Publications by authors named "Benjamin W Van Tassell"

105 Publications

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.

J Cardiovasc Pharmacol 2020 Oct 24;77(1):49-60. Epub 2020 Oct 24.

Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Pauley Heart Center, Richmond, VA.

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.
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http://dx.doi.org/10.1097/FJC.0000000000000931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774821PMC
October 2020

Left ventricular concentric remodeling and impaired cardiorespiratory fitness in patients with heart failure and preserved ejection fraction.

Minerva Cardioangiol 2020 Sep 30. Epub 2020 Sep 30.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA -

Background: Left ventricular (LV) concentric remodeling refers to a process by which increased LV relative wall thickness alters myocardial geometry, resulting in reduced LV end-diastolic volume (LVEDV) and stroke volume (SV). While the degree of concentric remodeling is a negative prognostic factor in heart failure with preserved ejection fraction (HFpEF), it is not known how it contributes to cardiorespiratory fitness (CRF).

Methods: We performed a retrospective analysis of patients with HFpEF who underwent treadmill single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and cardiopulmonary exercise testing (CPX). From exercise SPECT-MPI, we recorded post-exercise LVEDVi, LVESVi, SVi, LVEF, the presence and extent of perfusion defects, and perfusion reversibility. Peak oxygen consumption (VO2), the oxygen uptake efficiency slope (OUES), oxygen (O2) pulse, ventilatory efficiency (VE/VCO2 slope), ventilatory anaerobic threshold, respiratory exchange ratio, exercise time, and maximum heart rate were obtained from CPX. Data are expressed as mean (±standard deviation). Univariate and multivariate linear regression was performed.

Results: We identified 23 subjects who had completed both an exercise SPECT-MPI and a CPX. Patients were more commonly women (83%), black (65%), middle-age (50 [±7.3] years), and obese (body mass index [BMI] 39.7 [±6.0] kg/m2). Greater LVEDVi and LVESVi correlated positively with peak VO2 (R=+0.648, p=0.001; R=+0.601, p=0.002), O2 pulse (R=+0.686, p<0.001; R=+0.625, p=0.001) and OUES (R=+0.882, p<0.001; R=+0.779, p<0.001). The LVEF correlated inversely with peak VO2 and OUES (R=-0.450, p=0.031; R=-0.485, p=0.035). Perfusion defect area, grade of severity, and presence of reversibility were not associated with CRF variables.

Conclusions: Post-exercise reduced LV volumes correlate with measures of impaired CRF in patients with HFpEF, thus supporting a pathophysiologic role of concentric remodeling in impaired CRF in HFpEF.
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http://dx.doi.org/10.23736/S0026-4725.20.05295-0DOI Listing
September 2020

Role for Anti-Cytokine Therapies in Severe Coronavirus Disease 2019.

Crit Care Explor 2020 Aug 10;2(8):e0178. Epub 2020 Aug 10.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA.

The causative agent for coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, appears exceptional in its virulence and immunopathology. In some patients, the resulting hyperinflammation resembles a cytokine release syndrome. Our knowledge of the immunopathogenesis of coronavirus disease 2019 is evolving and anti-cytokine therapies are under active investigation. This narrative review summarizes existing knowledge of the immune response to coronavirus infection and highlights the current and potential future roles of therapeutic strategies to combat the hyperinflammatory response of patients with coronavirus disease 2019.

Data Sources: Relevant and up-to-date literature, media reports, and author experiences were included from Medline, national newspapers, and public clinical trial databases.

Study Selection: The authors selected studies for inclusion by consensus.

Data Extraction: The authors reviewed each study and selected approrpriate data for inclusion through consensus.

Data Synthesis: Hyperinflammation, reminiscent of cytokine release syndromes such as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, appears to drive outcomes among adults with severe coronavirus disease 2019. Cytokines, particularly interleukin-1 and interleukin-6, appear to contribute importantly to such systemic hyperinflammation. Ongoing clinical trials will determine the efficacy and safety of anti-cytokine therapies in coronavirus disease 2019. In the interim, anti-cytokine therapies may provide a treatment option for adults with severe coronavirus disease 2019 unresponsive to standard critical care management, including ventilation.

Conclusions: This review provides an overview of the current understanding of the immunopathogenesis of coronavirus disease 2019 in adults and proposes treatment considerations for anti-cytokine therapy use in adults with severe disease.
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http://dx.doi.org/10.1097/CCE.0000000000000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419062PMC
August 2020

Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies.

Front Immunol 2020 3;11:1625. Epub 2020 Jul 3.

Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States.

COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.
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http://dx.doi.org/10.3389/fimmu.2020.01625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348297PMC
August 2020

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

Chest 2020 Dec 24;158(6):2556-2567. Epub 2020 Jul 24.

Pauley Heart Center, Virginia Commonwealth University, Richmond, VA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.chest.2020.07.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768931PMC
December 2020

Impact of Different Doses of Omega-3 Fatty Acids on Cardiovascular Outcomes: a Pairwise and Network Meta-analysis.

Curr Atheroscler Rep 2020 07 16;22(9):45. Epub 2020 Jul 16.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA.

Purpose Of Review: Omega-3 fatty acid (O3FA) supplementation has shown conflicting evidence regarding its benefit in cardiovascular events. We performed a pairwise and network meta-analysis to elucidate the benefit of different doses of O3FA supplementation in cardiovascular prevention.

Recent Findings: Fourteen studies were identified providing data on 125,763 patients. A prespecified cut-off value of < 1 g per day was set for low-dose (LD) O3FA and > 1 g per day for high-dose (HD) O3FA. The efficacy outcomes of interest were total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina, and major vascular events. Safety outcomes of interest were bleeding, gastrointestinal disturbances, and atrial fibrillation events. HD treatment was associated with a lower risk of cardiac death (IRR 0.79, 95% CI [0.65-0.96], p = 0.03 versus control), myocardial infarction (0.71 [0.62-0.82], p < 0.0001 versus control and 0.79 [0.67-0.92], p = 0.003 versus LD), coronary revascularization (0.74 [0.66-0.83], p < 0.0001 versus control and 0.74 [0.66-0.84], p < 0.0001 versus LD), unstable angina (0.73 [0.62-0.86], p = 0.0001 versus control and 0.74 [0.62-0.89], p = 0.002 versus LD), and major vascular events (0.78 [0.71-0.85], p < 0.0001 versus control and 0.79 [0.72-0.88], p < 0.0001 versus LD). HD treatment was associated with increased risk for bleeding events (1.49 [1.2-1.84], p = 0.0002 versus control and 1.63 [1.16-2.3], p = 0.005 versus LD) and increased atrial fibrillation events compared to control (1.35 [1.1-1.66], p = 0.004). HD O3FA treatment was associated with lower cardiovascular events compared to LD and to control, but increased risk for bleeding and atrial fibrillation events.
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http://dx.doi.org/10.1007/s11883-020-00865-5DOI Listing
July 2020

Early changes in NT-proBNP levels predict new-onset heart failure in patients with STEMI.

Minerva Cardioangiol 2020 Jul 10. Epub 2020 Jul 10.

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA -

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.
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http://dx.doi.org/10.23736/S0026-4725.20.05303-7DOI Listing
July 2020

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.

Diabetes Metab Res Rev 2020 11 15;36(8):e3335. Epub 2020 Jun 15.

Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.

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 (VO ) and minute ventilation/carbon dioxide production (VE/VCO ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO , 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 VO and VE/VCO slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO (+2.4 mL kg min , P = .036), VAT (+1.5 mL kg min , P = .012) and VO matched for respiratory exchange ratio (+2.4 mL Kg min , 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 VO or VE/VCO slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO , VAT and quality of life.
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http://dx.doi.org/10.1002/dmrr.3335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685099PMC
November 2020

Could recruiting former college athletes be the answer to less pharmacy student burnout?

Curr Pharm Teach Learn 2020 04 30;12(4):357-362. Epub 2019 Dec 30.

Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, 410 North 12th Street, PO Box 980533, Richmond, VA 23298-0533, United States. Electronic address:

Introduction: Student pharmacists are in a notable wellness deficit. Pharmacy organizations are issuing statements and providing resources addressing efforts to increase student wellness. This commentary suggests that institutions refocus recruiting efforts on students with experience balancing the demands of school, wellness, and mental health.

Perspective: The purpose of this commentary is to start the conversation on increasing efforts to recruit candidates who already possess the resilience needed to perform in pharmacy school, with a focus on former college athletes. This piece in no way suggests decreased attention on wellness programs or efforts to reduce burnout. Former student athletes, through their training, have increased experience in resilience and may be less at risk for burnout. These candidates will likely have an increased team mentality and acceptance of constructive criticism. Additionally, this is an untapped resource for candidates as only 2% of collegiate athletes pursuing professional athletic careers. Of the 140 accredited pharmacy schools, 82.9% have an undergraduate program that offers at least one National Collegiate Athletic Association sport.

Implications: Schools of pharmacy should consider additional recruitment efforts and admissions criteria weight for former student athletes who meet the same standards as other candidates. As many pharmacy faculty direct significant effort toward the prevention of student burnout, perhaps an additional approach is to recruit students who are already capable of the expected demands. The athletic community may answer both the need for additional pharmacy recruits and provide a cohort with advanced abilities in stress management, wellness, and teamwork.
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http://dx.doi.org/10.1016/j.cptl.2019.12.019DOI Listing
April 2020

Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease.

Circ Res 2020 04 23;126(9):1260-1280. Epub 2020 Apr 23.

Department of Pharmacotherapy and Outcome Sciences, School of Pharmacy, Richmond, VA (C.M., C.A.D.).

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the IL-1 family of cytokines, including 11 members, among which are IL-1α and IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression, and complications of atherosclerosis, in ischemic (acute myocardial infarction), and nonischemic injury to the myocardium (myocarditis) and the progression to heart failure. We also review the clinically available IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST-segment-elevation acute myocardial infarction or heart failure with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315937DOI Listing
April 2020

Cardiovascular Considerations in Treating Patients With Coronavirus Disease 2019 (COVID-19).

J Cardiovasc Pharmacol 2020 05;75(5):359-367

Division of Cardiology, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA.

A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly across the globe since December 2019. Coronavirus disease 2019 (COVID-19) has a significantly higher mortality rate than seasonal influenza and has disproportionately affected older adults, especially those with cardiovascular disease and related risk factors. Adverse cardiovascular sequelae, such as myocarditis, acute myocardial infarction, and heart failure, have been reported in patients with COVID-19. No established treatment is currently available; however, several therapies, including remdesivir, hydroxychloroquine and chloroquine, and interleukin (IL)-6 inhibitors, are being used off-label and evaluated in ongoing clinical trials. Considering these therapies are not familiar to cardiovascular clinicians managing these patients, this review describes the pharmacology of these therapies in the context of their use in patients with cardiovascular-related conditions.
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http://dx.doi.org/10.1097/FJC.0000000000000836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219860PMC
May 2020

Increased C-reactive protein is associated with the severity of thoracic radiotherapy-induced cardiomyopathy.

Cardiooncology 2020 28;6. Epub 2020 Feb 28.

1VCU Pauley Heart Center, Virginia Commonwealth University, P.O. Box 980335, 1200 E. Broad Street, Richmond, Virginia, 23298 USA.

Background: Irradiation of the heart during cancer radiotherapy is associated with a dose-dependent risk of heart failure. Animal studies have demonstrated that irradiation leads to an inflammatory response within the heart as well as a reduction in cardiac reserve. In the current study we aimed to evaluate whether inflammatory biomarkers correlated with changes in cardiac function and reserve after radiotherapy for breast or lung cancer.

Methods And Results: We studied 25 subjects with a history of breast or lung cancer without a prior diagnosis of cardiovascular disease or heart failure, 1.8 years [0.4-3.6] post-radiotherapy involving at least 5 Gray (Gy) to at least 10% of the heart. High-sensitivity C-reactive protein (CRP) was abnormal (≥2 mg/L) in 16 (64%) subjects. Cardiac function and reserve was measured with Doppler echocardiography before and after exercise and defined as left-ventricular ejection fraction (LVEF), early diastolic mitral annulus velocity (e'), and increase in LV outflow tract velocity time integral cardiac output (cardiac reserve) with exercise. Subjects with abnormal CRP had significantly lower LVEF (51 [44-59] % vs 61 [52-64] %,  = 0.039), lower e' (7.4 [6.6-7.9] cm/sec vs 9.9 [8.3-12.0] cm/sec,  = 0.010), and smaller cardiac reserve (+ 1.5 [1.2-1.7] L/min vs + 1.9 [1.7-2.2] L/min,  = 0.024).

Conclusion: Elevated systemic inflammation is associated with impaired left-ventricular systolic and diastolic function both at rest and during exercise in subjects who have received radiotherapy with significant incidental heart dose for the treatment of cancer.
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http://dx.doi.org/10.1186/s40959-020-0058-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048115PMC
February 2020

Interleukin-1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST-Segment-Elevation Myocardial Infarction.

J Am Heart Assoc 2020 03 3;9(5):e014941. Epub 2020 Mar 3.

Virginia Commonwealth University Pauley Heart Center MedStar Washington Hospital Center Washington DC.

Background ST-segment-elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin-1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C-reactive protein) levels during the first 14 days in patients with ST-segment-elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo-controlled, double-blind, clinical trial in 99 patients with ST-segment-elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39-120] versus 214 [interquartile range, 131-394] mg·day/L; <0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end-systolic volume (median, 1.4 [interquartile range, -9.8 to 9.8] versus -3.9 [interquartile range, -15.4 to 1.4] mL; =0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, -1.6% to 10.2%] versus 2.7% [interquartile range, -1.8% to 9.3%]; =0.61) at 12 months. The incidence of death or new-onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [=0.046] and 0% versus 11.4% [=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; =0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; =0.016). Conclusions In patients presenting with ST-segment-elevation myocardial infarction, interleukin-1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299.
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http://dx.doi.org/10.1161/JAHA.119.014941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335541PMC
March 2020

Efficacy of different doses of omega-3 fatty acids on cardiovascular outcomes: rationale and design of a network meta-analysis.

Minerva Cardioangiol 2020 Feb;68(1):47-50

Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy -

Introduction: The impact of omega-3 fatty acids (O3FA) supplementation on cardiovascular risk is still in debate, largely due to the heterogeneity of population enrolled and variable dose and composition of the formulations used in the previous studies. Yet, O3FA may favorably impact on cardiovascular risk by reducing major cardiovascular events (including cardiac death and ischemic events).

Evidence Acquisition: We aim to perform a comprehensive review of the topic of O3FA for cardiovascular prevention, stemming from a systematic review, to pairwise meta-analysis and network meta-analysis, limiting our inclusion only to randomized clinical trials comparing low dose (LD) (<1 g per day) O3FA and high dose (HD) (>1 g per day) O3FA versus placebo. The efficacy outcomes of interest are total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina and major vascular events. Safety outcomes of interest are bleeding, gastrointestinal disturbances and atrial fibrillation events.

Evidence Synthesis: This meta-analysis is expected to include several important studies on cardiovascular primary and secondary prevention and detail on important cardiovascular outcomes. Furthermore, we intend to highlight safety outcomes related to O3FA supplementation.

Conclusions: The present network meta-analysis results will aid physicians in the decision to prescribe O3FA in patients with or at risk of cardiovascular events. In particular, it will be able to solve controversies emerged from previous randomized clinical trials and meta-analyses regarding the benefit of different doses of O3FA supplementation in the cardiovascular prevention.
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http://dx.doi.org/10.23736/S0026-4725.19.05117-XDOI Listing
February 2020

Determinants of Cardiorespiratory Fitness Following Thoracic Radiotherapy in Lung or Breast Cancer Survivors.

Am J Cardiol 2020 03 26;125(6):988-996. Epub 2019 Dec 26.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

We measured peak oxygen consumption (VO) in previous recipients of thoracic radiotherapy and assessed the determinants of cardiorespiratory fitness with an emphasis on cardiac and pulmonary function. Cancer survivors who have received thoracic radiotherapy with incidental cardiac involvement often experience impaired cardiorespiratory fitness, as measured by reduced peak VO, a marker of impaired cardiovascular reserve. We enrolled 25 subjects 1.8 (0.1 to 8.2) years following completion of thoracic radiotherapy with significant heart exposure (at least 10% of heart volume receiving at least 5 Gray). All subjects underwent cardiopulmonary exercise testing, Doppler echocardiography, and circulating biomarkers assessment. The cohort included 16 Caucasians (64%), 15 women (60%) with a median age of 63 (59 to 66) years. The peak VO was 16.8 (13.5 to 21.9) ml·kg·min or moderately reduced at 62% (50% to 93%) of predicted. The mean cardiac radiation dose was 5.4 (3.7 to 14.7) Gray, and it significantly correlated inversely with peak VO (R = -0.445, p = 0.02). Multivariate regression analysis revealed the diastolic functional reserve index and the N-terminal pro-brain natriuretic peptide (NTproBNP) serum levels were independent predictors of peak VO (ß = +0.813, p <0.01 and ß = -0.414, p = 0.04, respectively). In conclusion, patients who had received thoracic radiation display a dose-dependent relation between the cardiac radiation dose received and the impairment in peak VO, the reduction in diastolic functional reserve index, and elevation of NTproBNP.
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http://dx.doi.org/10.1016/j.amjcard.2019.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510169PMC
March 2020

Educational Outcomes Resulting From Restructuring a Scholarship Course for Doctor of Pharmacy Students.

Am J Pharm Educ 2019 10;83(8):7246

Virginia Commonwealth University School of Pharmacy, Richmond, Virginia.

To compare educational outcomes between two iterations of a scholarship and research course for Doctor of Pharmacy (PharmD) students at Virginia Commonwealth University's School of Pharmacy. The first iteration of a course intended to teach pharmacy students the knowledge and skills necessary to design and conduct research involved lectures and application exercises, including limited guided questions about different aspects of the research process. In the fall of 2015, multiple structured activities and accompanying grading rubrics, each designed around the structure and content of a section of a research proposal, were introduced to the course to supplement lectures. Both iterations of the course culminated with students submitting a research proposal. After establishing interrater reliability, faculty members graded a random sample of 20 research proposals, 10 from each version of the course, and section-specific and overall proposal scores were compared. In the proposals submitted after the course revisions, significant improvements in three areas were identified: the overall score, the section-specific scores for research hypothesis/specific aims, and institutional review board (IRB) discussion/informed consent. Nominal, though not statistically significant, improvements were observed in other sections. Additional research is needed regarding the best instructional strategies to reinforce data analysis and statistical testing knowledge and skills in PharmD students. Overall, our findings support the hypothesis that a more formalized, guided approach for teaching research methods improves learning outcomes for PharmD students.
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http://dx.doi.org/10.5688/ajpe7246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900817PMC
October 2019

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

J Cardiovasc Pharmacol 2019 12;74(6):528-534

Wright Center for Clinical and Translational Research, Richmond, VA.

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.
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http://dx.doi.org/10.1097/FJC.0000000000000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905125PMC
December 2019

COLCOT and CANTOS: piecing together the puzzle of inflammation and cardiovascular events.

Minerva Cardioangiol 2020 02 28;68(1):5-8. Epub 2019 Nov 28.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA -

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http://dx.doi.org/10.23736/S0026-4725.19.05104-1DOI Listing
February 2020

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

J Cardiovasc Pharmacol 2019 09;74(3):266-269

Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA.

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.
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http://dx.doi.org/10.1097/FJC.0000000000000706DOI Listing
September 2019

Metabolic modulation predicts heart failure tests performance.

PLoS One 2019 20;14(6):e0218153. Epub 2019 Jun 20.

Department of Pharmacotherapy and Outcomes Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, United States of America.

The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO2), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO2 slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with a left ventricular ejection fraction < 50%, predominantly males African American, presenting a high frequency of diabetes, hyperlipidemia, and hypertension were used in the study. MRA revealed that metabolic models for VE/VCO2 and Peak VO2 were the most fitted models, and the highest predictors' coefficients were from Acylcarnitine C18:2, palmitic acid, citric acid, asparagine, and 3-hydroxybutiric acid. Metabolic Pathway Analysis (MetPA) used predictors to identify the most relevant metabolic pathways associated to the study, aminoacyl-tRNA and amino acid biosynthesis, amino acid metabolism, nitrogen metabolism, pantothenate and CoA biosynthesis, sphingolipid and glycerolipid metabolism, fatty acid biosynthesis, glutathione metabolism, and pentose phosphate pathway (PPP). Metabolite Set Enrichment Analysis (MSEA) found associations of our findings with pre-existing biological knowledge from studies of human plasma metabolism as brain dysfunction and enzyme deficiencies associated with lactic acidosis. Our results indicate a profile of oxidative stress, lactic acidosis, and metabolic syndrome coupled with mitochondria dysfunction in patients with HF tests poor performance. The insights resulting from this study coincides with what has previously been discussed in existing literature thereby supporting the validity of our findings while at the same time characterizing the metabolic underpinning of CPET and HFBio.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586291PMC
February 2020

The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse.

J Cardiovasc Pharmacol 2019 04;73(4):215-222

VCU Pauley Heart Center, Richmond, VA.

Background: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse.

Methods: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery and measured the effects of OLT1177 (6, 60, or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion.

Results: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (-36%, -67%, and -62% for 6, 60, and 600 mg/kg, respectively; P < 0.001 for linear trend, P = 0.010 vs. vehicle for 6 mg/kg, and P < 0.001 vs. vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as left ventricular fractional shortening at 24 hours and 7 days after injury (P = 0.015 for 6 mg/kg and P < 0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (-71%, P < 0.001 vs. vehicle).

Conclusion: OLT1177 (dapansutrile) limits infarct size and prevents left ventricular systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse.
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http://dx.doi.org/10.1097/FJC.0000000000000658DOI Listing
April 2019

Potential role for interleukin-1 in the cardio-renal syndrome.

Eur J Heart Fail 2019 03 22;21(3):385-386. Epub 2019 Jan 22.

Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA.

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http://dx.doi.org/10.1002/ejhf.1403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422755PMC
March 2019

An Orally Available NLRP3 Inflammasome Inhibitor Prevents Western Diet-Induced Cardiac Dysfunction in Mice.

J Cardiovasc Pharmacol 2018 12;72(6):303-307

VCU Pauley Heart Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA.

Background: A diet rich in saturated fat and sugars (Western diet, WD) induces myocardial expression of the NLRP3 inflammasome and dysfunction in mice. We therefore hypothesized that a diet enriched with an orally available NLRP3 inflammasome inhibitor could prevent WD-induced cardiac dysfunction in mice.

Methods: Ten-week-old CD-1 male mice were fed WD or standard diet (SD) for 8 weeks. The compound 16673-34-0, an orally active NLRP3 inhibitor, was added to the diet at a concentration of 100 mg/Kg. The plasmatic levels of the NLRP3 inflammasome inhibitor were measured. Food intake, body weight, and glucose tolerance were assessed. Cardiac systolic and diastolic functions were measured by Doppler echocardiography at baseline, 4 weeks, and 8 weeks.

Results: WD induced a significant increase in body weight (+14%, P = 0.02), impaired glucose tolerance (+34%, P = 0.03), and a significant increase in isovolumetric relaxation time (+129%, P = 0.03) and reduction in left ventricular ejection fraction (-10%, P = 0.03), as compared to standard chow diet (SD). The treatment with NLRP3 inhibitor in the diet prevented cardiac systolic and diastolic dysfunction (P < 0.05 for left ventricular ejection fraction, isovolumetric relaxation time, and myocardial performance index in WD with drug vs. WD without drug), without significant changes in heart rate and metabolic parameters.

Conclusions: An orally available NLRP3 inhibitor prevented WD-induced cardiac dysfunction in obese mice.
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http://dx.doi.org/10.1097/FJC.0000000000000628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511457PMC
December 2018

IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2018 08;11(8):e005036

Division of Cardiology, Virginia Commonwealth University Pauley Heart Center, Richmond (B.W.V.T., C.R.T., J.C., S.C., D.K., M.G.D.B., H.B., G.W., M.V., C.O.-E., N.A.A., D.D., A.A.).

Background Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. Methods and Results Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo), ventilatory efficiency (V/Vco slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo or V/Vco slope between groups at baseline. Peak Vo was not changed after 12 weeks of anakinra (from 13.6 [11.8-18.0] to 14.2 [11.2-18.5] mL·kg·min, P=0.89), or placebo (14.9 [11.7-17.2] to 15.0 [13.8-16.9] mL·kg·min, P=0.40), without significant between-group differences in changes at 12 weeks (-0.4 [95% CI, -2.2 to +1.4], P=0.64). V/Vco slope was also unchanged with anakinra (from 28.3 [27.2-33.0] to 30.5 [26.3-32.8], P=0.97) or placebo (from 31.6 [27.3-36.9] to 31.2 [27.8-33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, -1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline ( P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). Conclusions Treatment with anakinra for 12 weeks failed to improve peak Vo and V/Vco slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02173548.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545106PMC
August 2018

Low-Density Lipoprotein Receptor-Related Protein-1 Is a Therapeutic Target in Acute Myocardial Infarction.

JACC Basic Transl Sci 2017 Oct 30;2(5):561-574. Epub 2017 Oct 30.

Division of Cardiology, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

Low-density lipoprotein receptor-related protein-1 (LRP1) is a ubiquitous membrane receptor functioning as a scavenger and regulatory receptor, inducing anti-inflammatory and prosurvival signals. Based on the known structure-activity of the LRP1 receptor binding site, the authors synthesized a small peptide (SP16). SP16 induced a >50% reduction in infarct size (p < 0.001) and preservation of left ventricular systolic function (p < 0.001), and treatment with an LRP1 blocking antibody eliminated the protective effects of SP16. In conclusion, LRP1 activation with SP16 given within 30 min of reperfusion during experimental acute myocardial infarction leads to a cardioprotective signal reducing infarct size and preservation of cardiac systolic function.
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http://dx.doi.org/10.1016/j.jacbts.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058925PMC
October 2017

Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction.

JACC Basic Transl Sci 2017 Oct 30;2(5):513-525. Epub 2017 Oct 30.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

Heart failure with preserved ejection fraction (HFpEF) is associated with obesity and, indirectly, with unhealthy diet. The role of dietary components in HFpEF is, however, largely unknown. In this study, the authors showed that in obese HFpEF patients, consumption of unsaturated fatty acids (UFA), was associated with better cardiorespiratory fitness, and UFA consumption correlated with better diastolic function and with greater fat-free mass. Similarly, mice fed with a high-fat diet rich in UFA and low in sugars had preserved myocardial function and reduced weight gain. Randomized clinical trials increasing dietary UFA consumption and reducing sugar consumption are warranted to confirm and expand our findings.
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http://dx.doi.org/10.1016/j.jacbts.2017.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058958PMC
October 2017

Interleukin-1 Blockade in Acute Myocardial Infarction and Heart Failure: Getting Closer and Closer.

JACC Basic Transl Sci 2017 Aug 28;2(4):431-433. Epub 2017 Aug 28.

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.

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http://dx.doi.org/10.1016/j.jacbts.2017.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034455PMC
August 2017