Publications by authors named "Richard C Becker"

394 Publications

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 Jan 13. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
January 2022

South Asian-Specific Deletion Carriers Display Hypercontraction and Impaired Diastolic Function Under Exercise Stress.

Front Cardiovasc Med 2021 23;8:766339. Epub 2021 Dec 23.

Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, College of Medicine, University of Cincinnati, Cincinnati, OH, United States.

A 25-base pair (25bp) intronic deletion in the gene enriched in South Asians (SAs) is a risk allele for late-onset left ventricular (LV) dysfunction, hypertrophy, and heart failure (HF) with several forms of cardiomyopathy. However, the effect of this variant on exercise parameters has not been evaluated. As a pilot study, 10 asymptomatic SA carriers of the variant (52.9 ± 2.14 years) and 10 age- and gender-matched non-carriers (NCs) (50.1 ± 2.7 years) were evaluated at baseline and under exercise stress conditions using bicycle exercise echocardiography and continuous cardiac monitoring. Baseline echocardiography parameters were not different between the two groups. However, in response to exercise stress, the carriers of Δ25bp had significantly higher LV ejection fraction (%) (CI: 4.57 ± 1.93; < 0.0001), LV outflow tract peak velocity (m/s) (CI: 0.19 ± 0.07; < 0.0001), and higher aortic valve (AV) peak velocity (m/s) (CI: 0.103 ± 0.08; = 0.01) in comparison to NCs, and E/A ratio, a marker of diastolic compliance, was significantly lower in Δ25bp carriers (CI: 0.107 ± 0.102; = 0.038). Interestingly, LV end-diastolic diameter (LVID) was augmented in NCs in response to stress, while it did not increase in Δ25bp carriers (CI: 0.239 ± 0.125; = 0.0002). Further, stress-induced right ventricular systolic excursion velocity s' (m/s), as a marker of right ventricle function, increased similarly in both groups, but tricuspid annular plane systolic excursion increased more in carriers (slope: 0.008; = 0.0001), suggesting right ventricle functional differences between the two groups. These data support that is associated with LV hypercontraction under stress conditions with evidence of diastolic impairment.
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http://dx.doi.org/10.3389/fcvm.2021.766339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8733148PMC
December 2021

Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.

Nat Commun 2021 11 25;12(1):6912. Epub 2021 Nov 25.

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a K of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.
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http://dx.doi.org/10.1038/s41467-021-27275-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617063PMC
November 2021

Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms.

J Am Heart Assoc 2021 12 19;10(24):e023601. Epub 2021 Nov 19.

Department of Cancer Biology University of Cincinnati College of Medicine Cincinnati OH.

Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth-leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.
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http://dx.doi.org/10.1161/JAHA.121.023601DOI Listing
December 2021

International COVID-19 biomarkers colloquium.

J Thromb Thrombolysis 2021 Nov 4;52(4):983-984. Epub 2021 Nov 4.

National Heart and Lung Institute, Imperial College, London, UK.

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http://dx.doi.org/10.1007/s11239-021-02601-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567123PMC
November 2021

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial.

J Am Heart Assoc 2021 10 25;10(19):e022485. Epub 2021 Sep 25.

Duke Clinical Research Institute Duke University Durham NC.

Background In event-driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy-event tracking in the per-protocol cohort during the on-treatment period versus the intention-to-treat (ITT) cohort during the ITT period. Methods and Results ROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per-protocol cohort during the on-treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; <0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68-0.99; =0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points. Conclusions Clinical trial termination based on event accrual in the ITT cohort versus the per-protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.
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http://dx.doi.org/10.1161/JAHA.121.022485DOI Listing
October 2021

Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series.

Authors:
Richard C Becker

J Thromb Thrombolysis 2021 Oct 17;52(3):692-707. Epub 2021 Aug 17.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

The autonomic nervous system (ANS) is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common observation among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] in the acute and chronic phases of the disease is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Because abnormalities in the ANS can contribute to each of these symptoms, herein a review of autonomic dysfunction in SARS-COV-2 infection is provided to guide diagnostic testing, patient care and research initiatives. The autonomic nervous system is a complex network of nerves originating in the brain, brain stem, spinal cord, heart and extracardiac organs that regulates neural and physiological responses to internal and external environments and conditions. A common collection of signs and symptoms among patients with the 2019 Coronavirus (CoV) (SARS-severe acute respiratory syndrome CoV-2) (SARS-CoV-2) or COVID-19 [CO for corona, VI for virus, D for disease and 19 for when the outbreak was first identified (31 December 2019)] is tachycardia, labile blood pressure, muscular fatigue and shortness of breath. Abnormalities in the autonomic nervous system (ANS) can contribute to each of these identifiers, potentially offering a unifying pathobiology for acute, subacute and the long-term sequelae of SARS-CoV-2 infection (PASC) and a target for intervention.
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http://dx.doi.org/10.1007/s11239-021-02549-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367772PMC
October 2021

COVID-19 and biomarkers of thrombosis: focus on von Willebrand factor and extracellular vesicles.

J Thromb Thrombolysis 2021 Nov 4;52(4):1010-1019. Epub 2021 Aug 4.

University of Arkansas for Medical Sciences, Little Rock, AK, USA.

COVID-19, caused by the SARS-CoV-2 virus, is responsible for a pandemic of unparalleled portion over the past century. While the acute phase of infection causes significant morbidity and mortality, post-acute sequelae that can affect essentially any organ system is rapidly taking on an equally large part of the overall impact on human health, quality of life, attempts to return to normalcy and the global economy. Herein, we summarize the potential role of von Willebrand Factor and extracellular vesicles toward understanding the pathophysiology, clinical presentation, duration of illness, diagnostic approach and management of COVID-19 and its sequelae.
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http://dx.doi.org/10.1007/s11239-021-02544-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336902PMC
November 2021

Pharmacotherapy for diabetes and stroke risk: Results from ROCKET AF.

Heart Rhythm O2 2021 Jun 20;2(3):215-222. Epub 2021 Apr 20.

Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina.

Background: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF).

Objectives: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin.

Methods: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial.

Results: In a cohort of 14,264 patients, there were 40.3% (n = 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non-insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06-1.68), MI (HR 1.64, 95% CI 1.17-2.30), all-cause death (HR 1.26, 95% CI 1.08-1.46), vascular death (HR 1.33, 95% CI 1.11-1.60), and composite outcomes (HR 1.37, 95% CI 1.18-1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33-4.01) and composite outcomes (HR 1.57, 95% CI 1.19-2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non-insulin-treated diabetes for any outcome.

Conclusion: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non-insulin-treated diabetes.
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http://dx.doi.org/10.1016/j.hroo.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322824PMC
June 2021

Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel.

Cell Rep Med 2021 Jun 4;2(6):100299. Epub 2021 Jun 4.

Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.

Untargeted metabolomics is used to refine the development of biomarkers for the diagnosis of cardiovascular disease. Myocardial infarction (MI) has major individual and societal consequences for patients, who remain at high risk of secondary events, despite advances in pharmacological therapy. To monitor their differential response to treatment, we performed untargeted plasma metabolomics on 175 patients from the platelet inhibition and patient outcomes (PLATO) trial treated with ticagrelor and clopidogrel, two common PY inhibitors. We identified a signature that discriminates patients, which involves polyunsaturated fatty acids (PUFAs) and particularly the omega-3 fatty acids docosahexaenoate and eicosapentaenoate. The known cardiovascular benefits of PUFAs could contribute to the efficacy of ticagrelor. Our work, beyond pointing out the high relevance of untargeted metabolomics in evaluating response to treatment, establishes PUFA metabolism as a pathway of clinical interest in the recovery path from MI.
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http://dx.doi.org/10.1016/j.xcrm.2021.100299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233657PMC
June 2021

Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy.

Platelets 2021 Jun 2:1-7. Epub 2021 Jun 2.

Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and polymorphisms.On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x10/L for clopidogrel and ticagrelor, respectively; < .001) or following cessation of clopidogrel (7.23 (1.97) x10/L, at 6 months vs 7.56 (2.28) x10/L after treatment cessation; < .001). This occurred independently of baseline biomarkers and genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC.Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel's efficacy as well as therapeutic interaction with anti-inflammatory drugs.
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http://dx.doi.org/10.1080/09537104.2021.1934667DOI Listing
June 2021

Factor Xa inhibitors: critical considerations for clinical development and testing.

Authors:
Richard C Becker

J Thromb Thrombolysis 2021 Aug 15;52(2):397-402. Epub 2021 May 15.

University of Cincinnati Heart, Lung and Vascular Institute, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

The selection of factor (F) X and its activated protease FXa for targeted inhibition to prevent and treat thrombotic conditions is based on an understanding of coagulation biochemistry, sequential steps that occur on tissue factor bearing cells and the interface of coagulation proteins, platelets, mononuclear cells and the nuclear constituents of inflammatory cells. The goal for developing direct oral FXa inhibitors was to achieve rapid, selective, predictable, safe and effective anticoagulation across a broad group of patients expected to derive benefit. The history and development in patient care are exemplars of knowledge, translation and collaboration between the public and private sectors.
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http://dx.doi.org/10.1007/s11239-021-02455-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122197PMC
August 2021

Team Science: American Heart Association's Hypertension Strategically Focused Research Network Experience.

Hypertension 2021 06 3;77(6):1857-1866. Epub 2021 May 3.

Internal Medicine (T.A.K., S.K.), Medical College of Wisconsin, Milwaukee, WI.

In 2015, the American Heart Association awarded 4-year funding for a Strategically Focused Research Network focused on hypertension composed of 4 Centers: Cincinnati Children's Hospital, Medical College of Wisconsin, University of Alabama at Birmingham, and University of Iowa. Each center proposed 3 integrated (basic, clinical, and population science) projects around a single area of focus relevant to hypertension. Along with scientific progress, the American Heart Association put a significant emphasis on training of next-generation hypertension researchers by sponsoring 3 postdoctoral fellows per center over 4 years. With the center projects being spread across the continuum of basic, clinical, and population sciences, postdoctoral fellows were expected to garner experience in various types of research methodologies. The American Heart Association also provided a number of leadership development opportunities for fellows and investigators in these centers. In addition, collaboration was highly encouraged among the centers (both within and outside the network) with the American Heart Association providing multiple opportunities for meeting and expanding associations. The area of focus for the Cincinnati Children's Hospital Center was hypertension and target organ damage in children utilizing ambulatory blood pressure measurements. The Medical College of Wisconsin Center focused on epigenetic modifications and their role in pathogenesis of hypertension using human and animal studies. The University of Alabama at Birmingham Center's areas of research were diurnal blood pressure patterns and clock genes. The University of Iowa Center evaluated copeptin as a possible early biomarker for preeclampsia and vascular endothelial function during pregnancy. In this review, challenges faced and successes achieved by the investigators of each of the centers are presented.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16296DOI Listing
June 2021

Medical publishing during the COVID-19 pandemic: then and now.

J Thromb Thrombolysis 2021 May 9;51(4):1101-1106. Epub 2021 Mar 9.

Heart Center, Freiburg University, Freiburg, Germany.

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http://dx.doi.org/10.1007/s11239-021-02422-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940450PMC
May 2021

Rivaroxaban versus warfarin in patients with atrial fibrillation enrolled in Latin America: Insights from ROCKET AF.

Am Heart J 2021 06 8;236:4-12. Epub 2021 Feb 8.

Division of Cardiology, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Durham, NC. Electronic address:

Background: ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW).

Methods: ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1,878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region.

Results: The annual rate of stroke/SE was similar in those from Latin American and ROW (P= .63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; P< .001). Rates of major or nonmajor clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; P= .05). Rates of stroke and/or SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs HR 0.89, 95% CI 0.75-1.07; interaction P= .77).

Conclusions: Patients with AF in Latin America had similar rates of stroke and/or SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted.
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http://dx.doi.org/10.1016/j.ahj.2021.02.004DOI Listing
June 2021

Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy.

Cells 2021 02 8;10(2). Epub 2021 Feb 8.

Heart, Lung and Vascular Institute, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.

Novel genetic variants exist in patients with hereditary neuromuscular disorders (NMD), including muscular dystrophy. These patients also develop cardiac manifestations. However, the association between these gene variants and cardiac abnormalities is understudied. To determine genetic modifiers and features of cardiac disease in NMD patients, we have reviewed electronic medical records of 651 patients referred to the Muscular Dystrophy Association Care Center at the University of Cincinnati and characterized the clinical phenotype of 14 patients correlating with their next-generation sequencing data. The data were retrieved from the electronic medical records of the 14 patients included in the current study and comprised neurologic and cardiac phenotype and genetic reports which included comparative genomic hybridization array and NGS. Novel associations were uncovered in the following eight patients diagnosed with Limb-girdle Muscular Dystrophy, Bethlem Myopathy, Necrotizing Myopathy, Charcot-Marie-Tooth Disease, Peripheral Polyneuropathy, and Valosin-containing Protein-related Myopathy. Mutations in COL6A1, COL6A3, SGCA, SYNE1, FKTN, PLEKHG5, ANO5, and SMCHD1 genes were the most common, and the associated cardiac features included bundle branch blocks, ventricular chamber dilation, septal thickening, and increased outflow track gradients. Our observations suggest that features of cardiac disease and modifying gene mutations in patients with NMD require further investigation to better characterize genotype-phenotype relationships.
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http://dx.doi.org/10.3390/cells10020349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915259PMC
February 2021

COVID-19 and its sequelae: a platform for optimal patient care, discovery and training.

Authors:
Richard C Becker

J Thromb Thrombolysis 2021 Apr 27;51(3):587-594. Epub 2021 Jan 27.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

COVID-19- related patient care and research have focused on short-term outcomes, particularly among those with underlying or preexisting medical conditions. A major focus has been on mortality rates. Broadening the dialogue is neither meant nor intended to disparage the near-term devastation felt globally each day, but rather to begin preparation for optimally caring for and addressing the needs of survivors. The sequelae of COVID-19 includes acute, subacute and chronic stages of the condition. If one applies current World Health Organization (WHO) statistics to calculate the global burden of disease, there are 98,000,000 COVID-19 survivors. The following editorial focuses on post-COVID sequelae as a continuum of patient care needs, as well as discovery and training opportunities in an academic setting.
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http://dx.doi.org/10.1007/s11239-021-02375-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838017PMC
April 2021

Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity.

Cancers (Basel) 2020 Dec 30;13(1). Epub 2020 Dec 30.

Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH 45267, USA.

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.
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http://dx.doi.org/10.3390/cancers13010086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795565PMC
December 2020

A Novel Homozygous Intronic Variant in TNNT2 Associates With Feline Cardiomyopathy.

Front Physiol 2020 16;11:608473. Epub 2020 Nov 16.

Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH, United States.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disease of the heart and the most common cause of sudden cardiac death in the young. HCM is considered a disease of the sarcomere owing to the large number of mutations in genes encoding sarcomeric proteins. The riddle lies in discovering how these mutations lead to disease. As a result, treatments to prevent and/or treat HCM are limited to invasive surgical myectomies or ablations. The A31P variant of cardiac myosin binding protein-C, encoded by , was found to be more prevalent in a cohort of Maine Coon cats with HCM. However, other mutations in and have also been associated with HCM in cats of other breeds. In this study, we expand the spectrum of genes associated with HCM in cats.

Results: Next Generation Whole Genome sequencing was performed using DNA isolated from peripheral blood of a Maine Coon with cardiomyopathy that tested negative for the A31P variant. Through risk stratification of variants, we identified a novel, homozygous intronic variant in cardiac troponin T (). analysis of the variant suggested that it may affect normal splicing of exon 3 of . Both parents tested heterozygous for the mutation, but were unaffected by the disease. Echocardiography analyses revealed that the proband had shown early onset congestive heart failure, which is managed with a treatment regime including ACE and aldosterone inhibitors.

Conclusion: In summary, we are the first to demonstrate the association between mutations and HCM in felines, suggesting that this gene should be included in the testing panel of genes when performing genetic testing for HCM in cats.
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http://dx.doi.org/10.3389/fphys.2020.608473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701303PMC
November 2020

Bridging Anticoagulation with Mechanical Heart Valves: Current Guidelines and Clinical Decisions.

Curr Cardiol Rep 2020 09 10;22(11):130. Epub 2020 Sep 10.

Division of Cardiovascular Health and Disease, Department of Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 0542, CVC, Room 4936, Cincinnati, OH, 45267-0542, USA.

Purpose Of Review: The management of patients with mechanical heart valves who require surgery or invasive procedures is a common clinical scenario in contemporary practice. The risk of thromboembolism versus the risk of bleeding is the foundation of optimal patient care.

Recent Findings: Randomized, controlled trials are not available; yet, there is a wealth of experience to guide best practice. Current guidelines represent a compilation of data from trials of atrial fibrillation and expert opinion. Results from the PERI-OP trial of patients with either a mechanical heart valve, atrial fibrillation, or atrial flutter requiring interruption of oral anticoagulant therapy for surgery will inform clinical practice. Patient-specific factors and valve-specific factors are paramount when deciding whether a period of anticoagulant therapy interruption is safe. Similarly, the safety and efficacy of bridging anticoagulant therapy and the optimal time after surgery for restarting oral anticoagulants is vital to optimal patient care.
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http://dx.doi.org/10.1007/s11886-020-01390-2DOI Listing
September 2020

Anticipating the long-term cardiovascular effects of COVID-19.

Authors:
Richard C Becker

J Thromb Thrombolysis 2020 Oct;50(3):512-524

Department of Medicine, University of Cincinnati Heart and Circulation Research Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

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http://dx.doi.org/10.1007/s11239-020-02266-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467860PMC
October 2020

Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial.

J Am Heart Assoc 2020 09 15;9(17):e016360. Epub 2020 Aug 15.

Research Institute for Internal Medicine Oslo University Hospital Rikshospitalet Oslo Norway.

Background The cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome. Methods and Results Serum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow-up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04-1.21), =0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02-1.19; =0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44-0.88; =0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37-0.88; =0.0114). Conclusions Baseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872.
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http://dx.doi.org/10.1161/JAHA.120.016360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660754PMC
September 2020

COVID-19-associated vasculitis and vasculopathy.

Authors:
Richard C Becker

J Thromb Thrombolysis 2020 Oct;50(3):499-511

University of Cincinnati Heart, Lung and Vascular Institute, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

The COVID-19 pandemic now totaling 13,000,000 cases and over 571,000 deaths has continued to teach the medical, scientific and lay communities about viral infectious disease in the modern era. Among the many lessons learned for the medical community is the potential for transmissibility and host infectivity of the SARS-CoV-2 virus. Moreover, it has become clear that the virus can affect any organ including the circulatory system, directly via either tissue tropism or indirectly stemming from inflammatory responses in the form of innate immunity, leukocyte debris such as cell-free DNA and histones and RNA viral particles. The following review considers COVID-19-associated vasculitis and vasculopathy as a defining feature of a virus-induced systemic disease with acute, subacute and potential chronic health implications.
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http://dx.doi.org/10.1007/s11239-020-02230-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373848PMC
October 2020

Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.

Am Heart J 2020 09 25;227:91-99. Epub 2020 Jun 25.

Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH.

Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN: PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY: PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin.
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http://dx.doi.org/10.1016/j.ahj.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484170PMC
September 2020

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3 variant.

Biophys Rev 2020 Aug 12;12(4):1065-1084. Epub 2020 Jul 12.

Division of Cardiovascular Health and Disease, Department of Internal Medicine, Heart, Lung and Vascular Institute, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575, USA.

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3 carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3 variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3 pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.
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http://dx.doi.org/10.1007/s12551-020-00725-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429610PMC
August 2020

Point-of-care platelet function tests: relevance to arterial thrombosis and opportunities for improvement.

J Thromb Thrombolysis 2021 Jan;51(1):1-11

University of Cincinnati College of Medicine, Cincinnati, USA.

Studies using whole blood platelet aggregometry as a laboratory research tool, provided important insights into the mechanism and modulators of platelet aggregation. Subsequently, a number of point-of-care (POC) platelet function tests (PFTs) were developed for clinical use, based on the concept that an individual's thrombotic profile could be assessed in vitro by assessing the response to stimulation of platelet aggregation by specific, usually solo agonists such as adenosine diphosphate (ADP), collagen and thrombin. However, adjusting antiplatelet medication in order to improve the results of such POC PFTs has not translated into a meaningful reduction in cardiovascular events, which may be attributable to important differences between the POC PFT techniques and in vivo conditions, including patient-to-patient variability. Important limitations of most tests include the use of citrate-anticoagulated blood. Citrate directly and irreversibly diminishes platelet function and even after recalcification, it may result in altered platelet aggregation in response to ADP, epinephrine or collagen, and interfere with thrombin generation from activated platelets. Furthermore, most tests do not employ flowing blood and therefore do not assess the effect of high shear forces on platelets that initiate, propagate and stabilize arterial thrombi. Finally, the effect of endogenous thrombolysis, due to fibrinolysis and dislodgement, which ultimately determines the outcome of a thrombotic stimulus, is mostly not assessed. In order to accurately reflect an individual's predisposition to arterial thrombosis, future tests of thrombotic status which overcome these limitations should be used, to improve cardiovascular risk prediction and to guide pharmacotherapy.
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http://dx.doi.org/10.1007/s11239-020-02170-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829242PMC
January 2021

The potential roles of Von Willebrand factor and neutrophil extracellular traps in the natural history of hypertrophic and hypertensive cardiomyopathy.

Thromb Res 2020 08 7;192:78-87. Epub 2020 May 7.

Division of Cardiovascular Health and Disease, Heart, Lung and Blood Institute, University of Cincinnati College of Medicine, United States of America.

Inflammation is often applied broadly to human disease. Despite its general familiarity, inflammation is highly complex. There are numerous injurious, immune and infectious determinants, functional elements and signaling pathways, ranging from genetic to epigenetic, environmental, racial, molecular and cellular that participate in disease onset and progression, phenotypic heterogeneity, and treatment selection and response. In addition, inflammation can be tissue and organ specific, adding a layer of complexity to achieving a detailed and translatable understanding of its role in health and disease. The following review takes a close look at inflammation in the context of two common heart diseases, hypertrophic cardiomyopathy and hypertensive cardiomyopathy.
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http://dx.doi.org/10.1016/j.thromres.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340095PMC
August 2020

COVID-19 update: Covid-19-associated coagulopathy.

Authors:
Richard C Becker

J Thromb Thrombolysis 2020 Jul;50(1):54-67

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA.

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http://dx.doi.org/10.1007/s11239-020-02134-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225095PMC
July 2020
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