Recent Cardiovascular Research highlights from the Americas

Cardiovascular Research is part of the European Society of Cardiology family of journals but is by no means restricted to European participation or distribution. Rather, Cardiovascular Research is expanding its global reach and to that end, features high-quality papers from around the world. In fact, a significant portion of the journal’s editorial board, particularly the Associate and Deputy Editors, is based in the United States. Almost 20% of all original research papers received by Cardiovascular Research in 2017 were from North, Central, or South America, marking an approximate 9% increase compared with the year prior. These submissions account for almost 25% of all original research papers published in the journal last year. In this commentary, we highlight the top five downloaded original research papers of 2017 from North, Central and South America. Collectively, these studies provide new insight into disease pathogenesis and provide novel therapeutic targets for many facets of cardiovascular disease including myocardial infarction (MI), cardiomyopathy, and pulmonary hypertension (PH).

Raleigh et al.¹ investigated the effects of serelaxin, a recombinant form of the human hormone relaxin-2, in a mouse model of reperfusion injury following MI. Serelaxin, given either 1 h prior to myocardial ischaemia or 5 min before reperfusion, improved survival, reduced infarct size, and preserved left ventricular function at 24 h compared with saline controls. Moreover, seralaxin treatment reduced cardiac inflammasome activity. These infarct-sparing and anti-inflammatory effects were not seen in endothelial nitric oxide synthase (eNOS) deficient mice, demonstrating the significance of eNOS in mediating the protective effects of seralaxin. This promising proof-of-concept study improved upon prior studies by extending reperfusion time and utilizing genetic deletion of eNOS instead of non-specific pharmacological NOS inhibition. Importantly, these findings highlight seralaxin as a promising adjunct therapy in patients undergoing ischaemia/reperfusion and suggest that serelaxin may have beneficial effects in other diseases that involve endothelial dysfunction or reduced nitric oxide bioavailability.

Li et al.² studied the role of the scaffold protein A-kinase anchoring protein 150 (AKAP150) in calcium (Ca²⁺) cycling, myocyte contractility, and heart failure following pathological stress. To eliminate confounding changes associated with global AKAP150 deletion seen in previous studies, a cardiac-specific AKAP150 knockout mouse was generated and showed no basal phenotype. However, deficiency of cardiac AKAP150 predisposed to adverse cardiac remodelling and dysfunction following pressure overload or MI as seen by ventricular dilation, interstitial fibrosis, cardiac hypertrophy, and pulmonary oedema. Moreover, this study identified new AKAP150 interacting proteins that together provide targeted regulation of sarcoplasmic reticulum Ca²⁺ cycling and myocyte contractility following pathological stress. Importantly, these results define a cardioprotective signalling complex involving AKAP150 that may serve as a novel therapeutic target for heart failure.

Te Riele et al.³ explored new genetic causes of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). A majority of patients with ARVD/C have mutations in genes encoding the cardiac desmosome; however, a cohort of patients without such mutations was identified and underwent whole-exome sequencing. In one patient, a rare missense variant in the gene SCN5A, encoding the voltage gated sodium channel subunit Na_v1.5, was discovered. Utilizing induced pluripotent stem cell-derived cardiomyocytes from that patient and CRISPR/Cas9 technology to correct the mutation, the group was able to demonstrate a functional role for that variant in reducing peak sodium current and abundance of Na_v1.5 clusters at the intercalated disc. Additionally, the SCN5A gene was sequenced in a larger cohort and a subset of patients were identified with putatively pathogenic variants. This work reveals potential novel non-canonical mechanisms by which SCN5A contributes to ARVD/C with important diagnostic and therapeutic implications.

Zhang et al.⁴ investigated the role of dynamin-related protein 1 (DRP1), which is known to be involved in mitochondrial fission, on regulation of mitochondrial respiration in adult cardiomyocytes. Through in vitro genetic and pharmacological alterations, they were able to elucidate a novel and non-canonical fission-independent function of DRP1. The advantage of their approach compared to prior studies is the acute in vitro manipulation in contrast to chronic in vivo DRP1 ablation which can be confounded by non-specific and compensatory responses. This work shows that DRP1 maintains or positively stimulates mitochondrial respiration, bioenergetics, and reactive oxygen species signalling in adult cardiomyocytes, likely independent of mitochondrial morphologic changes, thus advancing our understanding of the role of DRP1 in both cardiac physiology and pathology.

Rogers et al.⁵ examined the role of thrombospondin-1 (TSP1)-CD47 signalling in PH. They found that lung tissue and distal pulmonary arteries from individuals with PH exhibit higher levels of the secreted glycoprotein TSP1 and its receptor CD47 compared with controls. Treating control pulmonary arteries with TSP1 potentiated vasoconstriction to endothelin-1 (ET-1), a known contributor to PH and a current therapeutic target. Inhibiting CD47 in diseased pulmonary arteries leads to improved sensitivity to vasodilators. These findings were confirmed in CD47 deficient mice, which demonstrated reduced PH and lower pulmonary ET-1 levels compared with control mice in response to hypoxia. The role of TSP1-CD47 signalling as a proximate regulator of ET-1 in PH is a novel finding that may lead to more effective therapeutics for this devastating disease.

As evidenced by the above articles, Cardiovascular Research is improved by global participation and is a premier forum for the dissemination of timely and highly impactful basic and translational findings to the international scientific community. Thus, we would like to encourage researchers in North, Central and South America to continue to submit their best work to Cardiovascular Research.

Conflict of interest: none declared.

Authors

Biography: Charles Duncan Smart graduated with a Bachelors degree in Biochemistry from the University of Texas at Austin honours program in 2016 and is currently an MD/PhD student at Vanderbilt University pursuing his graduate studies in the Department of Molecular Physiology and Biophysics in the laboratory of Dr Meena Madhur.

Biography: Dr Meena Madhur graduated from Duke University with a Bachelors degree in Biomedical Engineering and Biology in 1996 before joining the MD/PhD Program at the University of Virginia. She obtained her PhD in Molecular Physiology and Biophysics in 2003 and graduated with honours from medical school in 2005. She then returned to Duke University for her internship and residency in Internal Medicine and completed her cardiology fellowship at Emory University. In 2012, she joined the faculty at Vanderbilt University Medical Center as an Assistant Professor in the Departments of Medicine and Molecular Physiology & Biophysics. Dr Madhur’s research focuses on defining the interplay between the immune system and hypertension, particularly the renal and vascular complications of hypertension, to identify novel diagnostic and therapeutic strategies. Dr Madhur is a recipient of the American Society of Clinical Investigation (ASCI) Young Physician-Scientist Award, American Heart Association (AHA) Hypertension Council Harry Goldblatt New Investigator Award, and American Physiological Society Water and Electrolyte Homeostasis Section New Investigator Award. She serves as Associate Editor of Cardiovascular Research, Social Media Editor of the Journal of the American College of Cardiology (JACC): Basic to Translational Science, and editorial board member of the AHA journal Hypertension.