Intestinal Microbiota-Dependent Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic Heart Failure

Background: Trimethylamine-N-oxide (TMAO) has been linked to increased cardiovascular risk. We aimed to determine the prognostic value of TMAO and its dietary precursors, choline and betaine, in heart failure (HF). Methods and Results: In 112 patients with chronic systolic HF with comprehensive echocardiographic evaluation, we measured plasma TMAO, choline, and betaine by mass spectrometry. Median (interquartile range) TMAO levels, choline, and betaine levels were 5.8 (3.6–12.1) μmol/L, 10.9 (8.4–14.0) μmol/L, and 43.8 (37.1–53.0) μmol/L, respectively, and were correlated with each other (all P \u3c .0001 for both). TMAO levels were significantly higher in patients with diabetes mellitus (9.4 [4.9–13.2] vs 4.8 [3.4–9.8] μmol/L; P = .005) and in subjects with New York Heart Association functional class III or greater (7.0 [4.7–14.8] vs 4.7 [3.4–11.3] μmol/L; P = .02). Elevated TMAO, choline, and betaine levels were each associated with higher plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and more advanced left ventricular diastolic dysfunction, but not systolic dysfunction or inflammatory and endothelial biomarkers. Higher choline (hazard ratio [HR] 1.64, 95% CI 1.22–2.20; P = .001), betaine (HR 1.51, 95% CI 1.10–2.08; P = .01), and TMAO (HR 1.48, 95% CI 1.10–1.96; P = .01) predicted increased risk for 5-year adverse clinical events (death/transplantation). Only higher TMAO levels predicted incident adverse clinical events independently from age, estimated glomerular filtration rate, mitral E/septal Ea, and NT-proBNP levels (HR 1.46, 95% CI 1.03–2.14; P = .03). Conclusion: Elevated plasma TMAO, choline, and betaine levels are each associated with more advanced left ventricular diastolic dysfunction and portend poorer long-term adverse clinical outcomes in chronic systolic HF. However, only higher plasma TMAO was associated with poor prognosis after adjustment for cardiorenal indices

Antecedent hypertension and heart failure after myocardial infarction

AbstractObjectivesWe sought to assess the relationship of antecedent hypertension to neurohormones, ventricular remodeling and clinical heart failure (HF) after myocardial infarction (MI).BackgroundHeart failure is a probable contributor to the increased mortality observed after MI in those with antecedent hypertension. Hence, neurohormonal activation, adverse ventricular remodeling and a higher incidence of clinical HF may be expected in this group. However, no previous report has documented serial postinfarction neurohumoral status, serial left ventricular imaging and clinical outcomes over prolonged follow-up in a broad spectrum of patients with and without antecedent hypertension.MethodsInpatient events were documented in 1,093 consecutive patients (436 hypertensive and 657 normotensive) with acute MI. In 68% (282 hypertensive, 465 normotensive) serial neurohormonal sampling and radionuclide ventriculography were performed one to four days and three to five months after infarction. Clinical outcomes were recorded over a mean follow-up of two years.ResultsPlasma neurohormones were significantly higher in hypertensives than in normotensives one to four days and three to five months after infarction. From similar initial values, left ventricular volumes increased significantly in hypertensives, compared with normotensives. Left ventricular ejection fraction rose significantly in normotensive but not hypertensive patients. Together with higher inpatient (8.1% vs. 4.4%, p < 0.002) and post-discharge mortality (9.5% vs. 5.5%, p = 0.043), hypertensive patients incurred more inpatient HF (33% vs. 24%, p < 0.001) and more late HF requiring readmission to hospital (12.4% vs. 5.5%, p < 0.001). Antecedent hypertension predicted late HF in patients >64 years of age with neurohormonal activation and early left ventricular dilation.ConclusionsAntecedent hypertension interacts with age, neurohumoral activation and early ventricular remodeling to confer greater risk of HF after MI

The utility of presentation and 4-hour high sensitivity troponin I to rule-out acute myocardial infarction in the emergency department

Objectives: International guidance recommends that early serial sampling of high sensitivity troponin be used to accurately identify acute myocardial infarction (AMI) in chest pain patients. The background evidence for this approach is limited. We evaluated whether on presentation and 4-hour high-sensitivity troponin I (hs-cTnI) could be used to accurately rule-out AMI. Design and methods: hs-cTnI was measured on presentation and at 4-hours in adult patients attending an emergency department with possible acute coronary syndrome. We determined the sensitivity for AMI for at least one hs-cTnI above the 99th percentile for a healthy population or alone or in combination with new ischemic ECG changes. Both overall and sex-specific 99th percentiles were assessed. Patients with negative tests were designated low-risk. Results: 63 (17.1%) of 368 patients had AMI. The median (interquartile range) time from symptom onset to first blood sampling was 4.8. h (2.8-8.6). The sensitivity of the presentation and 4. h hs-cTnI using the overall 99th percentile was 92.1% (95% CI 82.4% to 97.4%) and negative predictive value 95.4% (92.3% to 97.4%) with 78.3% low-risk. Applying the sex-specific 99th percentile did not change the sensitivity. The addition of ECG did not change the sensitivity. Conclusion: Hs-cTnI >. 99th percentile thresholds measured on presentation and at 4-hours was not a safe strategy to rule-out AMI in this clinical setting irrespective of whether sex-specific 99th percentiles were used, or whether hs-cTnI was combined with ECG results

Heart Fatty Acid Binding Protein and cardiac troponin: development of an optimal rule-out strategy for acute myocardial infarction

Background: Improved ability to rapidly rule-out Acute Myocardial Infarction (AMI) in patients presenting with chest pain will promote decongestion of the Emergency Department (ED) and reduce unnecessary hospital admissions. We assessed a new commercial Heart Fatty Acid Binding Protein (H-FABP) assay for additional diagnostic value when combined with cardiac troponin (using a high sensitivity assay). Methods: H-FABP and high-sensitivity troponins I (hs-cTnI) and T (hs-cTnT) were measured in samples taken on-presentation from patients, attending the ED, with symptoms triggering investigation for possible acute coronary syndrome. The optimal combination of H-FABP with each hs-cTn was defined as that which maximized the proportion of patients with a negative test (low-risk) whilst maintaining at least 99 % sensitivity for AMI. A negative test comprised both H-FABP and hs-cTn below the chosen threshold in the absence of ischemic changes on the ECG. Results: One thousand seventy-nine patients were recruited including 248 with AMI. H-FABP 99 % sensitivity for AMI whilst classifying 40.9 % of patients as low-risk. The combination of H-FABP < 3.9 ng/mL and hs-cTnT < 7.6 ng/L with a negative ECG maintained the same sensitivity whilst classifying 32.1 % of patients as low risk. Conclusions: In patients requiring rule-out of AMI, the addition of H-FABP to hs-cTn at presentation (in the absence of new ischaemic ECG findings) may accelerate clinical diagnostic decision making by identifying up to 40 % of such patients as low-risk for AMI on the basis of blood tests performed on presentation. If implemented this has the potential to significantly accelerate triaging of patients for early discharge from the ED

Betaine and Secondary Events in an Acute Coronary Syndrome Cohort

BACKGROUND: Betaine insufficiency is associated with unfavourable vascular risk profiles in metabolic syndrome patients. We investigated associations between betaine insufficiency and secondary events in acute coronary syndrome patients. METHODS: Plasma (531) and urine (415) samples were collected four months after discharge following an acute coronary event. Death (34), secondary acute myocardial infarction (MI) (70) and hospital admission for heart failure (45) events were recorded over a median follow-up of 832 days. PRINCIPAL FINDINGS: The highest and lowest quintiles of urinary betaine excretion associated with risk of heart failure (p = 0.0046, p = 0.013 compared with middle 60%) but not with subsequent acute MI. The lowest quintile of plasma betaine was associated with subsequent acute MI (p = 0.014), and the top quintile plasma betaine with heart failure (p = 0.043), especially in patients with diabetes (p<0.001). Top quintile plasma concentrations of dimethylglycine (betaine metabolite) and top quintile plasma homocysteine both associated with all three outcomes, acute MI (p = 0.004, <0.001), heart failure (p = 0.027, p<0.001) and survival (p<0.001, p<0.001). High homocysteine was associated with high or low betaine excretion in >60% of these subjects (p = 0.017). Median NT-proBNP concentrations were lowest in the middle quintile of plasma betaine concentration (p = 0.002). CONCLUSIONS: Betaine insufficiency indicates increased risk of secondary heart failure and acute MI. Its association with elevated homocysteine may partly explain the disappointing results of folate supplementation. In some patients, especially with diabetes, elevated plasma betaine also indicates increased risk

N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes

OBJECTIVES The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization. BACKGROUND Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further. METHODS This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, tog-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log(2) transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels 8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome. CONCLUSIONS A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Monitoring of heart failure: comparison of left atrial pressure with intrathoracic impedance and natriuretic peptide measurements in an experimental model of ovine heart failure

Monitoring of HF (heart failure) with intracardiac pressure, intrathoracic impedance and/or natriuretic peptide levels has been advocated. We aimed to investigate possible differences in the response patterns of each of these monitoring modalities during HF decompensation that may have an impact on the potential for early therapeutic intervention. Six sheep were implanted with a LAP (left atrial pressure) sensor and a CRT-D (cardiac resynchronization therapy defibrillator) capable of monitoring impedance along six lead configuration vectors. An estimate of ALAP (LAP from admittance) was determined by linear regression. HF was induced by rapid ventricular pacing at 180 and 220 bpm (beats/min) for a week each, followed by a third week with daily pacing suspensions for increasing durations (1–5 h). Incremental pacing induced progressively severe HF reflected in increases in LAP (5.9 ± 0.4 to 24.5 ± 1.6 mmHg) and plasma atrial (20 ± 3 to 197 ± 36 pmol/l) and B-type natriuretic peptide (3.7 ± 0.7 to 32.7 ± 5.4 pmol/l) (all P<0.001) levels. All impedance vectors decreased in proportion to HF severity (all P<0.001), with the LVring (left ventricular)-case vector correlating best with LAP (r2=0.63, P<0.001). Natriuretic peptides closely paralleled rapid acute changes in LAP during alterations in pacing (P<0.001), whereas impedance changes were delayed relative to LAP. ALAP exhibited good agreement with LAP. In summary, impedance measured with an LV lead correlates significantly with changes in LAP, but exhibits a delayed response to acute alterations. Natriuretic peptides respond rapidly to acute LAP changes. Direct LAP, impedance and natriuretic peptide measurements all show promise as early indicators of worsening HF. ALAP provides an estimate of LAP that may be clinically useful

2-Hour Accelerated Diagnostic Protocol to Assess Patients With Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker

Objectives The purpose of this study was to determine whether a new accelerated diagnostic protocol (ADP) for possible cardiac chest pain could identify low-risk patients suitable for early discharge (with follow-up shortly after discharge). Background Patients presenting with possible acute coronary syndrome (ACS), who have a low short-term risk of adverse cardiac events may be suitable for early discharge and shorter hospital stays. Methods This prospective observational study tested an ADP that included pre-test probability scoring by the Thrombolysis In Myocardial Infarction (TIMI) score, electrocardiography, and 0 + 2 h values of laboratory troponin I as the sole biomarker. Patients presenting with chest pain due to suspected ACS were included. The primary endpoint was major adverse cardiac event (MACE) within 30 days. Results Of 1,975 patients, 302 (15.3%) had a MACE. The ADP classified 392 patients (20%) as low risk. One (0.25%) of these patients had a MACE, giving the ADP a sensitivity of 99.7% (95% confidence interval [CI]: 98.1% to 99.9%), negative predictive value of 99.7% (95% CI: 98.6% to 100.0%), specificity of 23.4% (95% CI: 21.4% to 25.4%), and positive predictive value of 19.0% (95% CI: 17.2% to 21.0%). Many ADP negative patients had further investigations (74.1%), and therapeutic (18.3%) or procedural (2.0%) interventions during the initial hospital attendance and/or 30-day follow-up. Conclusions Using the ADP, a large group of patients was successfully identified as at low short-term risk of a MACE and therefore suitable for rapid discharge from the emergency department with early follow-up. This approach could decrease the observation period required for some patients with chest pain. (An observational study of the diagnostic utility of an accelerated diagnostic protocol using contemporary central laboratory cardiac troponin in the assessment of patients presenting to two Australasian hospitals with chest pain of possible cardiac origin; ACTRN12611001069943

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis

Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45-0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45-0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75-1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67-0.94); P = 0.009] or cardiovascular disease [0.82 (0.67-0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalizatio