Plasma Levels Of Natriuretic Peptide Research Articles

Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.

Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.

Plasma N-terminal pro-brain natriuretic peptide concentrations may help to identify patients with very low-risk acute pulmonary embolism: A preliminary study.

Patients with an acute pulmonary embolism (APE) are a heterogeneous group, and some of them may benefit from early discharge and an ambulatory care referral. We aimed to evaluate the use of N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma level assessment in patients with low-risk APE based on clinical findings (0 points on the simplified Pulmonary Embolism Severity Index (sPESI)). Preliminary analysis of an ongoing prospective study including 1,151 normotensive patients with at least a segmental APE. In the final analysis, 348 patients with a 0-point sPESI were included. Blood samples were collected within the first 24 h of admission. The clinical endpoint (CE) included APE-related mortality and/or rescue thrombolysis in patients with clinical deterioration. Clinical endpoints occurred in 3 patients who had higher plasma NT-proBNP levels than study participants with a favorable clinical course (164 [64-650] pg/mL compared to 2,930 [2,285.5-13,965] pg/mL; p = 0.01). Receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) for NT-proBNP for the prediction of the CEs was 0.918 (95% confidence interval [95% CI]: 0.831-1.00; p = 0.013). We defined the cutoff value of NT-proBNP at ≥1,641 pg/mL. Among subjects with 0 points on the sPESI, those with concentrations of NT-proBNP exceeding 1,641 pg/mL might require closer attention; remaining patients could be considered candidates for outpatient treatment. However, these findings warrant further investigation in a large, prospective group of patients.

High plasma BNP concentration associates with clinical outcome after mechanical thrombectomy: Post hoc analysis of SKIP

ObjectivesHeart failure may result in reduced brain perfusion, limiting the blood flow needed to achieve clinical recovery. We investigated whether plasma levels of brain natriuretic peptide (BNP), a biological marker of heart failure, were related to clinical outcomes after mechanical thrombectomy (MT). Materials and MethodsData were analyzed from stroke patients with internal carotid or middle cerebral artery occlusion enrolled in the SKIP trial for whom plasma level of BNP was evaluated on admission. Favorable outcome was defined as a modified Rankin scale score of 0–2 at 3 months. ResultsAmong 169 patients (median age, 74 years; 62% men, median National Institutes of Health Stroke Scale score, 18), 104 (62%) achieved favorable outcomes. Median plasma BNP level was lower in the favorable outcome group (124.1 pg/mL; interquartile range [IQR], 62.1–215.5 pg/mL) than in the unfavorable outcome group (198.0 pg/mL; IQR, 74.8–334.0 pg/mL; p=0.005). In multivariate regression analysis, the adjusted odds ratio for BNP for favorable outcomes was 0.971 (95% confidence interval, 0.993–0.999; p=0.048). At 3 months after onset, the favorable outcome rate was lower in the ≥186 pg/mL group (45%) than in the <186 pg/mL group (72%; p=0.001). This significant difference remained regardless of the presence of atrial fibrillation (AF), with rates of 47% and 76%, respectively, in AF patients (p=0.003) and 33% and 68%, respectively, in patients without AF (p=0.046). ConclusionHigh plasma BNP concentration appears associated with unfavorable outcomes after MT.

Cardiotoxicity Induced by Intratracheal Instillation of Diesel Exhaust Particles in Mice, and the Protective Effects of Carnosol: Suppression of Inflammation and Oxidative and Nitrosative Stress via Modulation of NF-κb/MAPKs Signaling Pathways.

Inhaled particulate air pollution is associated with cardiotoxicity with underlying mechanisms including oxidative stress and inflammation. Carnosol, commonly found in rosemary and sage, is known to possess a broad range of therapeutic properties such as antioxidant, anti-inflammatory and antiapoptotic. However, its cardioprotective effects on diesel exhaust particles (DEPs)-induced toxicity have not been studied yet. Hence, we evaluated the potential ameliorative effects of carnosol on DEPs-induced heart toxicity in mice, and the underlying mechanisms involved. Mice were intratracheally instilled with DEPs (1 mg/kg) or saline, and 1 hour prior to instillation they were given intraperitoneally either carnosol (20 mg/kg) or saline. Twenty-four hours after the DEPs instillation, multiple parameters were evaluated in the heart by enzyme-linked immunosorbent assay, colorimetric assay, Comet assay and Western blot technique. Carnosol has significantly reduced the elevation in the plasma levels of lactate hydrogenase and brain natriuretic peptide induced by DEPs. Likewise, the augmented cardiac levels of proinflammatory cytokines, lipid peroxidation, and total nitric oxide in DEPs-treated groups were significantly normalized with the treatment of carnosol. Moreover, carnosol has markedly reduced the heart mitochondrial dysfunction, as well as DNA damage and apoptosis of mice treated with DEPs. Similarly, carnosol significantly reduced the elevated expressions of phosphorylated nuclear factor-кB (NF-кB) and mitogen-activated protein kinases (MAPKs) in the hearts. Furthermore, the treatment with carnosol has restored the decrease in the expression of sirtuin-1 in the hearts of mice exposed to DEPs. Carnosol significantly attenuated DEP-induced cardiotoxicity in mice by suppressing inflammation, oxidative stress, DNA damage, and apoptosis, at least partly via mechanisms involving sirtuin-1 activation and the inhibition of NF-кB and MAPKs activation.

Contemporary pharmacological treatment and management of heart failure.

The prevention and treatment strategies for heart failure (HF) have evolved in the past two decades. The stages of HF have been redefined, with recognition of the pre-HF state, which encompasses asymptomatic patients who have developed either structural or functional cardiac abnormalities or have elevated plasma levels of natriuretic peptides or cardiac troponin. The first-line treatment of patients with HF with reduced ejection fraction includes foundational therapies with angiotensin receptor-neprilysin inhibitors, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors and diuretics. The first-line treatment of patients with HF with mildly reduced ejection fraction or with HF with preserved ejection fraction includes SGLT2 inhibitors and diuretics. The timely initiation of these disease-modifying therapies and the optimization of treatment are crucial in all patients with HF. Reassessment after initiation of these therapies is recommended to evaluate patient symptoms, health status and left ventricular function, and timely referral to a HF specialist is necessary if a patient has persistent advanced HF symptoms or worsening HF. Lifestyle modification and treatment of comorbidities such as diabetes mellitus, ischaemic heart disease and atrial fibrillation are crucial through each stage of HF. This Review provides an overview of the management strategies for HF according to disease stages that are derived from the recommendations in the latest US and European HF guidelines.

Biomarkers for predicting atrial fibrillation: An explorative sub-analysis of the randomised SCREEN-AF trial

Background Atrial fibrillation (AF) is a common treatable risk factor for stroke. Screening for paroxysmal AF in general practice is difficult, but biomarkers might help improve screening strategies. Objectives We investigated six blood biomarkers for predicting paroxysmal AF in general practice. Methods This was a pre-specified sub-study of the SCREEN-AF RCT done in Germany. Between 12/2017-03/2019, we enrolled ambulatory individuals aged 75 years or older with a history of hypertension but without known AF. Participants in the intervention group received active AF screening with a wearable patch, continuous ECG monitoring for 2x2 weeks and usual care in the control group. The primary endpoint was ECG-confirmed AF within six months after randomisation. High-sensitive Troponin I (hsTnI), brain natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), N-terminal pro atrial natriuretic peptide (NT-ANP), mid-regional pro atrial natriuretic peptide (MR-pro ANP) and C-reactive protein (CRP) plasma levels were investigated at randomisation for predicting AF within six months after randomisation. Results Blood samples were available for 291 of 301 (96.7%) participants, including 8 with AF (3%). Five biomarkers showed higher median results in AF-patients: BNP 78 vs. 41 ng/L (p = 0.012), NT-pro BNP 273 vs. 186 ng/L (p = 0.029), NT-proANP 4.4 vs. 3.5 nmol/L (p = 0.027), MR-pro ANP 164 vs. 125 pmol/L (p = 0.016) and hsTnI 7.4 vs. 3.9 ng/L (p = 0.012). CRP levels were not different between groups (2.8 vs 1.9 mg/L, p = 0.1706). Conclusion Natriuretic peptide levels and hsTnI are higher in patients with AF than without and may help select patients for AF screening, but larger trials are needed.

Vasoactive peptides as biomarkers for the prediction of retinopathy of prematurity

BackgroundRetinopathy of prematurity (ROP) is a major complication in preterm infants. We assessed if plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) serve as early markers for subsequent ROP development in preterm infants <32 weeks gestation.MethodsProspective, two-centre, observational cohort study. MR-proANP and CT-proET1 were measured on day seven of life. Associations with ROP ≥ stage II were investigated by univariable and multivariable logistic regression models.ResultsWe included 224 infants born at median (IQR) 29.6 (27.1–30.8) weeks gestation and birth weight of 1160 (860–1435) g. Nineteen patients developed ROP ≥ stage II. MR-proANP and CT-proET1 levels were higher in these infants (median (IQR) 864 (659–1564) pmol/L and 348 (300–382) pmol/L, respectively) compared to infants without ROP (median (IQR) 299 (210–502) pmol/L and 196 (156–268) pmol/L, respectively; both P < 0.001). MR-proANP and CT-proET1 levels were significantly associated with ROP ≥ stage II in univariable logistic regression models and after adjusting for co-factors, including gestational age and birth weight z-score.ConclusionsMR-proANP and CT-proET1 measured on day seven of life are strongly associated with ROP ≥ stage II in very preterm infants and might improve early prediction of ROP in the future.ImpactPlasma levels of midregional pro-atrial natriuretic peptide and C-terminal pro-endothelin-1 measured on day seven of life in very preterm infants show a strong association with development of retinopathy of prematurity ≥ stage II.Both biomarkers have the potential to improve early prediction of retinopathy of prematurity.Vasoactive peptides might allow to reduce the proportion of screened infants substantially.

Secretoneurin levels are higher in dilated cardiomyopathy than in ischaemic cardiomyopathy: preliminary results.

Secretoneurin (SN) is a neuropeptide with potential utility as a biomarker of cardiovascular episodes. The main effect of SN is mediated through its inhibition of calmodulin-dependent kinase II (CaMKII), which influences calcium handling. We aimed to associate the levels of SN in plasma with different causes of heart failure. We prospectively enrolled consecutive patients with ischaemic (ICM) and dilated (DCM) cardiomyopathy from the outpatient heart failure clinic and healthy individuals. SN was analysed from venous blood by use of the ELISA method. SN plasma levels were compared in DCM, ICM and healthy individuals with non-parametric tests. A total of 53 patients (81.1% male, 18.9% female; mean age 67.9 ± 12.6 years) and 34 healthy individuals (38% male, 62% female) were included in the analysis. Plasma SN levels were significantly higher in the dilated cardiomyopathy (38.8 ± 27 pmol/L) as compared with the ischaemic cardiomyopathy (19.7 ± 22.6 pmol/L) group (P = 0.006). There was no significant difference between females vs. males (27.1 ± 23 vs. 25.5 ± 26.2 pmol/L, P = NS). Plasma SN levels allowed DCM and ICM to be differentiated with 88% sensitivity and 61% specificity (P = 0.007), the cut of value is 13.3 pmol/L. Plasma SN levels differed significantly between healthy volunteers and both ICM (P < 0.0001) and DCM (P = 0.049). Plasma SN levels did not differ according to age and were not associated with comorbidities, left ventricular ejection fraction, heart failure medication, troponin, creatinine, or natriuretic peptide plasma levels. Plasma secretoneurin levels differed significantly in DCM vs. ICM, being higher in the former. Based on plasma SN levels, discrimination between DCM and ICM might be possible. Healthy individuals produce higher SN plasma levels than stable HFrEF patients.

Corin deficiency impairs cardiac function in mouse models of heart failure.

Corin is a protease in the natriuretic peptide system. Deleterious CORIN variants are associated with hypertension and heart disease. It remains unclear if and to what extent corin deficiency may contribute to heart failure (HF). Corin knockout (KO) mice were used as a model. Cardiac function was assessed by echocardiography and tissue analysis in Corin KO mice at different ages or subjected to transverse aortic constriction (TAC), which increased pressure overload. Heart and lung tissues were analyzed for cardiac hypertrophy and lung edema using wheat germ agglutinin, Sirius red, Masson's trichrome, and Prussian blue staining. Recombinant corin was tested for its effect on cardiac function in the TAC-operated Corin KO mice. Selected gene expression in the heart was examined by RT-PCR. ELISA was used to analyze factors in plasma. Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension. When Corin KO mice were subjected to TAC at 10-12 weeks of age, cardiac function decreased more rapidly than in similarly treated wild-type mice. When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated. The corin treatment also decreased the gene expression associated with cardiac hypertrophy and fibrosis, increased plasma cGMP levels, lowered plasma levels of N-terminal pro-atrial natriuretic peptide, angiotensin II, and aldosterone, and lessened lung edema in the Corin KO mice subjected to TAC. Corin deficiency impairs cardiac function and exacerbates HF development in mice. Corin protein may be used to reduce cardiac hypertrophy and fibrosis, suppress the renin-angiotensin-aldosterone system, and improve cardiac function in HF.

Insights into the management of pulmonary arterial hypertension patients in Spain

Introduction and objectivesAccurate risk stratification is pivotal to tailor therapy according to the prognosis of pulmonary arterial hypertension (PAH) patients to positively impact the course of the disease. We conducted a nationwide study to assess how the current European Society of Cardiology/European Respiratory Society guidelines for risk assessment and management of PAH patients are followed in real-world practice in Spain. MethodsHospital-based physicians answered an online questionnaire describing their yearly caseload of PAH patients and their management of virtual cases scenarios for Word Health Organization functional class (FC) II–III PAH patients. ResultsThe main tests requested for a regular risk assessment were echocardiography, 6-minute walk test, measurement of brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide plasma levels and right heart catheterization. The main treatment prescribed was an oral double-combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 inhibitor (PDE5i) or guanylate cyclase stimulator. Around 20% of the clinicians would also add the selective prostacyclin-receptor agonist (selexipag) to ERA and PDE5i as initial therapy for FC III patients, and nearly all clinicians (99%) would add a prostacyclin pathway agent to FC III PAH patients presenting multiple new intermediate-risk parameters despite a 6-month dual therapy with ERA and PDE5i. ConclusionsThe main decisive factor for the management of PAH patients in Spanish hospitals is their functional class and intermediate-risk parameters. Selexipag was more frequently prescribed than parenteral prostacyclin-analogs in triple-combination therapy for FC II–III PAH patients presenting low-risk and intermediate-risk parameters.

P2Y4 nucleotide receptor: A novel target for anti-inflammatory therapies to improve myocardial infarction outcome

Human P2Y4 is a UTP receptor, while in mice it is activated by both ATP and UTP. P2Y4 knockout (KO) in mice protects against myocardial infarction and leads to increased adiponectin secretion by adipocytes and lower cardiac inflammation under ischemia. The main objective is to investigate the anti-inflammatory mechanisms of cardioprotection in P2Y4 KO ischemic mice, and explore the relevance of these data in humans. We performed left anterior descending artery ligation on wild-type and P2Y4 KO mice to investigate the inflammatory state of their pericardial adipose tissue under ischemia. In parallel, in a population study comprising patients with coronary artery disease (CAD) and age-matched control individuals, we analyzed P2RY4 gene mutations and their potential association with CAD severity and fasting plasma parameters. We demonstrated that P2Y4 KO mice displayed adipocyte beiging with increased PD-L1 expression and a higher number of regulatory leukocytes in their pericardial adipose tissue after left anterior descending artery ligation, compared to wild-type mice. Interestingly, the reduction of T cell infiltration and cardiac fibrosis observed in P2Y4 KO heart was lost after injection of anti-PD-L1 blocking antibody in ischemic mice. We also identified a N178T loss-of-function mutation of the human P2Y4 receptor found less frequently in CAD patients than in control individuals. In coronary patients, carriers of the N178T variant had significantly reduced Duke jeopardy and Gensini cardiac severity scores, as well as lower resting heart rates and reduced plasma levels of N-terminal pro-brain natriuretic peptide and fasting glucose. Accordingly, P2Y4 KO mice had significantly improved glucose tolerance and insulin sensitivity compared with their wild-type littermate controls. The present study defines P2Y4 receptor as a negative regulator of PD-L1 and adiponectin, and as a potential target for anti-inflammatory therapies. The combined effect of P2Y4 loss on adipocyte beiging and regulatory leukocyte increase highlights this nucleotide receptor as an important player in post-ischemic cardiac response. We also identified a frequent loss-of-function P2Y4 variant associated with less severe coronary artery atherosclerosis and lower fasting plasma glucose in CAD patients. P2Y4 antagonists could thus have therapeutic applications in the treatment of myocardial infarction and type 2 diabetes.

Longitudinal association between N-terminal B-type natriuretic peptide, anxiety and social support in patients with HFpEF: results from the multicentre randomized controlled Aldo-DHF trial

BackgroundHigher plasma levels of natriuretic peptides (NPs) have been associated with reduced anxiety in experimental research and a number of patient samples. As NP levels are elevated in heart failure patients, we investigate whether this elevation is related to anxiety in patients with heart failure with preserved ejection fraction (HFpEF).MethodsPost-hoc regression and mediation analyses were conducted, using data of 422 patients with HFpEF from the randomized, placebo-controlled, double-blinded, two-armed, multicentre aldosterone in diastolic heart failure trial, testing associations and their mediators between the N-terminal B-type natriuretic peptide (NT-proBNP) and anxiety at baseline and over 12-month follow-up. Anxiety was measured by the Hospital Anxiety and Depression Scale (HADS), social support by the ENRICHD Social Support Inventory and physical functioning by the Short Form 36 Health Survey.ResultsThe mean age of the study population was 66.8 ± 7.6 years, 47.6% were male and 86.0% had NYHA class II. NT-proBNP showed a weak negative correlation with HADS anxiety scores at baseline (r = − 0.087; p = 0.092), which was significant (r = − 0.165; p = 0.028) in men but not in women. NT-proBNP also tended to predict lower anxiety at 12-months in men. On the other hand, higher anxiety at baseline was associated with lower NT-proBNP scores 12 months later (r = − 0.116; p = 0.026). All associations lost significance in multivariate regression for age, perceived social support (ESSI), physical function (SF-36) and study arm. Mediation analyses revealed that social support acts as a full mediator for the link between NT-proBNP levels and anxiety.ConclusionThe mechanisms linking NT-proBNP to anxiety may be more complex than originally assumed. While effects of NT-proBNP on anxiety may be mediated by perceived social support, there may be an additional negative effect of anxiety on NT-proBNP. Future research should consider this possible bi-directionality of the association and assess the potential influence of gender, social support, oxytocin and vagal tone on the interaction of anxiety and natriuretic peptide levels.Trial Registrationhttp://www.controlled-trials.com (ISRCTN94726526) on 07/11/2006.Eudra-CT-number: 2006–002,605-31.

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction

BackgroundWe examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling.MethodsThis is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24.ResultsANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (− 76.9% vs. −9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24.ConclusionSwitching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

The prognostic role of the echocardiographic tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio and its relationship with NT-proANP plasma level in systemic sclerosis.

The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio is an echocardiographic estimation of the right ventricle to pulmonary artery (RV/PA) coupling, with a validated prognostic role in different clinical settings. Systemic sclerosis (SSc) patients without evident cardiovascular involvement frequently display subtle RV impairment. The amino-terminal atrial natriuretic peptide (NT-proANP) plasma level relates to SSc disease progression and mortality. We aimed to assess the prognostic value of the TAPSE/sPAP ratio and its relationship with NT-proANP plasma level in SSc patients without overt cardiovascular involvement. We retrospectively analysed 70 SSc consecutive patients, with no clinical evidence of cardiovascular involvement or pulmonary hypertension (PH), and 30 healthy controls (HC) in a retrospective, single-centre study. All SSc patients underwent recurrent clinical and echocardiographic assessments and NT-proANP plasma level was assessed at baseline. SSc-related cardiovascular events and deaths were extracted during a 6-year follow-up. The complete work-up for the diagnosis, treatment and management of PH performed along the 6 years of follow-up referred to the 2015 European Society of Cardiology guidelines. Systemic sclerosis patients showed lower TAPSE/sPAP ratio at baseline compared to HC [SSc median value = 0.71 mm/mmHg, (IQR 0.62-0.88) vs. HC median value = 1.00 mm/mmHg, (IQR 0.96-1.05); p < 0.001]. Multivariable Cox analysis revealed TAPSE/sPAP ratio as an independent predictor for SSc-related cardiovascular events [HR = 3.436 (95% CI 1.577-7.448); p = 0.002] and mortality [HR = 3.653 (95% CI 1.712-8.892); p = 0.014]. The value of TAPSE/sPAP ratio < 0.7 mm/mmHg was identified as an optimal cut-off for predicting adverse outcomes (p < 0.001) by receiver operating characteristic (ROC) analyses. NT-proANP level significantly related to TAPSE/sPAP ratio (r = 0.52, p < 0.001). TAPSE/sPAP ratio combined with NT-proANP showed an overall significant prognostic role in this SSc population, confirmed by Kaplan-Meier analysis (Log rank p < 0.001). The TAPSE/sPAP ratio, as an index of RV/PA coupling, is an affordable predictor of cardiovascular events and mortality in SSc and, combined with NT-proANP level, may improve the clinical phenotyping and prognostic stratification of SSc patients.

Waterpipe smoke inhalation potentiates cardiac oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and autophagy in experimental hypertension

Cigarette smoking worsens the health of hypertensive patients. However, less is known about the actions and underlying mechanisms of waterpipe smoke (WPS) in hypertension. Therefore, we evaluated the effects of WPS inhalation in mice made hypertensive (HT) by infusing angiotensin II for six weeks. On day 14 of the infusion of angiotensin II or vehicle (normotensive; NT), mice were exposed either to air or WPS for four consecutive weeks. Each session was 30 min/day and 5 days/week. In NT mice, WPS increased systolic blood pressure (SBP) compared with NT air-exposed group. SBP increase was elevated in HT+WPS group versus either HT+air or NT+WPS. Similarly, the plasma levels of brain natriuretic peptide, C-reactive protein, 8-isoprostane and superoxide dismutase were increased in HT+WPS compared with either HT+air or NT+WPS. In the heart tissue, several markers of oxidative stress and inflammation were increased in HT+WPS group vs the controls. Furthermore, mitochondrial dysfunction in HT+WPS group was more affected than in the HT+air or HT+WPS groups. WPS inhalation in HT mice significantly increased cardiac DNA damage, cleaved caspase 3, expression of the autophagy proteins beclin 1 and microtubule-associated protein light chain 3B, and phosphorylated nuclear factor κ B, compared with the controls. Compared with HT+air mice, heart histology of WPS-exposed HT mice showed increased cardiomyocyte damage, neutrophilic and lymphocytic infiltration and focal fibrosis. We conclude that, in HT mice, WPS inhalation worsened hypertension, cardiac oxidative stress, inflammation, mitochondrial dysfunction, DNA damage, apoptosis and autophagy. The latter effects were associated with a mechanism involving NF-κB activation.

802 DIAGNOSTIC YIELD AND PREDICTIVE VALUE ON LEFT VENTRICULAR REVERSE REMODELING OF GENETIC TESTING IN DILATED CARDIOMYOPATHY

Abstract Background Genetic testing is one essential element in the diagnostic workup of patients with idiopathic dilated cardiomyopathy (DCM), and genotype-phenotype correlations are still poorly understood. We assessed the diagnostic yield of genetic testing in a selected DCM cohort including both familial and nonfamilial cases and evaluated phenotypic differences and the relationship of left ventricular reverse remodeling (LVRR) with the presence of pathogenic (P) or likely pathogenic (LP) variants of disease-associated DCM genes. Methods From 680 outpatients with heart with reduced ejection fraction followed at our Heart Failure Outpatient Clinic we selected subjects with a diagnosis of DCM before 65 years of age and without secondary causes of DCM including ischemic, valvular, hypertensive, or drug-induced heart disease or myocarditis. All patients underwent extensive clinical, laboratory, and imaging evaluation at the time of diagnosis and during regular follow-up visits and were offered genetic investigations with Next Generation Sequencing (NGS) of 42 disease-associated DCM genes. Results Of 680 DCM outpatients, 70 fulfilled the definition of idiopathic DCM and 66 gave consent to undergo genetic investigation (median age at diagnosis 57 years, 68% males). A total of 18 pathogenic/likely pathogenic (P/LP) variants were identified in 16 patients (diagnostic yield 24%), the most common (7, 39% of all variants) involving the TTN gene, followed by lamin A/C (n=3), cytoskeleton Z-disk (n=3), motor sarcomeric (n=2), desmosomal (n=1), and ion channel (n=1) gene variants. At the time of DCM diagnosis, patients with P/LP had a higher left ventricular (LV) ejection fraction (LVEF) compared with subjects (31±11% vs 28±8%, p=0.17). After a median follow-up of 53 (IQR 20-111) months, P/LP-positive patients had lower systolic and diastolic blood pressure and higher plasma natriuretic peptide levels than patients without P/LP variants. Patients without P/LP variants exhibited a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, p=0.0008) and decrease in LVEDDi (-3 vs. -1 mm/m2, p=0.03) compared with subjects carrying P/LP variants (Figure). Conclusions Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer left ventricular reverse remodeling in response to guideline-directed medical therapy.

Loss-of-function N178T variant of the human P2Y4 receptor is associated with decreased severity of coronary artery disease and improved glucose homeostasis.

Human P2Y4 is a UTP receptor, while in mice it is activated by both ATP and UTP. P2Y4 knockout (KO) in mice protects against myocardial infarction and is characterized by increased adiponectin secretion by adipocytes, and decreased cardiac inflammation and permeability under ischemic conditions. The relevance of these data has, however, not been explored to date in humans. In a population study comprising 50 patients with coronary artery disease (CAD) and 50 age-matched control individuals, we analyzed P2RY4 mutations and their potential association with CAD severity and fasting plasma parameters. Among the mutations identified, we focused our attention on a coding region polymorphism (rs3745601) that results in replacement of the asparagine at residue 178 with threonine (N178T) located in the second extracellular loop of the P2Y4 receptor. The N178T variant is a loss-of-function mutation of the human P2Y4 receptor and is encountered less frequently in coronary patients than in control individuals. In coronary patients, carriers of the N178T variant had significantly reduced jeopardy and Gensini cardiac severity scores, as well as lower resting heart rates and plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). Regarding fasting plasma parameters, the N178T variant was associated with a lower concentration of glucose. Accordingly, P2Y4 KO mice had significantly improved glucose tolerance and insulin sensitivity compared with their WT littermate controls. The improvement of insulin sensitivity resulting from lack of the P2Y4 receptor was no longer observed in the absence of adiponectin. The present study identifies a frequent loss-of-function P2Y4 variant associated with less severe coronary artery atherosclerosis and lower fasting plasma glucose in coronary patients. The role of the P2Y4 receptor in glucose homeostasis was confirmed in mouse. P2Y4 antagonists could thus have therapeutic applications in the treatment of myocardial infarction and type 2 diabetes.

Correlation between Glycated Haemoglobin Level, Cardiac Function, and Prognosis in Patients with Diabetes Mellitus Combined with Myocardial Infarction.

Objective This study was to investigate the correlation between glycated haemoglobin (HbA1c) level, cardiac function, and prognosis in patients with diabetes mellitus combined with myocardial infarction. Methods Ninety-three patients with type 2 diabetes mellitus combined with acute myocardial infarction who were hospitalized and treated in our hospital from January 2021 to June 2021 were recruited for prospective analysis and equally divided into group A (HbA1c < 6.5%), group B (6.5% ≤ HbA1c ≤ 8.5%), and group C (HbA1c > 8.5%) using the random number table method, with 31 patients in each group. General data of patients were collected on admission and blood glucose and cardiac function indexes were measured; the incidence of myocardial infarction and death during the follow-up period was recorded at 6 months after discharge. Results There was a significant difference in blood glucose (FBG) and HbA1c levels at fasting between the three groups (P < 0.05). There were statistically significant differences in plasma levels of N-terminal probrain natriuretic peptide (NT-proBNP) and uric acid (UA), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic volume (LVESV), left ventricular ejection fraction (LVEF), and cardiac function classification of the New York Heart Association (NYHA) among the three groups (P < 0.05). By statistical analysis, the HbA1c level was positively correlated with FBG, NT-proBNP, UA, LVEDD, LVESD, and NYHA grades but negatively correlated with LVEF (P < 0.05). The incidence rate of myocardial infarction and mortality was significantly higher in group C than in groups A and B (P < 0.05). Conclusion HbA1c level in patients with diabetes mellitus combined with myocardial infarction is closely related to the degree of cardiac function damage. Glycated haemoglobin levels are associated with the development of cardiac insufficiency in patients with acute myocardial infarction; glycated haemoglobin is also an independent predictor of major adverse cardiovascular events. Reasonable and effective blood glucose control is of great significance to the prognosis of patients.

Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Inversely Associated with N-Terminal Pro B-Type Natriuretic Peptide in Older Men and Women.

Background and Aims: Cardiac natriuretic peptides (NPs) exert several metabolic effects, including some on lipid metabolism. Higher NPs levels are likely to be associated with a favorable lipid profile. In in vitro studies, NPs have been found to modulate low-density lipoprotein receptor (LDLR) trafficking by preventing proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression. The aim of our study is to investigate a possible association between plasma levels of PCSK9 and N-terminal pro B-type natriuretic peptide (NT-proBNP) in vivo. Methods: We performed a cross-sectional study on 160 consecutive older male and female patients hospitalized for medical conditions. Patients taking lipid-lowering drugs and patients with an admission diagnosis of acute heart failure were excluded. Fasting blood samples were collected after clinical stabilization of the acute illness, the day before discharge. Results: The mean age was 87.8 ± 6.4 years with a female prevalence (62.5%). The median NT-proBNP was 2340 (814–5397) pg/mL. The mean plasma PCSK9 was 275.2 ± 113.2 ng/mL. We found an inverse correlation between plasma PCSK9 and NT-proBNP (r = −0.280; p = 0.001). This association was confirmed after taking into account NT-proBNP tertiles (plasma PCSK9 levels: 317.4 ± 123.6 ng/mL in the first tertile, 283.3 ± 101.8 ng/mL in the second tertile, 231.3 ± 99.0 ng/mL in the third tertile, p = 0.001) and even after an adjustment for confounding factors (beta = −0.361, p = 0.001 for ln(NT-proBNP); beta = −0.330, p = 0.001 for NT-proBNP tertiles). The strength of the correlation between plasma PCSK9 and NT-proBNP was likely greater in patients affected by type 2 diabetes mellitus (r = −0.483; p = 0.006) and in male patients (r = −0.431, p = 0.001). Conclusion: The inverse association found between PCSK9 and NT-proBNP plasma levels in our real-life clinical study supports the hypothesis that NPs may play a role in cholesterol metabolism, possibly through an inhibitory action on circulating PCSK9 concentrations, thus increasing the availability of LDLR.

Early donepezil monotherapy or combination with metoprolol significantly prevents subsequent chronic heart failure in rats with reperfused myocardial infarction

Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial infarction remains a leading cause of chronic heart failure (CHF). In this study, we compared the effects of donepezil, metoprolol, and their combination on the progression of cardiac remodeling in rats with RMI. The animals were randomly assigned to untreated (UT), donepezil-treated (DT), metoprolol-treated (MT), and a combination of donepezil and metoprolol (DMT) groups. On day 8 after surgery, compared to the UT, the DT and DMT significantly improved myocardial salvage, owing to the suppression of macrophage infiltration and apoptosis. After the 10-week treatment, the DT and DMT exhibited decreased heart rate, reduced myocardial infarct size, attenuated cardiac dysfunction, and decreased plasma levels of brain natriuretic peptide and catecholamine, thereby preventing subsequent CHF. These results suggest that donepezil monotherapy or combined therapy with β-blocker may be an alternative pharmacotherapy post-RMI.