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.

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.

The role of C. elegans Ena/VASP homolog UNC-34 in neuronal polarity and motility.

Ena/VASP proteins mediate the effects of guidance cues on the actin cytoskeleton. The single C. elegans homolog of the Ena/VASP family of proteins, UNC-34, is required for the migrations of cells and growth cones. Here we show that unc-34 mutant alleles also interact genetically with Wnt mutants to reveal a role for unc-34 in the establishment of neuronal polarity along the C. elegans anterior-posterior axis. Our mutant analysis shows that eliminating UNC-34 function results in neuronal migration and polarity phenotypes that are enhanced at higher temperatures, revealing a heat-sensitive process that is normally masked by the presence of UNC-34. Finally, we show that the UNC-34 protein is expressed broadly and accumulates in axons and at the apical junctions of epithelial cells. While most mutants lacked detectable UNC-34, three unc-34 mutants that contained missense mutations in the EVH1 domain produced full-length UNC-34 that failed to localize to apical junctions and axons, supporting the role for the EVH1 domain in localizing Ena/VASP family members.

Recurrent pericarditis: an update on diagnosis and management.

Acute pericarditis is a disease of the pericardium characterized by inflammation. Around 16-38% of patients develop recurrent events after the first episode. Recurrent pericarditis (RP) seems to be caused by a pathological immune response. An inadequate treatment in terms of drug choice, dose, duration of therapy or tapering, has been shown to increase the risk of recurrences. Symptoms, physical and electrocardiographic signs are usually less severe during a recurrent event as compared to the first episode, thus favoring imaging as a tool to confirm the diagnosis of RP. Cardiac magnetic resonance is becoming the technique of choice because of its ability to detect active pericardial inflammation. Inflammatory biomarkers can be used to assess the risk of recurrences and to guide the tapering of treatments. First-line treatment is based on non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. NSAIDs are useful for pain control, and colchicine has shown to reduce the risk of further recurrences. Glucocorticoids are often used as second-line drugs, but they are associated with a high rate of recurrent events. Interleukin-1 inhibitors, such as anakinra and rilonacept, significantly reduce the risk of recurrences in patients with RP while on treatment.

Pericarditis Recurrence After Initial Uncomplicated Clinical Course.

Acute pericarditis is an inflammatory disease associated with a non-negligible risk of acute complications and future recurrence. However, the exact incidence of pericarditis recurrence in patients with a first uncomplicated clinical course is unknown. We sought to evaluate the incidence and clinical predictors of recurrence after a first episode of acute uncomplicated pericarditis in a large urban hospital in the United States. We conducted a retrospective review, through electronic health records, to complete a database that includes patients admitted with a first episode of acute pericarditis and selected only those with an uncomplicated course (without in-hospital death, large pericardial effusion [>20 mm] or tamponade, constriction, or incessant pericarditis) at the VCU Medical Center (Richmond, Virginia) from 2009 to 2018. A total of 240 patients met acute pericarditis criteria: of the 240 patients, 164 patients (68%) had an uncomplicated course (median age [interquartile range] in years: 50 [32 to 62], 43% females). The median follow-up time was 186 (19 to 467) days. Pericarditis was idiopathic in 84 patients (51%). Fifteen patients (9%) had at least 1 episode of recurrent pericarditis. Compared with those without recurrence, patients with recurrent pericarditis were younger (37 [25 to 59] vs 51 [34 to 62] years, p = 0.034), had a higher prevalence of subacute/delayed presentation (2 [13%] vs 1 [1%], p = 0.023), and less frequently received colchicine (6 [40%] vs 100 [67%], p = 0.036). At multivariate logistic regression analysis, subacute presentation and younger age remained predictors of recurrence at follow-up. In conclusion, 9% of patients with acute pericarditis experienced a recurrence over a 6-month median follow-up despite an initial uncomplicated course. Younger age and subacute presentation were associated with a significantly increased risk of recurrence.

Clinical features and outcomes between African American and Caucasian patients with Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome (TS) is an acute, reversible form of heart failure, often mimicking an acute coronary syndrome (ACS). Data regarding racial differences in TS are inconsistent. The aim is to assess clinical features associated with unfavorable in-hospital outcomes between African American (AA) and Caucasian (CAU) patients. METHODS: A retrospective electronic health record query identified 44 AA patients and 110 CAU patients with a diagnosis of TS. Our primary outcome was a composite of death, stroke, and cardiogenic shock during hospitalization. Variables associated with an increased risk of the primary composite outcomes were included in a logistic regression model. RESULTS: Compared to CAU patients, AA patients were a more comorbid population, and presented a higher prevalence of history of illicit drug use (27.3% vs. 13.6% P=0.044). There were no significant differences regarding in-hospital complication rates between AA and CAU patients. In the logistic regression model, infection was associated with greater risk of developing the primary outcome in AA patients (OR=7.26 [95% CI 1.22-43.17], P=0.029), whereas angina was a protective factor (OR=0.11 [95% CI 0.02-0.65], P=0.015). In CAU patients, severely depressed ejection fraction and worse peak creatinine during hospitalization increased risk of developing the primary outcome (OR=5.88 95% CI [2.01-17.17], P<0.001 and OR=1.64 [95% CI 1.15-2.58], P=0.031, respectively). Meanwhile, emotional stressors were protective (OR=0.16 [95% CI 0.03-0.88], P=0.004). CONCLUSIONS: Despite experiencing the same rate of in-hospital complications, the clinical profiles of AA patients are distinct from CAU patients admitted for TS, and clinical variables correlated with worse in-hospital outcomes also differ by race.

Clinical Presentation and Outcomes of Acute Pericarditis in a Large Urban Hospital in the United States of America.

BACKGROUND: Acute pericarditis is the most common presentation of pericardial diseases. Although generally benign, complications such as constrictive pericarditis, cardiac tamponade, and recurrence can occur. RESEARCH QUESTION: What are the clinical factors associated with adverse outcomes in acute pericarditis? STUDY DESIGN AND METHODS: We used an informatics-based search engine to search for International Classification of Diseases codes related to pericardial disease between January 1, 2009 and November 14, 2018 and then extracted clinical information, including only patients meeting the European Society of Cardiology criteria for acute pericarditis. We then evaluated the predictive value of clinical characteristics for adverse outcomes (cardiac tamponade, constrictive pericarditis, failure of therapy, recurrences, or death). RESULTS: We identified 240 patients with a first episode of pericarditis (51 [34-62] years, 56% males and 50% white). Pericarditis was determined to be idiopathic in 126 (53%) cases and related to cardiac injury in 79 (33%). During a median follow-up time of 179 (20-450) days, 82 (34%) patients experienced at least one adverse outcome. Subacute presentation was an independent predictor of adverse outcomes. Patients with postcardiac injury pericarditis had a lower incidence in the composite of failure of treatment and recurrence (13% vs 26%; P = .022) compared with patients with idiopathic pericarditis. Troponin I measurements were obtained in 167 patients (70%). Elevated troponin I levels were associated with lower incidence of recurrences (4% vs 17%; P = .024) and of the composite outcome (13% vs 36%; P = .004). INTERPRETATION: Acute pericarditis is associated with at least one adverse outcome in 34% of patients. Subacute presentation and idiopathic etiology are associated with higher incidence of adverse outcomes, whereas elevated troponin I levels identify a group with reduced risk of recurrences.