Prohormone B-type Natriuretic Peptide Research Articles

Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction.

To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1-3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ -10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35-1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09-1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09-1.26; P < 0.001 vs. 1.07, 95% CI 1.02-1.13; P=0.011). Heart rate was not predictive of any outcome in AF. In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

Towards Point-of-Care Heart Failure Diagnostic Platforms: BNP and NT-proBNP Biosensors.

Heart failure is a class of cardiovascular diseases that remains the number one cause of death worldwide with a substantial economic burden of around $18 billion incurred by the healthcare sector in 2017 due to heart failure hospitalization and disease management. Although several laboratory tests have been used for early detection of heart failure, these traditional diagnostic methods still fail to effectively guide clinical decisions, prognosis, and therapy in a timely and cost-effective manner. Recent advances in the design and development of biosensors coupled with the discovery of new clinically relevant cardiac biomarkers are paving the way for breakthroughs in heart failure management. Natriuretic neurohormone peptides, B-type natriuretic peptide (BNP) and N-terminal prohormone of BNP (NT-proBNP), are among the most promising biomarkers for clinical use. Remarkably, they result in an increased diagnostic accuracy of around 80% owing to the strong correlation between their circulating concentrations and different heart failure events. The latter has encouraged research towards developing and optimizing BNP biosensors for rapid and highly sensitive detection in the scope of point-of-care testing. This review sheds light on the advances in BNP and NT-proBNP sensing technologies for point-of-care (POC) applications and highlights the challenges of potential integration of these technologies in the clinic. Optical and electrochemical immunosensors are currently used for BNP sensing. The performance metrics of these biosensors—expressed in terms of sensitivity, selectivity, reproducibility, and other criteria—are compared to those of traditional diagnostic techniques, and the clinical applicability of these biosensors is assessed for their potential integration in point-of-care diagnostic platforms.

Cardiac Biomarkers Predict Long-term Survival After Cardiac Surgery

Cardiac biomarkers soluble ST-2 (sST-2) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) may be associated with long-term survival after cardiac surgery. This study explored the relationship between long-term survival after cardiac surgery and serum biomarker levels. Patients undergoing cardiac surgery from 2004 to 2007 were enrolled in a prospective biomarker cohort in the Northern New England Cardiovascular Disease Study Group Registry. Preoperative serum biomarker levels, postoperative serum biomarker levels, and the change in serum biomarker levels were categorized by quartile. The study used Kaplan-Meier survival analysis and Cox regression models adjusted for variables in the American College of Cardiology Foundation-Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategy (ASCERT) long-term survival calculator to study the association of biomarker levels with long-term survival. After Kaplan-Meier analysis, quartiles 2 and 3 were found to have similar survival and were therefore combined into 1 category. In the study cohort (n= 1648), median follow-up time was 8.5 years (interquartile range, 7.6-9.7 years), during which there were 227 deaths. The 10-year survival rate was 86%. Kaplan-Meier survival analysis demonstrated a significant (P < .001) difference across quartiles of each biomarker level measurement. After adjustment, preoperative levels, postoperative levels, and the change in biomarker levels in quartile 4 (highest serum levels or change) were significantly predictive of worse survival (hazard ratio range, 1.77-2.89; all P < .05) compared with quartile 1; however, levels of sST-2 and NT-proBNP in quartiles 2 and 3 demonstrated a nonstatistically significant trend with long-term survival. Elevated preoperative and postoperative levels of sST-2 or NT-proBNP and large changes in these biomarkers' levels are associated with an increased risk of worse survival after cardiac surgery. These biomarkers can be used for risk stratification or assessing postsurgical prognosis.

Characteristics and Outcomes in Patients With Electrical Storm

Electrical storm (ES) is a life-threatening condition with diverse clinical presentation, caused by recurrent malignant ventricular arrhythmia--≥3 episodes of ventricular tachycardia (VT) or ventricular fibrillation within 24hours and is associated with high mortality. The aim of this study was analysis of clinical profile, treatment, and prognosis of patients with ES admitted to a high-volume cardiovascular center. We present results of a single-center, retrospective, ongoing observational registry enrolling consecutive patients presenting with ES admitted between 2006 and 2017. Clinical history, results of diagnostic investigations, and treatment were collected for all patients. Follow-up data were collected from hospital documentation, outpatient clinic, remote monitoring systems, and from data gathered from national health services. Registry enrolled 101 consecutive patients admitted with ES. Two-thirds of patients had ischemic cardiomyopathy. Mean left ventricle ejection fraction was 26%. In 56.4% of the patients coronary angiogram was performed and in 20.8% cases percutaneous coronary intervention was needed. 18.8% of the patients underwent VT ablation. 12-month mortality from first ES in our population was 21.8%. NYHA class III and IV, raised N-terminal fragment of prohormone B-type Natriuretic Peptide and creatinine levels, and lower hemoglobin levels were independent predictors of death. In conclusion, most patients admitted with ES have ischemic cardiomyopathy. Over 1/3 of the population had significant narrowing of at least one coronary artery with ES masking ischemia and underwent percutaneous coronary intervention. Nearly 1/5 of the patients were treated with VT ablation. 12-month mortality was high and exceeded 1/4 of patients with ES.

Utility of the FRAIL Questionnaire in Detecting Heart Failure with Preserved Ejection Fraction.

To test the utility of the FRAIL questionnaire as a screening tool for heart failure. Cross sectional study. Chinese older people in Hong Kong. Participants aged 60 years and over were recruited from a territory-wide primary care needs assessment for older people based in community centers as well as two nonacute hospitals. Questionnaire administered included the five-item FRAIL scale, and information regarding sociodemographic data, smoking and alcohol use, history of cardiovascular disease and diabetes, and heart failure symptoms. Handgrip strength, walking speed and 6 minute walk distance were recorded. Cardiac assessment included electrocardiogram, echocardiography, and blood assay for N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). The prevalence of diastolic dysfunction was high, being 52% in the robust group, increasing to 65% in the pre-frail and 85% in the frail group. This finding is accompanied by a corresponding increase in NT-proBNP from 64.18 pg/ml in the robust group, to 118.57 pg/ml in the pre-frail and 167.98 pg/ml in the frail group. Three of the five components of the FRAIL scale, fatigue, resistance and ambulation, were associated with increased odds ratios of diastolic dysfunction among those aged 75 years and older, while resistance alone was associated with increased odds ratio among those less than 75 years old. Frailty is associated with heart failure with preserved ejection fraction (HFpEF), and frailty screening may be used to detect undiagnosed HFpEF. The findings support the proposal that HFpEF be considered a geriatric syndrome.

Baroreflex sensitivity assessed with the sequence method is associated with ventricular arrhythmias in patients implanted with a defibrillator for the primary prevention of sudden cardiac death

Left ventricular ejection fraction lacks accuracy in predicting sudden cardiac death, resulting in unnecessary implantation of cardioverter defibrillators for the primary prevention of sudden cardiac death. Baroreflex sensitivity could help to stratify patients at risk of ventricular arrhythmia. To assess the association between cardiac baroreflex sensitivity and ventricular arrhythmias in patients implanted with an implantable cardioverter defibrillator for the primary prevention of sudden cardiac death after myocardial infarction. This case-control single-centre study took place between 2015 and 2016. Cases (n=10) had experienced ventricular arrhythmias treated by the implantable cardioverter defibrillator in the previous 3 years; controls (n=22) had no arrhythmia during the same period. Baroreflex sensitivity was assessed using the temporal sequence method (mean slope) and cross-spectral analysis (low-frequency gain and high-frequency gain). The mean age was 65 years; 94% of the patients were men. 24-hour Holter electrocardiogram autonomous nervous system variables, left ventricular ejection fraction and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) concentration did not differ between cases and controls. The mean slope was lower in cases than in controls (8 vs. 15ms/mmHg [P=0.009] in the supine position; 7 vs. 12ms/mmHg [P=0.038] in the standing position). The mean slope in the supine position was still significantly different between groups after adjustment for age, left ventricular ejection fraction and NT-proBNP (P=0.03). By comparison, low-frequency gain and high-frequency gain did not differ between groups in either the supine or the standing position. Patients with ventricular arrhythmias had a lower mean slope compared with those who were free of arrhythmia. A prospective study is needed to confirm this association.

Conversion formula from B-type natriuretic peptide to N-terminal proBNP values in patients with cardiovascular diseases

BackgroundAlthough B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are released in equimolar proportions, their values differ depending on clinical conditions. A useful conversion formula between BNP and NT-proBNP remains to be developed for the clinical use. AimTo develop a conversion formula from BNP to NT-proBNP. MethodsIn the derivation cohort, 923 patients with chronic heart failure, in whom both BNP and NT-proBNP values were available, were enrolled from our SUPPORT (Supplemental Benefit of ARB in Hypertensive Patients with Stable Heart Failure using Olmesartan) trial. The validation cohort included 1154 consecutive patients with or at risk of cardiovascular diseases, in whom both BNP and NT-proBNP values were measured simultaneously at Tohoku University Hospital. We regressed log10 NT-proBNP onto log10 BNP and factors influencing BNP and NT-proBNP values. ResultsWe adopted the model with the smallest Akaike information criterion consisting of log10 BNP, age, sex, BMI, creatinine clearance (CCr), hemoglobin, and atrial fibrillation (AF). As compared with the previously reported conversion formulas, the present conversion formula utilized non-linear transformation by spline function, and exhibited the strongest correlation between actual and calculated values of NT-proBNP (r = 0.928). The root mean squared error (RMSE) of the present conversion formula was smallest compared with the previously reported conversion formulas, indicating that this formula most effectively converts BNP values to NT-proBNP values. ConclusionsWe have developed a useful conversion formula from BNP to NT-proBNP values, using age, sex, BMI, CCr, hemoglobin, and AF, which could be widely used in daily clinical practice.

Rationale and Design of the High Platelet Inhibition with Ticagrelor to Improve Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction (HEALING-AMI) Trial

Background and ObjectivesImpaired recovery from left ventricular (LV) dysfunction is a major prognostic factor after myocardial infarction (MI). Because P2Y12 receptor blockade inhibits myocardial injury, ticagrelor with off-target properties may have myocardial protection over clopidogrel. In animal models, ticagrelor vs. clopidogrel protects myocardium against reperfusion injury and improves remodeling after MI. We aimed to investigate the effect of ticagrelor on sequential myocardial remodeling process after MI.MethodsHigh platelet inhibition with ticagrelor to improve LV remodeling in patients with ST-segment elevation MI (HEALING-AMI) is an investigator-initiated, randomized, open-label, assessor-blinded, multi-center trial done at 10 sites in Korea. Patients will be enrolled if they have ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention and a planned duration of dual antiplatelet treatment of at least 6 months. Screened patients will be randomly assigned (1:1) using an internet-based randomization with a computer-generated blocking with stratification across study sites to either ticagrelor or clopidogrel treatment. The co-primary primary endpoints are LV remodeling index with three-dimensional echocardiography and the level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) at 6 months representing post-MI remodeling processes. Changes of LV end-systolic/diastolic volume indices and LV ejection fraction between baseline and 6-month follow-up will be also evaluated. Analysis is per protocol.ConclusionsHEALING-AMI is testing the effect of ticagrelor in reducing adverse LV remodeling following STEMI. Our trial would show the benefit of ticagrelor vs. clopidogrel related to the recovery of post-MI LV dysfunction beyond potent platelet inhibition.Trial RegistrationClinicalTrials.gov Identifier: NCT02224534

The journey of the heart failure patient, based on data from a single center.

Care for patients with heart failure (HF) in Poland requires improvement. The aim of this study was to define the journey of the HF patient, taking into account the specialization of the hospital ward and further, highly specialized outpatient care. Using the medical system CliniNET®, we analyzed 214 consecutive patients hospitalized due to HF (International Statistical Classification of Diseases and Health Related Problems - ICD-10: I50) in the period from September 1 to December 31, 2015, and also the data from post-discharge outpatient care in a 3-month period. To fairly compare the management of care and outcomes of patients hospitalized in the internal medicine (IM) ward and in the cardiac ward, propensity score matching was performed. The multivariate regression analysis was performed to determine the independent predictors of the hospital ward selection and the risk of rehospitalization due to HF and/or death. The majority of patients were hospitalized due to HF for the first time (72%) and in the cardiac ward (65%). For 55% of rehospitalized patients, the subsequent admission was within 3 months after initial discharge. The independent predictors of a higher risk of rehospitalization due to HF and/or death were ischemic heart disease, atrial fibrillation (AF), chronic kidney disease (CKD), mineralocorticoid antagonism (MRA) therapy, and hospitalization in the last year (for all, p < 0.05). Internal medicine ward patients differed from cardiac ward patients in: mode of admission (urgent 100% vs 83.5%; p < 0.001), length of hospitalization (median: 8 days vs 5 days; p = 0.001), death rate (24% vs 4.3%; p < 0.001), echocardiography (43% vs 98%; p < 0.001), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) measurements (43% vs 96%; p < 0.001). The burden of 5-9 accompanying diseases enhanced the choice of the cardiac ward (p < 0.05), while age and urgent mode of hospitalization decreased the chance of being referred to the cardiac ward (p < 0.01). Cardiac patients were more likely to receive β-blockers, diuretics, angiotensin receptor blockers (ARB), and MRA. Over 90% of cardiac ward patients were referred to cardiac ambulatory care after discharge from hospital, while among patients discharged from the IM ward, this rate was 60% (p < 0.001). There were significant differences among the 2 wards in relation to the course of hospitalization and post-discharge outpatient care.

Cutting Edge of Brain Natriuretic Peptide (BNP) Research - The Diversity of BNP Immunoreactivity and Its Clinical Relevance.

Brain (or B-type) natriuretic peptide (BNP) is a cardiac hormone produced in the heart and an established biochemical marker for heart failure (HF) because the level in plasma increases in proportion to disease severity. Recently, the diversity of BNP molecular forms in the peripheral circulation, which includes mature BNP (BNP1-32) and its metabolites (BNP3-32, BNP4-32, and BNP5-32), was demonstrated. Moreover, studies showed that unprocessed BNP prohormone (proBNP) is also secreted from the heart, and its secretion is increased in patients with HF. Interestingly, BNP1-32, its metabolites, and proBNP are all detected as immunoreactive BNP by the currently available BNP assay system. Current N-terminal proBNP (NT-proBNP) assay systems also can react to both NT-proBNP and proBNP. In addition, the N-terminal region of proBNP and NT-proBNP are often O-glycosylated, which may result in underestimation of total NT-proBNP level, which includes both glycosylated and non-glycosylated NT-proBNP, by the NT-proBNP assay system. More recently, we have shown that miR30-GALNT-dependent O-glycosylation in the N-terminal region of proBNP affects the processing of proBNP and contributes to its secretion from the heart. The level of proBNP relative to BNP (proBNP/BNP ratio) in the coronary sinus is higher in patients with more severe HF. The proBNP/BNP ratio and the deglycosylated NT-proBNP level may be new and clinically useful biomarkers of HF.

NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure

PurposeHeart failure (HF) is considered to be a complex syndrome associated with neurohormonal and cytokine activation, that contribute to its progression. There are evidences which showed that, carbohydrate antigen 125 (CA 125), a tumor marker widely used for ovarian cancer therapy monitoring, was significantly elevated in HF patients. We hypothesized that inflammatory stimuli may be responsible for amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and CA-125 production and release in chronic HF (CHF). We aimed to measure the levels of NT-proBNP, CA 125, pro-anti-inflammatory cytokines (IL-6, IL-1β, IL-8, TNF-α and IL-4), from peripheral venous (PV) and coronary sinus (CS) blood samples, in patients with CHF and to assess their correlation with echocardiographic indices. MethodsWe enrolled 32 subjects (20M/12F) with CHF (III-IV NYHA functional class) who were to undergo cardiac resynchronization therapy (CRT) device implantation and 30 healthy controls (18M/12F). Two blood samples, from PV and CS, were collected at the time of CRT for each CHF patient. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. ResultsAll investigated biomarkers were significantly higher in CHF patients than in non-CHF controls (P < 0.001). There were positive correlations between biomarkers concentrations in PV and CS (r between 0.54 and 0.98, all P < 0.003). NT-proBNP, IL-6 and IL-1β levels were 17%, 86% and 36% higher in CS than in PV, these increases being very well correlated each other, while CA 125 levels were 86% higher in PV than in CS. Moreover, CS NT-proBNP, CS IL-6 and CS IL-1β serum concentrations were inversely related to the echocardiographically determined left ventricular ejection fraction (LVEF) (r = −0.61, P < 0.001; r = −0.71, P < 0.001 and r = −0.48, P = 0.005, respectively). A positive relationship was found between CA 125 and IL-1β (r = 0.51, P = 0.003) in CS serum and between CA 125 and IL-6 (r = 0.43, P = 0.015), TNF-α (r = 0.46, P = 0.008) in PV serum. CA 125 concentrations were closely related to NT-proBNP both in CS (r = 0.46, P = 0.008) and PV (r = 0.52, P = 0.002). ConclusionsCS sampling of NT-proBNP, CA 125 and pro-anti-inflammatory cytokines provides an additional insight into the possible mechanisms by which these biomarkers lead to left ventricular remodeling. Our results clearly suggest that serum NT-proBNP and CA 125 levels not only in PV, but also in CS of patients with CHF, may be dependent on inflammation as a consequence of cytokine network activation.

Early changes in N-terminal pro-B-type natriuretic peptide levels after transcatheter aortic valve replacement and its impact on long-term mortality

BackgroundN-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) levels correlate with higher peri-procedural mortality after transcatheter aortic valve replacement (TAVR). The long-term prognostic value of NT-proBNP within the first days after TAVR, however, remains unclear. This study examined early changes in NT-proBNP prior to and within 6 days after TAVR, the diagnostic value of this biomarker regarding aortic regurgitation (AR), and its prognostic value regarding one-year mortality. Methods and resultsNT-proBNP concentrations were measured in 504 consecutive patients undergoing transapical (TA) or transfemoral (TF) TAVR before and directly after TAVR as well as 4 h and 1, 2, 3, and 6 days after TAVR. The follow-up period was 1 year. NT-proBNP was elevated in all patients at baseline (median 2141 ng/L [IQR 1021–5319 ng/L]). NT-proBNP changes in the first 6 days after TAVR showed significant differences depending on the approach, with a greater and more prolonged rise evident in TA-TAVR patients. NT-proBNP was an independent predictor of mortality in TA patients with AR, with an AUC of 0.794 (95% CI 0.663–0.925; P = 0.003) when measured on day 3 after TAVR. For TF patients with AR and reduced left ventricular systolic function, the AUC for prediction of mortality was 0.897 (95% CI 0.778–1.0; P = 0.004) on day 2. ConclusionsThe prognostic information of early post-procedural NT-proBNP concentrations is superior to pre-procedural values regarding all-cause mortality within 1 year. Post-procedural NT-proBNP must be interpreted in relation to the TAVR approach. NT-proBNP predicts mortality in TF-TAVR patients with AR and reduced left ventricular function.

Role of Soluble ST2 Levels and Beta-Blockers Dosage on Cardiovascular Events of Patients with Unselected ST-Segment Elevation Myocardial Infarction.

Background:Serum soluble ST2 (sST2) levels are elevated early after acute myocardial infarction and are related to adverse left ventricular (LV) remodeling and cardiovascular outcomes in ST-segment elevation myocardial infarction (STEMI). Beta-blockers (BB) have been shown to improve LV remodeling and survival. However, the relationship between sST2, final therapeutic BB dose, and cardiovascular outcomes in STEMI patients remains unknown.Methods:A total of 186 STEMI patients were enrolled at the Wuhan Asia Heart Hospital between January 2015 and June 2015. All patients received standard treatment and were followed up for 1 year. Serum sST2 was measured at baseline. Patients were divided into four groups according to their baseline sST2 values (high >56 ng/ml vs. low ≤56 ng/ml) and final therapeutic BB dose (high ≥47.5 mg/d vs. low <47.5 mg/d). Cox regression analyses were performed to determine whether sST2 and BB were independent risk factors for cardiovascular events in STEMI.Results:Baseline sST2 levels were positively correlated with heart rate (r = 0.327, P = 0.002), Killip class (r = 0.408, P = 0.000), lg N-terminal prohormone B-type natriuretic peptide (r = 0.467, P = 0.000), lg troponin I (r = 0.331, P = 0.000), and lg C-reactive protein (r = 0.307, P = 0.000) and negatively correlated to systolic blood pressure (r = −0.243, P = 0.009) and LV ejection fraction (r = −0.402, P = 0.000). Patients with higher baseline sST2 concentrations who were not titrated to high-dose BB therapy (P < 0.0001) had worse outcomes. Baseline high sST2 (hazard ratio [HR]: 2.653; 95% confidence interval [CI]: 1.201–8.929; P = 0.041) and final low BB dosage (HR: 1.904; 95% CI, 1.084–3.053; P = 0.035) were independent predictors of cardiovascular events in STEMI.Conclusions:High baseline sST2 levels and final low BB dosage predicted cardiovascular events in STEMI. Hence, sST2 may be a useful biomarker in cardiac pathophysiology.

Impact of echocardiographic wall motion abnormality and cardiac biomarker elevation on outcome after subarachnoid hemorrhage: a meta-analysis.

Cardiac abnormalities (echocardiographic wall motion abnormality (WMA), biomarker elevation of cardiac troponin (cTn), B-type natriuretic peptide (BNP), or N-terminal prohormone of B-type natriuretic peptide (NT-proBNP)) frequently occur after subarachnoid hemorrhage (SAH). The clinical significance of cardiac abnormalities after SAH remains controversial. This meta-analysis was performed to assess the association between cardiac abnormalities and patient outcomes, including delayed cerebral ischemia (DCI), poor outcome, and death in SAH patients. PubMed and Embase were searched for observational studies reporting an association between cardiac abnormalities and outcome after SAH that were published before 31 December 2017. We extracted data regarding patient characteristics, cardiac abnormalities, and outcome measurements (DCI, poor outcome, or death). Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Twenty-six studies involving 3917 patients were included in our data analysis. WMA showed significant associations with higher rates of DCI (RR, 2.03; 95% CI, 0.99-4.15), poor outcome (RR, 1.45; 95% CI, 1.08-1.93), and death (RR, 2.54; 95% CI, 1.59-4.05). cTn elevation was associated with an increased risk of DCI (RR, 1.48; 95% CI, 1.23-1.79), poor outcome (RR, 1.85; 95% CI, 1.49-2.30), and death (RR, 2.68; 95% CI, 2.19-3.27). Elevation of BNP or NT-proBNT was significantly associated with higher rates of DCI (RR, 1.87; 95% CI, 1.16-3.02). WMA and elevation of cTn, BNP, and NT-proBNP in SAH patients are associated with an increased risk of DCI, poor outcome, and death after SAH.

Apolipoprotein CIII and N-terminal prohormone b-type natriuretic peptide as independent predictors for cardiovascular disease in type 2 diabetes

Background and aimsDeveloping sparse panels of biomarkers for cardiovascular disease in type 2 diabetes would enable risk stratification for clinical decision making and selection into clinical trials. We examined the individual and joint performance of five candidate biomarkers for incident cardiovascular disease (CVD) in type 2 diabetes that an earlier discovery study had yielded. MethodsApolipoprotein CIII (apoCIII), N-terminal prohormone B-type natriuretic peptide (NT-proBNP), high sensitivity Troponin T (hsTnT), Interleukin-6, and Interleukin-15 were measured in baseline serum samples from the Collaborative Atorvastatin Diabetes trial (CARDS) of atorvastatin versus placebo. Among 2105 persons with type 2 diabetes and median age of 62.9 years (range 39.2–77.3), there were 144 incident CVD (acute coronary heart disease or stroke) cases during the maximum 5-year follow up. We used Cox Proportional Hazards models to identify biomarkers associated with incident CVD and the area under the receiver operating characteristic curves (AUROC) to assess overall model prediction. ResultsThree of the biomarkers were singly associated with incident CVD independently of other risk factors; NT-proBNP (Hazard Ratio per standardised unit 2.02, 95% Confidence Interval [CI] 1.63, 2.50), apoCIII (1.34, 95% CI 1.12, 1.60) and hsTnT (1.40, 95% CI 1.16, 1.69). When combined in a single model, only NT-proBNP and apoCIII were independent predictors of CVD, together increasing the AUROC using Framingham risk variables from 0.661 to 0.745. ConclusionsThe biomarkers NT-proBNP and apoCIII substantially increment the prediction of CVD in type 2 diabetes beyond that obtained with the variables used in the Framingham risk score.

Pharmacology of Cardio-Oncology: Chronotropic and Lusitropic Effects of B-Type Natriuretic Peptide in Cancer Patients with Early Diastolic Dysfunction Induced by Anthracycline or Nonanthracycline Chemotherapy.

B-type natriuretic peptide (BNP) is widely used as a diagnostic marker of systolic dysfunction. We previously conducted a clinical study in which anthracycline or nonanthracycline chemotherapy did not cause systolic dysfunction in cancer patients; however, some patients showed asymptomatic alterations in diastolic relaxation, whereas others showed persistent elevations of BNP, measured as prohormone BNP amino-terminal fragment. Here we describe post hoc pharmacologic analyses showing that: 1) impaired relaxation and persistent elevations of BNP were mutually exclusive manifestations of diastolic dysfunction; 2) in some patients, BNP elevations were induced by an early compromise of myocardial relaxation; 3) BNP elevations then halted further deterioration of relaxation in a concentration-dependent manner; and 4) high BNP increased heart rate (HR). BNP elevations therefore caused positive lusitropy and chronotropism, which might be explained by activation of natriuretic receptor-associated guanylyl cyclase and production of cGMP in ventricular myocytes and sinoatrial node, respectively. BNP levels also influenced responses to a lusitropic drug, ranolazine, that was given to treat diastolic dysfunction. For patients with impaired relaxation and normal or only transiently high levels of BNP, ranolazine improved myocardial relaxation without inducing chronotropic effects. For patients in whom relaxation abnormalities were corrected by persistently high BNP levels, ranolazine substituted for BNP and decreased HR by diminishing BNP levels. These findings describe a pharmacologic scenario in which cancer drugs cause an early diastolic dysfunction that in some patients is both heralded and modulated by BNP elevations. Patients showing BNP elevations should therefore receive the adequate pharmacologic treatment of correcting diastolic dysfunction and tachycardia.

Outcome of patients with cardiac amyloidosis admitted to an intensive care unit for acute heart failure

The outcome of cardiac amyloidosis (CA) has been reported mainly in stable populations; limited data are available in patients referred for acute heart failure (AHF) to an intensive cardiac care unit (ICCU). To address the characteristics and outcomes of patients with confirmed CA admitted to an ICCU for AHF and then to identify the predictors of evolution to cardiogenic shock. All patients with CA referred to an ICCU for AHF between 2009 and 2015 were included. The clinical endpoint was 3-month death. Data from the population with cardiogenic shock, obtained in a stable haemodynamic state, were matched with data from a control group to determine predictors of evolution to cardiogenic shock. Among the 421 patients followed for CA in our expert centre, 46 patients (mean age: 64±14 years; 65% light-chain [AL] CA) were referred to the ICCU for AHF (n=26 with cardiogenic shock). At 3 months, death occurred in 24 (52%) patients, mostly in the cardiogenic shock group (n=21/26, 81%). Most deaths occurred 5 days [interquartile range 3-9 days] after catecholamine infusion and 50% occurred in patients aged<65 years. The majority of deaths were reported in patients with AL CA (n=19/24, 79%). Independent variables associated with in-hospital mortality were cardiogenic shock and uraemia level. N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) concentration obtained in a stable haemodynamic state was the only predictor of short-term evolution to cardiogenic shock (odds ratio: 8.7, 95% confidence interval: 2.2-34.6), with an optimal cut-off of 4040pg/mL (sensitivity=92%; specificity=81%). The study confirms the dramatic mortality associated with CA when presenting as cardiogenic shock and underlines the limited efficiency of conventional treatments. Given the rapid occurrence of death in a young population, an alternative strategy to dobutamine support should be investigated in patients with elevated NT-proBNP concentration.

Advanced and traditional electrocardiographic risk factors in pulmonary arterial hypertension: the significance of ventricular late potentials.

Whether non-invasive electrocardiographic parameters may be of similar relevance in pulmonary arterial hy-pertension (PAH) as in left ventricular heart failure (LVHF) remains unclear. To examine a profile of electrocardiographic parameters in PAH and to determine their prognostic significance. Com-parison of profile in patients with pulmonary hypertension secondary to left ventricular dysfunction was planned in order to put PAH group results into context. We included 41 patients with type 1.1/1.4.4 (according to the European Society of Cardiology) PAH and 31 patients with LVHF and type 2.1 pulmonary hypertension. All patients underwent 24-h ambulatory electrocardiography monitoring. Among heart rate variability parameters, only RMSSD was different (mean, 75 ms [PAH] vs. 112 ms [LVHF], p = 0.016). In PAH, fewer patients had ventricular tachycardia (15% vs. 48%, p = 0.004), abnormal deceleration capacity (54% vs. 84%, p = 0.011), positive heart rate turbulence (11% vs. 48%, p = 0.003), severe autonomic failure (10% vs. 39%, p = 0.005), and ventricular late potentials (LP) (19% vs. 62%, p = 0.001). In PAH, four deaths occurred in 42 months. In univariate analysis, the risk factors for death were: LP (hazard ratio 13.55, 95% confidence interval 1.41-130.72; p = 0.024), age, N-terminal prohormone of B-type natriuretic peptide, while the protective factors were minimal and mean heart rate, as well as the six-minute walk test (6MWT) distance. In multivariate analysis, the influence of LP and the 6MWT distance remained significant. Ventricular LP were present in 19% of PAH patients and were the most powerful risk factor of mortality .

The Serum Biomarkers of Cardiovascular Disease Are Elevated in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) With Advanced Fibrosis and Histologically-Proven Non-alcoholic Steatohepatitis (NASH): 2017 Presidential Poster Award

Introduction: NAFLD is associated with increased risk for cardiovascular disease (CVD) and CV mortality. The progressive NAFLD or NASH and especially those with hepatic fibrosis are at risk for mortality. Given that CVD is the top cause of death in NAFLD/NASH, it is possible that these subjects may share the same pathogenic environment as those with CVD. Recently, N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and osteopontin (OPN) have been shown to be associated with CVD. Our aim was to see if these biomarkers are associated with the aggressive form of NAFLD such as NASH or significant hepatic fibrosis. Methods: The study cohort included 170 biopsy-proven NAFLD subjects who were prospectively consented and enrolled. Liver biopsies were assessed by the study hepatopathologists and graded for degree of steatosis (0-3), necroinflammation and fibrosis (0-4). Sera samples were frozen from the time of biopsy were used to measure serum levels of OPN (pg/mL), NT-proBNP (pg/mL) and adiponectin (ng/mL) using MILIPLEX® MAP assays by Luminex®. Results: Histologic NASH was seen in 52% of NAFLD and % had stage 2 or higher fibrosis. The median OPN levels were higher in NASH as compared to steatosis alone (3109 vs. 2251, p < 0.01). Additionally, adiponectin levels were lower in NASH as compared to hepatic steatosis by using quartile 4 as cutoff point (34% vs. 53%, p < 0.05). Furthermore, as compared to fibrosis stage (0-1) (2598), the median OPN levels were higher in patients with advance fibrosis (fibrosis stage ≥2) (3360, p < 0.01) as well as bridging fibrosis (3242 vs 2598, p < 0.05). Also, higher levels of OPN positively correlated with AST (r=0.17; p=0.03) and serum ferritin (r=0.28; p=0.03), while adiponectin only positively correlated with HDL (r=0.33; p < 0.01). Histologically, serum OPN significantly correlated with the presence of polymorphonuclear (r=0.24; p < 0.01), and Mallory-Denk body (r=0.28; p < 0.01) in the liver biopsy. In the multivariate analysis, serum OPN was independently associated with presence of histologic NASH in NAFLD patients (OR 2.9 [95% CI 1.2-6.7]). In contrast NT-proBNP was not detectable in both groups. Conclusion: Increased serum levels of OPN seem to be associated with presence of NASH and advanced hepatic fibrosis in patients with NAFLD. Further studies are needed to validate these findings and to determine if serum OPN can also predict presence of development of CVD in subjects with NAFLD.

Plasma dipeptidyl-peptidase-4 activity is associated with left ventricular systolic function in patients with ST-segment elevation myocardial infarction

Plasma dipeptidyl-peptidase-4 activity (DPP4a) is inversely associated with left ventricular function in patients with heart failure (HF) or diabetes. However, the association between DPP4a and left ventricular function in ST-segment elevation myocardial infarction (STEMI) patients has not been reported. We studied this association in 584 consecutive STEMI patients at a tertiary referral center from July 2014 to October 2015. DPP4a and plasma N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels were quantified by enzymatic assays. The median serum NT-proBNP levels were highest in patients of the lowest tertile (T1) of DPP4a compared with that of the highest tertile (T3) (p = 0.028). The STEMI patients in T1 exhibited lower left ventricular systolic function (T1 vs. T3: left ventricular ejection fraction (LVEF): 50.13 ± 9.12 vs. 52.85 ± 6.82%, p = 0.001). Multivariate logistic-regression analyses (adjusted for confounding variables) showed that a 1 U/L increase in DPP4a was associated with a decreased incidence of left ventricular systolic dysfunction (LVSD) (adjusted odds ratio: 0.90; 95% CI: 0.87–0.94; p < 0.01). In conclusion, low DPP4a is independently associated with LVSD in STEMI patients, which suggests that DPP4 may be involved in the mechanisms of LVSD in STEMI patients.