulated, possibly involving their coregulation by an evolutionary conserved enhancer cluster., Objective: To explore the physiological functions of the enhancer cluster and elucidate the genomic mechanism underlying Nppa-Nppb coregulation in vivo., Methods and Results: By analyzing epigenetic data we uncovered an enhancer cluster with super enhancer characteristics upstream of Nppb . Using CRISPR/Cas9 genome editing, the enhancer cluster or parts thereof, Nppb and flanking regions or the entire genomic block spanning Nppa-Nppb , respectively, were deleted from the mouse genome. The impact on gene regulation and phenotype of the respective mouse lines was investigated by transcriptomic, epigenomic, and phenotypic analyses. The enhancer cluster was essential for prenatal and postnatal ventricular expression of Nppa and Nppb but not of any other gene. Enhancer cluster-deficient mice showed enlarged hearts before and after birth, similar to Nppa-Nppb compound knockout mice we generated. Analysis of the other deletion alleles indicated the enhancer cluster engages the promoters of Nppa and Nppb in a competitive rather than a cooperative mode, resulting in increased Nppa expression when Nppb and flanking sequences were deleted. The enhancer cluster maintained its active epigenetic state and selectivity when its target genes are absent. In enhancer cluster-deficient animals, Nppa was induced but remained low in the postmyocardial infarction border zone and in the hypertrophic ventricle, involving regulatory sequences proximal to Nppa ., Conclusions: Coordinated ventricular expression of Nppa and Nppb is controlled in a competitive manner by a shared super enhancer, which is also required to augment stress-induced expression and to prevent premature hypertrophy.

Background: Several large trials have demonstrated cardiac benefits in patients with and without established cardiovascular disease treated with sodium-glucose co-transporter 2 inhibitors (SGLT2i). Most recently, in patients with heart failure with reduced ejection fraction (HFrEF), the risk of worsening HF or cardiovascular death was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. Biomarkers may provide insight into understanding the mechanism of cardiovascular benefit observed in patients receiving SLGT2i. Several mechanisms have been proposed, including improvement in ventricular unloading due to the natriuretic effects, afterload reduction via reduction in blood pressure and improvement in vascular function, improvement in cardiac metabolism and bioenergetics, and reduction in cardiac fibrosis and necrosis, among others., Content: We discuss several animal and human studies on the effect of SGLT2i on various biomarkers. Modest reduction or blunting of rise over time in concentrations of atrial natriuretic peptide, B-type natriuretic peptide, and N-terminal pro B-type natriuretic peptide and reduction in high-sensitivity troponin has been observed in patients receiving SLGT2i. Concentrations of biomarkers such as sST2 and galectin-3 have been unchanged whereas inflammatory markers such as fibronectin 1, interleukin-6, matrix metalloproteinase 7, and tumor necrosis factor-1 are decreased with SGLT2i therapy., Summary: The effect of SLGT2i on various circulating biomarkers allows insight into the understanding of mechanisms of cardiovascular benefits with SGLT2i use. Further studies are needed to understand such mechanisms and to understand how biomarkers can be used for risk prediction and personalization of care in patients receiving SLGT2i., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: ST2 is a circulating biomarker that is well established for predicting outcome in heart failure (HF). This is the first study to look at ST2 concentrations in optimally treated patients with stable but significant left ventricular systolic dysfunction (LVSD) compared to patients with severe aortic stenosis (AS)., Methods: Two cohorts were retrospectively studied: 94 patients undergoing transcatheter aortic valve implantation for severe AS (63 with normal ejection fraction [EF] and 31 with reduced EF), and 50 patients with severe LVSD from non-valvular causes. ST2 pre-procedural samples were taken, and repeated again at 3 and 6 months. Patients were followed-up for 2 years. Data was analyzed using SPSS software., Results: Baseline concentrations of soluble ST2 did not differ significantly between the HF group and AS group with normal EF (EF ≥ 50%). However, in the AS group with a low EF (EF < 50%) ST2 concentrations were significantly higher that the HF group (p = 0.009). New York Heart Association class IV HF, baseline N-terminal pro-B-type natriuretic peptide and gender were all independent predictors of soluble ST2 (sST2) baseline concentrations., Conclusions: Raised ST2 concentrations in the context of severe AS may be a marker for subclinical or clinical left ventricular dysfunction. More research is required to assess its use for assessment of prognosis and response to treatment.

Metabolic shift is an important contributory factor for progression of hypertension-induced left ventricular hypertrophy into cardiac failure. Under hypertrophic conditions, heart switches its substrate preference from fatty acid to glucose. Prolonged dependence on glucose for energy production has adverse cardiovascular consequences. It was reported earlier that reactivation of fatty acid metabolism with medium chain triglycerides ameliorated cardiac hypertrophy, oxidative stress and energy level in spontaneously hypertensive rat. However, the molecular mechanism mediating the beneficial effect of medium chain triglycerides remained elusive. It was hypothesized that reduction of cardiomyocyte hypertrophy by medium chain fatty acid (MCFA) is mediated by modulation of signaling pathways over expressed in cardiac hypertrophy. The protective effect of medium chain fatty acid (MCFA) was evaluated in cellular model of myocyte hypertrophy. H9c2 cells were stimulated with Arginine vasopressin (AVP) for the induction of hypertrophy. Cell volume and secretion of brain natriuretic peptide (BNP) were used for assessment of cardiomyocyte hypertrophy. Cells were pretreated with MCFA (Caprylic acid) and metabolic modulation was assessed from the expression of medium-chain acyl-CoA dehydrogenase (MCAD), cluster of differentiation-36 (CD36) and peroxisome proliferator-activated receptor (PPAR)-α mRNA. The signaling molecules modified by MCFA was evaluated from protein expression of mitogen activated protein kinases (MAPK: ERK1/2, p38 and JNK) and Calcineurin A. Pretreatment with MCFA stimulated fatty acid metabolism in hypertrophic H9c2, with concomitant reduction of cell volume and BNP secretion. MCFA reduced activated ERK1/2, JNK and calicineurin A expression mediated by AVP. In conclusion, the beneficial effect of MCFA is possibly mediated by stimulation of fatty acid metabolism and modulation of MAPK and Calcineurin A.

Tolvaptan (TLV) carries the risk of serious side effects, and its introduction requires hospitalization. Therefore, it is important from the viewpoints of safety and medical economics to predict in advance, the patients for whom it will be effective and introduce it. The purpose of this study was to investigate the noninvasive and simple predictors for identifying TLV responders. We conducted a retrospective observational study of patients with heart failure who had TLV introduced at our hospital from January 1, 2017, to December 31, 2018. By using the body weight and BNP reduction as the effect indices, predictors of body weight and BNP reduction were extracted by logistic analysis. The sensitivity and specificity at the cutoff value obtained by ROC analysis were also examined. Among 85 subjects, urine sodium concentration >63 mEq/L [odds ratio (OR): 6.11, 95% confidence interval (CI): 1.36-27.4] was detected as a predictor of body weight reduction. The sensitivity at this cutoff value was 81%, and the specificity was 70%. Serum osmolarity>291 mOsm/L (OR: 3.76, 95% CI: 1.00-14.2), urine potassium concentration<21 mEq/L (OR: 4.45, 95% CI: 1.09-18.2), and urine sodium concentration>71 mEq/L (OR: 7.38, 95% CI: 2.05-26.6) were detected as predictors of BNP reduction. The sensitivities were 62%, 53%, and 73%, and the specificities were 58%, 68%, and 68%, respectively. Therefore, it was suggested that urine sodium concentration may be useful as a predictor of body weight and BNP decrease after TLV induction.

Clinical studies have indicated that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, can potentially inhibit chronic heart failure. In the Stat-LVDF study, a difference was noted in terms of the effect of lipophilic pitavastatin (PTV) and hydrophilic rosuvastatin (RSV) on plasma BNP, suggesting that statin lipophilicity and pharmacokinetics change the pleiotropic effect on heart failure in humans. Therefore, we assessed the beneficial effects of PTV on hypertrophy in cardiac myocytes compared with RSV at clinically used doses. Cultured cardiomyocytes were stimulated with 30 μM phenylephrine (PE) in the presence of PTV (250 nM) or RSV (50 nM). These doses were calculated based on the maximum blood concentration of statins used in clinical situations in Japan. The results showed that PTV, but not RSV, significantly inhibits the PE-induced increase in cell size and leucine incorporation without causing cell toxicity. In addition, PTV significantly suppressed PE-induced mRNA expression of hypertrophic response genes. PE-induced ERK phosphorylation was inhibited by PTV, but not by RSV. Furthermore, PTV significantly suppressed the angiotensin-II-induced proline incorporation in primary cultured cardiac fibroblasts. In conclusion, a clinical dose of PTV was noted to directly inhibit cardiomyocyte hypertrophy and cardiac fibrosis, suggesting that lipophilic PTV can be a potential drug candidate against chronic heart failure.

Background: Pulmonary arterial compliance (PAC) is a prognostic parameter in pulmonary arterial hypertension (PAH) reflecting the elasticity of the pulmonary vessels., Objectives: The objective of this post hoc analysis of a prospective randomized controlled trial (RCT) was to assess the effect of exercise training on PAC and stroke volume (SV) in patients with PAH and persistent/inoperable chronic thromboembolic pulmonary hypertension (CTEPH)., Method: From the previous RCT, 43 out of 87 patients with severe PAH (n = 29) and CTEPH (n = 14) had complete haemodynamic examinations at baseline and after 15 weeks by right heart catheterization and were analysed (53% female, 79% World Health Organization functional class III/IV, 58% combination therapy, 42% on supplemental oxygen therapy, training group n = 24, and control group n = 19). Medication remained unchanged for all patients., Results: Low-dose exercise training at 4-7 days/week significantly improved PAC (training group 0.33 ± 0.65 mL/mm Hg vs. control group -0.06 ± 1.10 mL/mm Hg; mean difference 0.39 mL/mm Hg, 95% confidence interval [CI] 0.15-0.94 mL/mm Hg; p = 0.004) and SV (training group 9.9 ± 13.4 mL/min vs. control group -4.2 ± 11.0 mL/min; mean difference 14.2 mL, 95% CI 6.5-21.8 mL; p < 0.001) in the training versus control group. Furthermore, exercise training significantly improved cardiac output and pulmonary vascular resistance at rest, peak oxygen consumption, and oxygen pulse., Conclusions: Our findings suggest that supervised exercise training may improve right ventricular function and PAC at the same time. Further prospective studies are needed to evaluate these findings., (© 2021 S. Karger AG, Basel.)

Background and Objective: This study presents the first results of 'SAUDIPH' registry, aiming to assess patient characteristics, treatment approach and clinical and survival outcomes in patients with PAH., Methods: The registry enrolled patients with Group 1 and Group 4 PH under clinical management in a specialized tertiary care centre from 2004 to 2018. Changes from baseline to last follow-up visit were assessed., Results: A total of 222 patients were enrolled, and Group 1 PH was the most frequent aetiology (57.7%). Mean age at diagnosis was 32 years. mPAP was 55.0 mm Hg and was higher for Group 1 PH (59.0 mm Hg, P < 0.001). At the last visit, most patients were on specific therapy (83.7%) and 30% shifted from FC III/IV to FC I/II. NT-proBNP improved by 29.2% in the overall population. The 1-, 3- and 5-year cumulative probabilities of survival were 95.6% (95% CI: 91.5-99.9%), 89.2% (95% CI: 82.1-96.9%) and 74.6% (95% CI: 59.4-93.7%), respectively. CHD-PAH demonstrated the best survival among Group 1 PAH with 1-, 3- and 5-year cumulative probability of 100%, 100%, and 75.0% (95% CI: 42.6-100), respectively., Conclusion: PAH was the most frequent aetiology and patients were younger at diagnosis compared to other cohorts. Most patients showed improvement in FC and NT-proBNP. The estimated 1-year survival was better than previous studies, possibly reflecting wider use of combination therapy and the high prevalence of CHD-PAH., (© 2020 Asian Pacific Society of Respirology.)

Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600 ppm for 45 min) and the survivors were sacrificed at 14 or 28 days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.

Patients older than 65 years hospitalized with COVID-19 have higher rates of intensive care unit admission and death when compared with younger patients. Cardiovascular conditions associated with COVID-19 include myocardial injury, acute myocarditis, cardiac arrhythmias, cardiomyopathies, cardiogenic shock, thromboembolic disease, and cardiac arrest. Few studies have described the clinical course of those at the upper extreme of age. We characterize the clinical course and outcomes of 73 patients with 80 years of age or older hospitalized at an academic center between March 15 and May 13, 2020. These patients had multiple comorbidities and often presented with atypical clinical findings such as altered sensorium, generalized weakness and falls. Cardiovascular manifestations observed at the time of presentation included new arrhythmia in 7/73 (10%), stroke/intracranial hemorrhage in 5/73 (7%), and elevated troponin in 27/58 (47%). During hospitalization, 38% of all patients required intensive care, 13% developed a need for renal replacement therapy, and 32% required vasopressor support. All-cause mortality was 47% and was highest in patients who were ever in intensive care (71%), required mechanical ventilation (83%), or vasopressors (91%), or developed a need for renal replacement therapy (100%). Patients older than 80 years old with COVID-19 have multiple unique risk factors which can be associated with increased cardiovascular involvement and death.

Objective: Mechanical ventilation is an important treatment for critically ill patients. Physicians generally perform a spontaneous breathing trial (SBT) to determine whether the patients can be weaned from mechanical ventilation, but almost 17% of the patients who pass the SBT still require respiratory support. Cardiac dysfunction is an important cause of weaning failure. The use of brain natriuretic peptide or N-terminal pro-BNP is a simple method to assess cardiac function. We performed a systematic review of investigations of brain natriuretic peptide or N-terminal pro-BNP as predictors of weaning from mechanical ventilation., Data Sources: PubMed (1950 to December 2020), Cochrane, and Embase (1974 to December 2020), and some Chinese databases for additional articles (China Biology Medicine (CBM), China Science and Technology Journal Database (CSTJ), and Wanfang Data and China National Knowledge Infrastructure (CNKI))., Study Selection: We systematically searched observation studies investigating the predictive value of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide in weaning outcome of patients with mechanical ventilation., Data Extraction: Two independent reviewers extracted data. The differences are resolved through consultation., Data Synthesis: We included 18 articles with 1416 patients and extracted six index tests with pooled sensitivity and specificity for each index test. For the BNP change rate predicting weaning success, the pooled sensitivity was 89% (83%-94%) and the pooled specificity was 82% (72%-89%) with the highest pooled AUC of 0.9511., Conclusions: The brain natriuretic peptide change rate is a reliable predictor of weaning outcome from mechanical ventilation.

Dysregulated inflammasome activation and interleukin (IL)-1β production are associated with several inflammatory disorders. Three different routes can lead to inflammasome activation: a canonical two-step, a non-canonical Caspase-4/5- and Gasdermin D-dependent, and an alternative Caspase-8-mediated pathway. Natriuretic Peptides (NPs), Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP), binding to Natriuretic Peptide Receptor-1 (NPR-1), signal by increasing cGMP (cyclic guanosine monophosphate) levels that, in turn, stimulate cGMP-dependent protein kinase-I (PKG-I). We previously demonstrated that, by counteracting inflammasome activation, NPs inhibit IL-1β secretion. Here we aimed to decipher the molecular mechanism underlying NPs effects on THP-1 cells stimulated with lipopolysaccharide (LPS) + ATP. Involvement of cGMP and PKG-I were assessed pre-treating THP-1 cells with the membrane-permeable analogue, 8-Br-cGMP, and the specific inhibitor KT-5823, respectively. We found that NPs, by activating NPR-1/cGMP/PKG-I axis, lead to phosphorylation of NLRP3 at Ser295 and to inflammasome platform disassembly. Moreover, by increasing intracellular cGMP levels and activating phosphodiesterases, NPs interfere with both Gasdermin D and Caspase-8 cleavage, indicating that they disturb non-canonical and alternative routes of inflammasome activation. These results showed that ANP and BNP anti-inflammatory and immunomodulatory actions may involve the inhibition of all the known routes of inflammasome activation. Thus, NPs might be proposed for the treatment of the plethora of diseases caused by a dysregulated inflammasome activation.

Among all diabetes mellitus-associated cardiovascular diseases, morbidity of diabetic myocardium with ischemia reperfusion injury (D-IRI) is increasing year by year. We aimed to discover a therapeutic biomarker and investigate its mechanism in D-IRI. High-fat diet and streptozotocin-induced diabetes rats were operated with IRI or sham. Recombined lentiviral vector encoding Apelin was injected into D-IRI rat via tail vein. Cardiac function, infarct size, cellular death and oxidative stress were major outcome measures. Cardiomyocyte ischemia reperfusion injury was more serious in D-IRI rats than in non-diabetes ischemia reperfusion injury (ND-IRI) rats. The secretion of NTproBNP was increased in D-IRI compared with ND-IRI. Bcl-2 expression was decreased, and Bax and cleaved caspase-3 expression was increased in D-IRI rats compared with ND-IRI rats, which were reversed after treatment with Apelin. Apelin-upregulation improved cardiomyocyte ischemia reperfusion injury and decreased NT-proBNP levels in D-IRI rats. Apelin overexpression enhanced PI3K and eNOS levels while reduced those of p38-MAPK and iNOS in D-IRI rats. Apelin overexpression protected against D-IRI through inhibiting apoptosis and oxidative stress via PI3K and p38MAPK signaling pathways in D-IRI rats. These findings provide critical new insight into understanding of Apelin's cardio-protective effects, which may become a novel therapeutic target for the diabetic IRI patients.

C. difficile infection (CDI) is not a merely "gut-confined" disease as toxemia could drive the development of CDI-related extra-intestinal effects. These effects could explain the high CDI-associated mortality, not just justified by diarrhea and dehydration. Here, the extra-intestinal effects of toxin A (TcdA) and B (TcdB) produced by C. difficile have been studied in vivo using the zebrafish embryo model. Noteworthy, protective properties of human serum albumin (HSA) towards toxins-induced extra-intestinal effects were also addressed. Zebrafish embryos were treated with TcdA, TcdB and/or HSA at 24 h post-fertilization. Embryos were analyzed for 48 h after treatment to check vital signs and morphological changes. Markers related to cardio-vascular damage and inflammation were evaluated by Real-Time quantitative PCR and/or western blotting. Both toxins induced cardiovascular damage in zebrafish embryos by different mechanisms: (i) direct toxicity (i.e., pericardial edema, cardiac chambers enlargement, endothelial alteration); (ii) increased hormonal production and release (i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), (iii) alteration of the vascular system through the increase of the vascular endothelial growth factor (VEGF-A) levels, as well as of its receptors, (iv) pro-inflammatory response through high cytokines production (i.e., CXCL8, IL1B, IL6 and TNFα) and (v) cell-mediated damage due to the increase in neutrophils number. In addition to cardiovascular damage, we observe skin alteration and inflammation. Finally, our data indicate a protective effect of HSA toward the toxins induced extra-intestinal effects. Together, our findings can serve as a starting point for humans' studies to substantiate and understand the extra-intestinal effects observed in CDI patients.

Background: Heart failure is a clinical diagnosis characterised by non-specific symptoms such as dyspnoea, fatigue and oedema. The aim of this pilot study was to investigate what role computed tomography pulmonary angiography could play in supporting a diagnosis of heart failure when a pulmonary embolism has been excluded., Methods: This was a prospective study using the National Integrated Medical Imaging System to assess the potential of computed tomography pulomary angiography (CTPA) as a diagnostic test for heart failure. Consecutive patients were collected from three hospitals of the University of Limerick Hospital Group. We reviewed 230 consecutive CTPA results for cardiac and lung features. Of these, we confirmed which had heart failure by comparison with brain natriuretic peptide (BNP) and echocardiogram criteria. Exclusion criteria included any patients with a diagnosis of pulmonary embolism., Results: Of these 230 patients, only 24 (10.4%) had both objective and clinical signs of heart failure. The most specific signs were shown to be left ventricular enlargement, left atrial enlargement and right ventricular enlargement, which approximated a specificity of 100% (CI 66.3-100.00%). CTPA was shown to match gold standard echocardiography closely in detecting abnormalities as per chi square; Right ventricular enlargement (value = 5.426 P = 0.02), left atrial enlargement (value = 4.9 P = 0.027) and left ventricular enlargement (value = 5.692 P = 0.017)., Conclusion: Findings on CTPA which included left ventricular enlargement, left atrial enlargement and right ventricular enlargement were shown to be specific for a diagnosis of heart failure. CTPA should be used by physicians awaiting echocardiography to help guide treatment in cases of suspected heart failure.

Objective: To investigate the relationship between Transient Receptor Potential Vanilloid 6 (TRPV6) and ST-elevation acute myocardial infarction (STEMI) patients., Methods: This observational research included a total of 221 patients with STEMI admitted during January 2017~August 2019. Additionally, 50 cases of non-ST-elevation acute myocardial infarction (NSTEMI) patients and 50 healthy individuals were enrolled as the control. Serum levels of TRPV6 were detected by ELISA method. The relationship between TRPV6, clinical characteristics, laboratory indices of CK-MB, TnI, NT-pro-B-type natriuretic peptide (NT-pro-BNP), C-reactive protein (CRP), and the left ventricular ejection fraction (LVEF%) was analyzed by statistical methods. K-M curve was performed for survival time., Results: Serum levels of TRPV6 were remarkably lower in STEMI and NSTEMI patients compared with the healthy control. Levels of NT-pro-BNP and CK-MB were significantly higher and serum levels of TRPV6 were dramatically lower in deceased STEMI patients in comparison with the surviving patients. The levels of TRPV6 were negatively correlated with CK-MB and NT-pro-BNP. Meanwhile, TRPV6 was negatively expressed in tissues of STEMI patients and positively expressed in normal tissues. Patients with lower TRPV6 levels had remarkably lower LVEF ratio, higher GRACE scores, higher CK-MB and NT-pro-BNP levels, as well as higher ratios of cardiovascular death, malignant arrhythmia, cumulative MACE, and shorter survival time than patients with higher TRPV6., Conclusion: The lower expression of TRPV6 was associated with poor clinical outcomes and prognosis of STEMI patients., (© 2020 by the Association of Clinical Scientists, Inc.)

Aims: Baseline elevated B-type Natriuretic Peptide (BNP) has been found in high altitude pulmonary edema susceptible population. Exaggerated pulmonary vascular response to hypoxia may be related to endothelial dysfunction in hypoxia susceptible. We hypothesize that baseline BNP levels can predict hypoxia susceptibility in healthy individuals., Main Methods: The pulmonary vascular response to hypoxia was compared in 35 male healthy individuals divided into two groups based on BNP levels (Group 1 ≤ 15 and Group 2 > 15 pg/ml). Acute normobaric hypoxia was administered to both the groups, to confirm hypoxia susceptibility in Group 2., Key Findings: Unlike Group 1, Group 2 had elevated post hypoxia BNP levels (26 vs 33.5 pg/ml, p = 0.002) while pulmonary artery pressure was comparable. A negative correlation with tissue oxygen consumption (delta pO 2 ) and compartmental fluid shift was seen in Group 1 only. Endothelial dysfunction in Group 2 resulted in reduced vascular compliance leading to elevation of mean blood pressure on acute hypoxia exposure. BNP showed a positive correlation with endothelial dysfunction in Group 2 and has been linked to pre-diabetic disorder (HbA1c 6 ± 0.44%) and may additionally represent a lower cross-sectional area of vascular bed related to vascular remodeling mediated by chronic hypoxia., Significance: Hypoxia susceptibility in healthy individuals may be related to endothelial dysfunction that limits vascular compliance during hypoxic stress. BNP level showed positive correlation with HbA1c (r = 0.49, p = 0.04) and negative correlation with delta pO 2 (r = -0.52, p = 0.04) can predict reduced microvascular compliance due to endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals. BNP levels≤15 pg/ml at sea level is indicative of hypoxia resistance., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Corynebacterium glutamicum is an important industrial organism for the production of a variety of biological commodities. We discovered a promoter encoded by the gene NCgl2319 in C. glutamicum, which could be induced by benzyl alcohol, could be used as an efficient tunable expression system. In initial attempts, this promoter failed to function in a recombinant expression system. This was remedied by extending the original genetic context of the promoter, generating a new version Pcat-B. The Pcat-B transcription initiation site, its critical active regions, and its effect of inducers were fully characterized resulting in tunable expression. This approach proved to be very efficient in producing a pharmaceutical protein, N-terminal pro-brain natriuretic peptide (NT-proBNP). Production of approximately 440.43 mg/L NT-proBNP was achieved with the Pcat-B expression system demonstrating its application for controllable pharmaceutical protein production in C. glutamicum., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.

Background: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown., Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes., Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines., Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.

Backgrounds: The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has spread worldwide. Cardiac injury after SARS-CoV-2 infection is a major concern. The present study investigated impact of the biomarkers indicating cardiac injury in coronavirus disease 2019 (COVID-19) on patients' outcomes., Methods: This study enrolled patients who were confirmed to have COVID-19 and admitted at a tertiary university referral hospital between February 19, 2020 and March 15, 2020. Cardiac injury was defined as an abnormality in one of the following result markers: 1) myocardial damage marker (creatine kinase-MB or troponin-I), 2) heart failure marker (N-terminal-pro B-type natriuretic peptide), and 3) electrical abnormality marker (electrocardiography). The relationship between each cardiac injury marker and mortality was evaluated. Survival analysis of mortality according to the scoring by numbers of cardiac injury markers was also performed., Results: A total of 38 patients with COVID-19 were enrolled. Twenty-two patients (57.9%) had at least one of cardiac injury markers. The patients with cardiac injuries were older (69.6 ± 14.9 vs. 58.6 ± 13.9 years old, P = 0.026), and were more male (59.1% vs. 18.8%, P = 0.013). They showed lower initial oxygen saturation (92.8 vs. 97.1%, P = 0.002) and a trend toward higher mortality (27.3 vs. 6.3%, P = 0.099). The increased number of cardiac injury markers was significantly related to a higher incidence of in-hospital mortality which was also evidenced by Kaplan-Meier survival analysis ( P = 0.008)., Conclusion: The increased number of cardiac injury markers is related to in-hospital mortality in patients with COVID-19., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Mesothelial cells and cardiomyocytes have shared embryonic mesodermal origin. Cardiomyocytes release BNP under stretch. We searched whether malignant mesothelioma cells also secrete BNP and if so, this has a meaningful impact., Methods: Part I: Prospectively, patients with pleural lesions on CT having malignant mesothelioma effusions (MME, n = 13) were compared to patients with malignant effusions with pleural lesions (MEa, n = 14). Age-matched patients with ME without pleural lesions (MEb, n = 16) and non-malignant effusions (NME, n = 25) were analysed. Part II: Retrospectively, samples from patients with mesothelioma (n = 14), lung cancer (n = 8) or heart failure (n = 9) were used. BNP was measured in pleural fluid and blood/plasma. Part III: BNP was assessed in the culture supernatants of benign (MeT-5A) and malignant mesothelioma cell lines (M14K-epithelioid, MSTO-biphasic and ZL34-sarcomatoid) (n = 10 per cell line in three different biological replicates)., Results: In vitro, BNP concentration was significantly higher in the supernatant of all malignant cell lines than benign ones (P < 0.01), denoting BNP's production from the former. The pleural fluid to blood BNP ratio in MME was extremely high in Part I and Part II subjects (28.3 ± 12.1 and 25.9 ± 8.6, respectively) versus 1.1 ± 0.3 and 0.4 ± 0.1 in Part I ME and NME, respectively (P < 0.0001), and 0.8 ± 0.1 and 0.4 ± 0.1 in Part II ME and NME, respectively (P < 0.0001). BNP ratio ≥2.11 in Part I had 92% sensitivity and 94.5% specificity for MME (P < 0.0001)., Conclusion: BNP is secreted from malignant mesothelial cells. In clinical practice, the pleural fluid to blood BNP ratio can help in the diagnosis of malignant mesothelioma., (© 2020 Asian Pacific Society of Respirology.)

Objective: To investigate the clinical effects of Xinkeshu combined with levosimendan on perioperative heart failure in oldest-old patients with hip fractures., Methods: Oldest-old patients over 80 years old with perioperative heart failure and hip fractures were randomly divided into the control and observation groups, with 50 patients in each group. All patients in both groups were treated with conventional anti-heart failure therapy and levosimendan, whereas patients in the observation group additionally received Xinkeshu tablets. Clinical manifestations; left ventricular ejection fraction (LVEF); left ventricular end-diastolic dimension (LVEDD); left ventricular end-systolic dimension (LVESD); B-type natriuretic peptide (BNP), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and endothelin-1 (ET-1) levels; and self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores were compared between before and after treatment to evaluate the curative effects of Xinkeshu combined with levosimendan., Results: After treatment, the efficacy rate was significantly higher in the observation group than in the control group. LVEF and the levels of SOD and NO were higher in the observation group than in the control group after treatment. However, LVEDD; LVESD; BNP, MDA, and ET-1 levels; and the SAS and SDS scores were lower after treatment in the observation group than in the control group., Conclusion: Levosimendan combined with Xinkeshu can improve cardiac function, alleviate oxidative stress, and relieve anxiety and depression in oldest-old patients with perioperative heart failure and hip fracture.

Objective: We investigated the performance of four prognostic tools in predicting 180-day mortality for patients admitted for acute decompensated heart failure (ADHF) by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) over a range of risk thresholds, in addition to discrimination and calibration., Study Design and Setting: We studied 1,458 patients. The risk assessment was performed using the Acute Decompensated Heart Failure National Registry (ADHERE) model and the Get With The Guidelines (GWTG), ADHF/NT-proBNP, and Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) risk scores., Results: C-statistics ranged from 0.727 for the ADHERE model to 0.767 for the ADHF/NT-proBNP score. The ADHF/NT-proBNP risk score, the ADHERE model, and the ASCEND risk score, but not the GWTG risk score, were also well calibrated. Sensitivity and PPV were modest at the >30% risk threshold and ranged from 55% for the ADHF/NT-proBNP risk score to 38.8% for the ADHERE model and from 46.7% for the ADHF/NT-proBNP risk score to 42.1% for the ASCEND risk score, respectively. There was a modest agreement between the risk scores in classifying the patients across risk strata or in classifying those who died as being at >30% risk of death., Conclusion: Although risk assessment tools work well for stratifying patients, their use in estimating the risk of mortality for individuals has limited clinical utility., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Natriuretic peptides (NP), especially B type (BNP) and its N-terminal pro-B type natriuretic peptide (NT-proBNP), have long been regarded as biomarkers of volume overload and tools to exclude heart failure in the general population. However, their role in end-stage kidney disease (ESKD) is less certain given that BNP and NT-proBNP are excreted by the kidney and so serum concentrations of NPs are nearly universally elevated compared to controls. Nevertheless, the accumulated evidence suggests thatserum concentrations of NPs in patients with ESKD show moderate or strong positive relationships with underlying heart disease, abnormal cardiac structure or function and mortality. Limited evidence also supports the role of BNP including NT-proBNP, ANP in some studies, rather than CNP or DNP in risk stratification among ESKD patients as well as the utility of BNP samplings pre- and post- hemodialysis. However, studies of the cut-off values of NPs have yielded inconsistent results, such that further large-scale studies are needed to clarify these issues. This review summarizes the pathophysiology and significance of NPs in ESKD patients, especially their potential role as risk stratification biomarkers in clinical management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Gut hormones affect cardiac function and contractility. In this study, we examined whether insulin affects the cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression and release of proANP-derived peptides in pigs. Anaesthetized pigs were included in an experimental study comparing the effect of hyperinsulinemia in 15 pigs submitted to two different protocols versus 11 control pigs receiving saline infusion. Phosphorylation of Akt on Thr308 was determined by western blotting with a pAkt-Thr308 antibody. The mRNA contents of ANP and BNP were determined with real-time PCR; plasma and cardiac tissue proANP was measured with an immunoluminometric assay targeted against the mid-region of the propeptide and a processing-independent assay. Insulin stimulation increased phosphorylation of Akt Thr308 in both left atrium and left ventricle of porcine hearts (p < 0.005). No change was observed in ANP and BNP mRNA contents in the right or left atrium. BNP mRNA contents in the left ventricle, however, decreased 3-fold (p = 0.02) compared to control animals, whereas the BNP mRNA content in the right ventricle as well as ANP mRNA content in the right and left ventricle did not change following hyperinsulinemia. Moreover, the peptide contents did not change in the four cardiac chambers. Finally, proANP concentrations in plasma did not change during the insulin infusion compared to the control animals. These results suggest that insulin does not have direct effect on atrial natriuretic peptide expression but may have a role in the left ventricle., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Heart failure (HF) is a worldwide disease with high levels of morbidity and mortality. The pathogenesis of HF is complicated and involves imbalances in hormone and electrolyte. B-type natriuretic peptide (BNP) has served as a biomarker of HF severity, and in recent years, it has been used to treat the disease, thanks to its cardio-protective effects, such as diuresis, natriuresis, and vasodilatation. In stage C/D HF, symptoms are severe despite elevated BNP. Disturbances in Ca 2+ homeostasis are often a dominating feature of the disease, causing Ca 2+ -regulatory protein dysfunction, including reduced expression and activity of sarcoplasmic reticulum Ca 2+ -ATPase2a (SERCA2a), impaired ryanodine receptors (RYRs) function, intensive Na + -Ca 2+ exchanger (NCX), and downregulation of S100A1. The relationship between natriuretic peptides (NPs) and Ca 2+ -regulatory proteins has been widely studied and represents important mechanisms in the etiology of HF. In this review, we present evidence that BNP may regulate Ca 2+ -regulatory proteins, in particular, suppressing SERCA2a and S100A1 expression. However, relationships between BNP and other Ca 2+ -regulatory proteins remain vague.

Stroke is a widespread condition that causes 7 million deaths globally. Survivors suffer from a range of disabilities that affect their everyday life. It is a complex condition and there is a need to monitor the different signals that are associated with it. Stroke patients need to be rapidly diagnosed in the emergency department in order to allow the admission of the time-limited treatment of tissue plasminogen activator (tPA). Stroke diagnostics show the use of sophisticated technologies; however, they still contain limitations. The hidden information and technological advancements behind the utilization of biomarkers for stroke triaging are significant. Stroke biomarkers can revolutionize the way stroke patients are diagnosed, monitored, and how they recover. Different biomarkers indicate different cascades and exhibit unique expression patterns which are connected to certain pathologies in the human body. Over the past decades, B-type natriuretic peptide (BNP) and its derivative N-terminal fragment (NT-proBNP) have been increasingly investigated and highlighted as significant cardiovascular biomarkers. This work reviews the recent studies that have reported on the usefulness of BNP and NT-proBNP for stroke triaging. Their classification association is also presented, with increased mortality in stroke, correlation with cardioembolic stroke, and an indication of a second stroke recurrence. Moreover, recent scientific efforts conducted for the technological advancement of a bedside point-of-care (POC) device for BNP and NT-proBNP measurements are discussed. The conclusions presented in this review may hopefully assist in the major efforts that are currently being conducted in order to improve the care of stroke patients.

Background: N-terminal pro brain natriuretic peptide (NT-proBNP) and troponin T are released during myocardial wall stress and/or ischemia and are strong predictors for postoperative cardiovascular complications. However, the relative effects of goal-directed, intravenous administration of crystalloid compared to colloid solutions on NT-proBNP and troponin T, especially in relatively healthy patients undergoing moderate- to high-risk noncardiac surgery, remains unclear. Thus, we evaluated in this sub-study the effect of a goal-directed crystalloid versus a goal-directed colloid fluid regimen on postoperative maximum NT-proBNP concentration. We further evaluated the incidence of myocardial injury after noncardiac surgery (MINS) between both study groups., Methods: Thirty patients were randomly assigned to receive additional intravenous fluid boluses of 6% hydroxyethyl starch 130/0.4 and 30 patients to receive lactated Ringer's solution. Intraoperative fluid management was guided by oesophageal Doppler-according to a previously published algorithm. The primary outcome were differences in postoperative maximum NT-proBNP (maxNT-proBNP) between both groups. As our secondary outcome we evaluated the incidence of MINS between both study groups. We defined maxNT-proBNP as the maximum value measured within 2 h after surgery and on the first and second postoperative day., Results: In total 56 patients were analysed. There was no significant difference in postoperative maximum NT-proBNP between the colloid group (258.7 ng/L (IQR 199.4 to 782.1)) and the crystalloid group (440.3 ng/L (IQR 177.9 to 691.2)) during the first 2 postoperative days (P = 0.29). Five patients in the colloid group and 7 patients in the crystalloid group developed MINS (P = 0.75)., Conclusions: Based on this relatively small study goal-directed colloid administration did not decrease postoperative maxNT-proBNP concentration as compared to goal-directed crystalloid administration., Trial Registration: ClinicalTrials.gov ( NCT01195883 ) Registered on 6th September 2010.

Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.

Cardiac hypertrophy causes heart failure and is associated with hyperglycemia in patients with diabetes mellitus. Mibefradil, which acts as a T-type calcium channel blocker, exerts beneficial effects in patients with heart failure. In this study, we explored the effects and mechanism of mibefradil on high-glucose-induced cardiac hypertrophy in H9c2 cells. H9c2 cells were incubated in a high-glucose medium and then treated with different concentrations of mibefradil in the presence or absence of the Akt inhibitor MK2206 or mTOR inhibitor rapamycin. Cell size was evaluated through immunofluorescence, and mRNA expression of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain) was assessed by using quantitative real-time polymerase chain reaction. Changes in the expression of p-PI3K, p-Akt, and p-mTOR were evaluated using Western blotting, and autophagosome formation was detected using transmission electron microscopy. Our results indicate that mibefradil reduced the size of H9c2 cells, decreased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain, and decreased the level of autophagic flux. However, MK2206 and rapamycin induced autophagy and reversed the effects of mibefradil on high-glucose-induced H9c2 cells. In conclusion, mibefradil ameliorated high-glucose-induced cardiac hypertrophy by activating the PI3K/Akt/mTOR pathway and inhibiting excessive autophagy. Our study shows that mibefradil can be used therapeutically to ameliorate cardiac hypertrophy in patients with diabetes mellitus.