Safety, Tolerability, and Effects of a Single Subcutaneous Administration of SP16 - a SERPIN-like, Small Peptide Agonist of the Low-Density Lipoprotein-like Receptor 1- on the Acute Inflammatory Response in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Modulation of the inflammatory response is a promising therapeutic strategy in acute myocardial infarction. The novel approach is based on the anti-inflammatory and cytoprotective properties mediated by the engagement of the low-density lipoprotein‒related protein 1 (LRP1) receptor. SERPIN peptide 16 (SP16) is a synthetic, selective LRP1 agonist. We herein present the results of a study with a single subcutaneous administration of SP16 in 10 patients with STEMI, to appraise its safety and tolerability and explore the effects on the acute inflammatory response, infarct size, and cardiac function. METHODS: Ten patients with ST-segment elevation myocardial infarction (STEMI) were enrolled within 12 hours of symptoms onset and 6 hours of percutaneous coronary intervention in a single-center, single-arm, open-label study of a single subcutaneous administration of SP16 (0.2 mg/kg). Serial clinical biomarkers and echocardiography data were collected up to 12 months. The data are presented separately for the treatment group and compared with historical controls from a placebo-treated arm in a recently completed clinical trial (N = 28) with similar enrollment criteria. RESULTS: All ten patients with STEMI received subcutaneous administration of SP16, 381 [272-478] minutes after percutaneous coronary intervention, without any treatment-related adverse events. The area under the curve for C-reactive protein was 133 [46-528] mg·d/L in the SP16-treated group versus 286 [141-581] mg·d/L in the historical placebo-treated group ( P = 0.161). The area under the curve for creatine kinase-myocardial band was 1432 [675-3089] ng·d/mL in the SP16-treated group versus 2367 [830-4750] ng·d/mL in the historical placebo-treated patients ( P = 0.428). Left ventricular ejection fraction was 46% [39-54] at baseline and 51% [46-58] at 1 year follow-up in SP16-treated patients (interval change 5% [-0.3% to +9%] P = 0.05) and 44% [38%-56%] at baseline and 53% [43%-59%] at 1 year follow-up in historical placebo-treated patients (interval change 3% [-5% to 10%], P = 0.305). CONCLUSION: A single subcutaneous administration of SP16, a synthetic targeted LRP1 agonist, was safe and well-tolerated in patients with STEMI. A trend toward reduction in the inflammatory response and infarct size with SP16 was noted; however, the sample size for this study was not based on formal statistical criteria. More extensive studies are planned to determine the clinical efficacy of SP16 in STEMI.NCT: NCT04225533.

Effect of Canagliflozin Compared With Sitagliptin on Serum Lipids in Patients with Type 2 Diabetes Mellitus and Heart Failure with Reduced Ejection Fraction: A Post-Hoc Analysis of the CANA-HF Study.

ABSTRACT: The sodium glucose co-transporter 2 inhibitors have demonstrated favorable effects on cardiovascular and renal disease; however, they may also increase low-density lipoprotein cholesterol (LDL-C). There are limited data directly comparing the effects of sodium glucose co-transporter 2inhibitors on serum lipids to other antihyperglycemic therapies. In this post-hoc analysis of the CANA-HF trial, we sought to compare the effects of canagliflozin to sitagliptin in patients with type 2 diabetes mellitus (T2DM) and heart failure and reduced ejection fraction (HFrEF). The CANA-HF trial was a prospective, randomized controlled study that compared the effects of canagliflozin 100 mg daily to sitagliptin 100 mg daily on cardiorespiratory fitness in patients with HFrEF and T2DM. Of the 36 patients enrolled in CANA-HF, 35 patients had both baseline and 12-weeks serum lipids obtained via venipuncture. The change in LDL-C from baseline to 12 weeks was 5 (-12.5 to 19.5) mg/dL versus -8 (-19 to -1) mg/dL (P = 0.82) and triglyceride levels was -4 (-26 to 9) mg/dL and -10.5 (-50 to 29.3) mg/dL (P = 0.52) for canagliflozin and sitagliptin, respectively. No significant differences were found between canagliflozin and sitagliptin for total cholesterol, high-density lipoprotein cholesterol or non-HDL-C (P > 0.5 for all). These data suggest that compared with sitagliptin, canagliflozin may not increase LDL-C in patients with T2DM and HFrEF.

Time of eating and cardiorespiratory fitness in patients with heart failure with preserved ejection fraction and obesity.

BACKGROUND AND AIMS: Our objective was to examine the impact of caloric intake before or after the mean time of evening meal on cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. METHODS AND RESULTS: Twelve patients with HFpEF and obesity completed a cardiorespiratory exercise test to measure CRF, defined as peak oxygen consumption (VO2). Three five-pass 24-h dietary recalls were performed for each participant and mean evening meal time was determined for each participant individually as well as the group. Participants were divided into those who ate before (Group I) and after (Group II) the mean time of evening meal, 7:25 PM. Peak VO2 and exercise time were significantly greater in Group II compared to Group I, moreover, delaying time of evening meal was associated with greater peak VO2. CONCLUSION: Caloric intake after the mean time of evening meal was associated with better CRF in patients with HFpEF and concomitant obesity. Later nutrient intake may help prevent fasting related stress associated with cardiac metabolic disturbances present in HFpEF. Based on these findings, prospective trials aimed at examining the effects of later evening meal times in patients with HFpEF and obesity are warranted.

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

ABSTRACT: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Noninvasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects With Chronic Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in the heart rate (HR) and blood pressure (BP) leading to a significant increase in the cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of nontreatment-seeking individuals with CUD without cardiovascular disease. METHODS AND RESULTS: Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10, 20, and 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous noninvasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowed for the measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment-related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. CONCLUSIONS: Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose-dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR.

Alirocumab in Acute Myocardial Infarction: Results From the Virginia Commonwealth University Alirocumab Response Trial (VCU-AlirocRT).

Alirocumab improves outcomes in patients with a history of recent acute coronary syndrome, but treatment acutely at the time of myocardial infarction is untested. We present the results of a randomized, placebo-controlled, double-blinded pilot study of alirocumab treatment at the time of non-ST elevation MI (NSTEMI). Twenty patients with type 1 NSTEMI and low-density lipoprotein cholesterol (LDL-C) >70 mg/dL despite high intensity statin therapy were randomized 1:1 to one dose of alirocumab 150 mg subcutaneously or placebo within 24 hours of presentation. LDL-C and inflammatory biomarkers-including C-reactive protein-were obtained at baseline, 72 hours, and 14 days. Median (interquartile range) and number (%) were: age 59 (49, 65) years, 7 (35%) men, 16 (80%) black; baseline characteristics were similar between groups. Alirocumab significantly reduced LDL-C from baseline to 14 days by 64 mg/dL (-96, -47) compared with placebo [+1 mg/dL (-25, +16)] (primary endpoint). There were no significant between-group differences in C-reactive protein changes at any time point (all P > 0.2) or serious adverse events attributable to the study treatment. In conclusion, alirocumab administration at the time of NSTEMI significantly reduced LDL-C levels at 14 days, was safe, and had neutral effects on inflammatory biomarkers. Further studies are warranted to explore the effects on clinical outcomes.

Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics.

The effects of empagliflozin on cardiorespiratory fitness in patients with type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) are unknown. In this pilot study we determined the effects of empagliflozin 10 mg/d for 4 weeks on peak oxygen consumption (VO2 ) in 15 patients with T2DM and HFrEF. As an exploratory analysis, we assessed whether there was an interaction of the effects of empagliflozin on peak VO2 of loop diuretics. Empagliflozin reduced body weight (-1.7 kg; P = .031), but did not change peak VO2 (from 14.5 mL kg-1 min-1 [12.6-17.8] to 15.8 [12.5-17.4] mL kg-1 min-1 ; P = .95). However, patients using loop diuretics (N = 9) demonstrated an improvement, whereas those without loop diuretics (N = 6) experienced a decrease in peak VO2 (+0.9 [0.1-1.4] vs -0.9 [-2.1 to -0.3] mL kg-1 min-1 ; P = .001), and peak VO2 changes correlated with the baseline daily dose of diuretics (R = +0.83; P < .001). Empagliflozin did not improve peak VO2 in patients with T2DM and HFrEF. However, as a result of exploratory analysis, patients concomitantly treated with loop diuretics experienced a significant improvement in peak VO2 .

Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials.

BACKGROUND: Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. METHODS: We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. RESULTS: LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients. CONCLUSIONS: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Cardiovascular Adverse Events Associated With Second-generation Bruton Tyrosine Kinase Inhibitor Therapy: A Systematic Review and Meta-analysis.

PURPOSE: Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients. METHODS: Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI. FINDINGS: Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I2 = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis. IMPLICATIONS: Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.

Differences in clinical presentation and outcomes in pregnancy-associated Takotsubo Syndrome- A scoping review of the literature: Outcomes in pregnancy-associated Takotsubo.

BACKGROUND: Takotsubo syndrome (TS) during pregnancy and postpartum is rare but may lead to significant maternal and fetal morbidity. We compared clinical characteristics and prognosis according to [a] timing of presentation (pregnancy vs post-partum) and [b] modes of delivery (cesarean section vs vaginal delivery). METHODS: Systematic review of articles published in PubMed, Scopus, Embase, and Medline databases from inception to July 30, 2023. Patient demographics, obstetric, electrocardiographic, laboratory, echocardiographic characteristics, and prognosis were summarized descriptively. RESULTS: An initial database search identified 2162 articles, of which 81 studies were included in this review. TS during pregnancy can have emotional, obstetric, and metabolic triggers and has a higher proportion of adverse fetal outcomes when compared with women who developed TS postpartum. Women with TS after cesarean section had an earlier onset and higher proportion of anesthesia use when compared with those who developed TS after vaginal delivery. There were no differences regarding the degree of systolic dysfunction or the need for advanced therapies, including ventilator support, intra-aortic balloon pump, and extracorporeal membrane oxygenation among groups. CONCLUSIONS: TS is associated with various triggers and adverse fetal outcomes when it develops during pregnancy than in the postpartum period. TS occurs more rapidly and with a more aggressive course after cesarean section than after vaginal delivery.

Euglycemic diabetic ketoacidosis caused by empagliflozin complicated by failure to thrive in a geriatric patient.

Euglycemic diabetic ketoacidosis (euDKA) is a rare but deadly complication of sodium-glucose cotransport-2 (SGLT-2) inhibitors. Primarily indicated for the treatment of Type 2 Diabetes Mellitus, the incidence of euDKA is expected to rise as SGLT-2 inhibitors become a mainstay therapy for diabetics with heart failure. Diagnosis of euDKA can be difficult given the presence of normoglycemia and is especially challenging among geriatric patients that are complicated by additional comorbidities. We present a case of an elderly male with multiple comorbidities who presented for dehydration and altered mentation from a nursing home facility. Laboratory investigations showed signs of acute renal failure, uremia, electrolyte abnormalities, and severe metabolic acidosis due to high levels of plasma beta-hydroxybutyrate. He was admitted to the medical intensive care unit (ICU) for further management. A presumptive diagnosis of euDKA was strongly suspected due to his laboratory data and medication reconciliation which revealed the recent initiation of empagliflozin. The patient was promptly started on a standardized treatment protocol for DKA with continuous infusion of regular insulin with strict glucose monitoring, along with intravenous fluids, and a small dose of sodium bicarbonate infusion as per current standard guidelines. With the rapid improvement in symptoms and metabolic derangements, the diagnosis was confirmed. Geriatric patients from nursing home facilities are a high-risk cohort who if not properly cared for by nursing staff can develop dehydration, malnutrition and worsening frailty including sarcopenia that exposes them to increased risk of medication side effects, such as euDKA. Clinicians should consider euDKA in their differential diagnosis in elderly patients with overt or relative insulinopenia who are receiving SGLT-2 inhibitors when presenting with acute changes in health and mentation.

High-Risk Apical Hypertrophic Cardiomyopathy Requiring an Implantable Cardioverter-Defibrillator: A Case Report of an Overlooked Etiology.

Apical hypertrophic cardiomyopathy is a rare variant of hypertrophic cardiomyopathy characterized by abnormal heart muscle thickening, specifically affecting the left ventricle's apex. Classically revealing both giant T-wave inversions in the precordial leads of an electrocardiogram and a spade-like configuration of the left ventricular cavity on ventriculograms, the diagnosis of the apical variant has evolved with cardiac magnetic resonance imaging. Despite being well known among East Asian populations, the diagnosis of apical hypertrophic cardiomyopathy is often underestimated and overlooked among American patients due to the non-specific nature of echocardiography. In this case report, we present the diagnosis of apical hypertrophic cardiomyopathy in a middle-aged African American male with chronic palpitations. The diagnosis was confirmed using cardiac magnetic resonance imaging, which revealed extensive myocardial fibrosis. Ultimately, the patient was treated with an implantable cardioverter-defibrillator. Our case aims to enhance the understanding and facilitate the recognition and management of apical hypertrophic cardiomyopathy, particularly among non-Asian individuals. Current challenges revolve around robust risk stratification strategies for patients at high risk for sudden cardiac death that require device therapy.

Midpoint of energy intake, non-fasting time and cardiorespiratory fitness in heart failure with preserved ejection fraction and obesity.

BACKGROUND: Delayed time of evening meal is associated with favorable cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. It is unknown, however, if increasing daily non-fasting time or delaying the midpoint of energy intake may also be associated with CRF. OBJECTIVE: Our aim was to examine whether a longer non-fasting time, delayed midpoint of energy intake, or both, are associated with greater CRF in patients with HFpEF and obesity. METHODS: We measured peak oxygen consumption (VO2), a measure of CRF, in 32 patients with HFpEF and obesity with cardiopulmonary exercise testing, and dietary intake using a five-pass 24-h dietary recall. Participants were divided into groups by having lesser (<11.6) or greater (≥11.6) periods of non-fasting time than the median and similarly, with earlier (<2:15 PM) or later (≥2:15 PM) than median midpoint of energy intake. RESULTS: Median non-fasting time was 11.6 [10.6-12.9] hours and midpoint of energy intake was 2:15 [1:04-3:00] PM. There were no differences in CRF between those with a shorter (<11.6) or longer (≥11.6) non-fasting time. Participants with a delayed midpoint of energy intake (≥2:15 PM) had greater peak VO2 and exercise time. Midpoint of energy intake (r = 0.444, P = 0.011) and time of last meal (r = 0.550, P = 0.001) displayed a positive association with peak VO2, but not non-fasting time nor time of first meal. CONCLUSIONS: Delaying the midpoint of energy intake by postponing last meal is associated with better peak VO2 and exercise time in patients with HFpEF and obesity.

Early changes in N-terminal pro-brain natriuretic peptide levels predict new-onset heart failure in patients with STEMI.

BACKGROUND: Previous studies suggested that N-terminal pro-brain natriuretic peptide (NT-proBNP) level is a powerful independent predictor of death or heart failure (HF) when measured at admission in patients with chest pain or acute coronary syndrome. Little is known about the role of NT-proBNP level measured during a hospitalization for ST segment elevation myocardial infarction (STEMI) in predicting clinical outcomes. We evaluated the optimal NT-proBNP timing (admission, 72 hours, or delta [Δ] NT-proBNP [72 hours minus admission]) to predict 1-year new-onset HF in STEMI patients. METHODS: We measured NT-proBNP levels at admission and 72 hours in 72 patients with STEMI. HF events were adjudicated and defined as hospitalization for HF or need for new initiation of a loop diuretic at 1-year follow-up. Values are presented as medians and interquartile range or frequencies (%) as appropriate. Cox regression analysis was used to determine predictors of adverse events. A receiver-operative-curve was constructed to identify the discriminative value and optimal cut-off points for NT-proBNP. RESULTS: Patients (age 56 [49-64] years, males 59 [82%]) were followed for a median duration of 365 [180-365] days. HF events were recorded in 9 (12.5%) patients. NT-proBNP values at admission, 72 hours, and ΔNT-proBNP were 89 (26-268) pg/mL, 452 (223-1064) pg/mL, and 283 (68-686) pg/mL, respectively. NT-proBNP at 72 hours and ΔNT-proBNP, but not admission NT-proBNP predicted new-onset HF events at follow-up (P=0.03, P=0.002 and P=0.89, respectively). The optimal area under the curve of 0.771 (95%, CI [0.630-0.912], P= 0.009) and cut-off value of 830 pg/mL (sensitivity 79%; specificity 76%) were found for NT-proBNP at 72 hours. The Kaplan-Meier survival curves for NT-proBNP at 72 hours dichotomized above and below this cut-off value, confirmed NT-proBNP at 72 hours >830 pg/mL as predictive of HF events (log-rank statistic = 8.688, P=0.003). CONCLUSIONS: NT-proBNP level at 72 hours and ΔNT-proBNP (72 hours minus admission), but not at time of admission, predicted HF events in patients following STEMI.

Interleukin-1 blockade with anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials.

AIMS: ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. METHODS AND RESULTS: We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7-147.47] vs. 222.82 [117.22-399.28] mg day/L, P < 0.001). CONCLUSION: IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.

Effect of interleukin-1 blockade with anakinra on leukocyte count in patients with ST-segment elevation acute myocardial infarction.

Leukocytosis is a common finding in patients with ST elevation myocardial infarction (STEMI) and portends a poor prognosis. Interleukin 1-ß regulates leukopoiesis and pre-clinical studies suggest that anakinra (recombinant human interleukin-1 [IL-1] receptor antagonist) suppresses leukocytosis in myocardial infarction. However, the effect of IL-1 blockade with anakinra on leukocyte count in patients with STEMI is unknown. We reviewed the white blood cell (WBC) and differential count of 99 patients enrolled in a clinical trial of anakinra (n = 64) versus placebo (n = 35) for 14 days after STEMI. A complete blood cell count with differential count were obtained at admission, and after 72 h, 14 days and 3 months. After 72 h from treatment, anakinra compared to placebo led to a statistically significant greater percent reduction in total WBC count (- 35% [- 48 to - 24] vs. - 21% [- 34 to - 10], P = 0.008), absolute neutrophil count (- 48% [- 60 to - 22] vs. - 27% [- 46 to - 5], P = 0.004) and to an increase in absolute eosinophil count (+ 50% [0 to + 100] vs. 0% [- 50 to + 62], P = 0.022). These changes persisted while on treatment at 14 days and were no longer apparent at 3 months after treatment discontinuation. We found that in patients with STEMI IL-1 blockade with anakinra accelerates resolution of leukocytosis and neutrophilia. This modulation may represent one of the mechanisms by which IL-1 blockade improves clinical outcomes.

Patient Perceptions of Exertion and Dyspnea With Interleukin-1 Blockade in Patients With Recently Decompensated Systolic Heart Failure.

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; ß = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; ß = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF.