Mutations in CYB561 Causing a Novel Orthostatic Hypotension Syndrome Circ. Res. (IF 13.965) Pub Date : 2018-01-17 Maarten p van den Berg, Rowida Almomani, Italo Biaggioni, Martijn van Faassen, Pim van der Harst, Herman H Silljé, Irene Mateo Leach, Marc Hemmelder, Gerjan Navis, Gert-Jan Luijckx, Arjan P de Brouwer, Hanka Venselaar, Marcel M Verbeek, Paul A van der Zwaag, Jan D Jongbloed, J P van Tintelen, Ron A Wevers, Ido P Kema
Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated.Objective: We describe two families, with four patients in total, suffering from severe life-threatening orthostatic hypotension due to a novel cause.Methods and Results: As in dopamine β-hydroxylase deficiency (DβH), concentrations of norepinephrine and epinephrine in the patients were very low. Plasma DβH activity, however, was normal and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional DβH deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of six CYB561 knockout mice (reporter-tagged deletion allele (post-Cre), genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole brain homogenates of the CYB561(-/-) mice compared to wild type mice (p<0.01) and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (p<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with L-dihydroxyphenylserine, which can be converted directly to norepinephrine.Conclusions: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension. as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.
Lack of Remuscularization Following Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitor Cells in Infarcted Nonhuman Primates Circ. Res. (IF 13.965) Pub Date : 2018-01-17 Keyang Zhu, Qiang Wu, Cheng Ni, Peng Zhang, Zhiwei Zhong, Yan Wu, Yingchao Wang, Yinchuan Xu, Minjian Kong, Haifeng Cheng, Zhihua Tao, Qian Yang, He Liang, Yun Jiang, Qingju Li, Jing Zhao, Jijun Huang, Fengjiang Zhang, Qi Chen, Yi Li, Jinghai Chen, Wei Zhu, Hong Yu, Jianyi Zhang, Huang-Tian Yang, Xinyang Hu, Jian'an Wang
Rationale: Human pluripotent stem cell-derived cardiovascular progenitor cells (hPSC-CVPCs) should be thoroughly investigated in large animal studies before testing in clinical trials.Objective: To clarify if hPSC-CVPCs can engraft for long time in the heart of primates after myo-cardial infarction (MI) and compare the effectiveness and safety of immunosuppression with cy-closporine alone or multiple-drug regimen (MDR) containing cyclosporine, methylprednisolone, and Simulect in cynomolgous monkeys that had received intramyocardial injections of 1×107 EGFP-expressing hPSC-CVPCs after MI. A third group of animals received the immunosuppression MDR but without cell therapy after MI (MI+MDR group).Methods and Results: Measurements of EGFP gene levels and EGFP immunofluorescence staining indicated that the hPSC-CVPC engraftment rate was greater in the MI+MDR+CVPC group than that in the MI+Cyclosporine+CVPC group. However, even in the MI+MDR+CVPC group, no transplanted cells could be detected at 140 days after transplantation. Concomitantly, immunofluorescent analysis of CD3, CD4, and CD8 expression indicated that T lymphocyte infiltration in the CVPC-transplanted hearts was less in the MDR-treated animals than in the cyclosporine alone-treated animals. The re-covery of left-ventricular (LV) function at day 28 post-MI in the MI+MDR+CVPC group was better than that in the MI+MDR group. Apoptotic cardiac cells were also less common in the MI+MDR+CVPC group than in the MI+MDR group, while both immunosuppression regimens were associated with transient hepatic dysfunction.Conclusions: This is the largest study of hPSCs in non-human primates in cardiovascular field so far (n=32). Compared to cyclosporine alone, MDR attenuates immune rejection and improves survival of hPSC-CVPCs in primates; this is associated with less apoptosis of native cardiac cells and better re-covery of LV function at 28 days. However, even with MDR, transplanted hPSC-CVPCs do not en-graft and do not survive at 140 days after transplantation, thereby excluding remuscularization as a mechanism for the functional effect.
A New Secretory Peptide of Natriuretic Peptide Family, Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction Circ. Res. (IF 13.965) Pub Date : 2018-01-11 Takahiro Miyazaki, Kentaro Otani, Ayano Chiba, Hirohito Nishimura, Takeshi Tokudome, Haruko Watanabe- Takano, Ayaka Matsuo, Hiroyuki Ishikawa, Keiko Shimamoto, Hajime Fukui, Yugo Kanai, Akihiro Yasoda, Soshiro Ogata, Kunihiro Nishimura, Naoto Minamino, Naoki Mochizuki
Rationale: An increase of severe ischemic heart diseases results in an increase of the patients with congestive heart failure (CHF). Therefore, new therapies are expected in addition to recanalization of coronary arteries. Previous clinical trials using natriuretic peptides (NPs) prove the improvement of CHF by NPs.Objective: We aimed at investigating whether osteocrin (OSTN) peptide potentially functioning as an NP clearance receptor (NPR3)-blocking peptide can be used as a new therapeutic peptide for treating CHF after myocardial infarction (MI) using animal models.Methods and Results: We examined the effect of OSTN on circulation using two mouse models; the continuous intravenous infusion of OSTN after MI (OSTN-iv) and the OSTN transgenic (OSTN-Tg) mice with MI. In vitro studies revealed that OSTN competitively bound to NPR3 with atrial NP (ANP). In both OSTN-iv model and OSTN-Tg model, acute inflammation within the first week after MI was reduced. Moreover, both models showed the improvement of prognosis at 28 days after MI by OSTN. Consistent with the in vitro study binding of OSTN to NPR3, the OSTN-Tg exhibited an increased plasma ANP and C-type natriuretic peptide (CNP), which might result in the improvement of CHF after MI as indicated by the reduced weight of hearts and lungs and by the reduced fibrosis.Conclusions: OSTN might suppress the worsening of CHF after MI by inhibiting clearance of NP family peptides.
Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies Circ. Res. (IF 13.965) Pub Date : 2018-01-09 Gaelle Auguste, Priyatansh Gurha, Raffaella Lombardi, Cristian Coarfa, James T Willerson, Ali J Marian
Rationale: Mutations in the LMNA gene, encoding nuclear inner membrane protein Lamin A/C, cause distinct phenotypes, collectively referred to as laminopathies. Heart failure, conduction defects, and arrhythmias are the common causes of death in laminopathies.Objective: To identify and therapeutically target the responsible mechanism(s) for cardiac phenotype in laminopathies.Methods and Results: Whole heart RNA sequencing was performed prior to the onset of cardiac dysfunction in the Lmna-/- and matched control mice. Differentially expressed transcripts and their upstream regulators were identified, validated, and targeted by AAV9-shRNA constructs. A total of 576 transcripts were upregulated and 233 were downregulated in the Lmna-/- mouse hearts (q<0.05). FOXO transcription factors (TFs) were the most activated, while E2Fs were the most suppressed transcriptional regulators. Transcript levels of FOXO targets were also upregulated in the isolated Lmna-/- cardiac myocytes and in the myocardium of human heart failure patients. Nuclear localization of FOXO1 and 3 was increased, whereas phosphorylated (inactive) FOXO1 and 3 levels were reduced in the Lmna-/- hearts. Gene Set Enrichment Analysis and Gene Ontology showed activation of apoptosis and inflammation and suppression of cell cycle, adipogenesis, and oxidative phosphorylation in the Lmna-/- hearts. AAV9-shRNA-mediated suppression of FOXO TFs rescued selected molecular signatures, improved apoptosis, and prolonged survival by ~2-fold.Conclusions: FOXO TFs are activated and contribute to the pathogenesis of cardiac phenotype in laminopathies. Suppression of the FOXO TFs in cardiac myocytes partially rescues the phenotype and prolongs survival. The findings identify FOXO TFs as potential therapeutic targets for cardiac phenotype in laminopathies.
Novel Reversible Model of Atherosclerosis and Regression Using Oligonucleotide Regulation of the LDL Receptor Circ. Res. (IF 13.965) Pub Date : 2018-01-10 Debapriya Basu, Yunying Hu, Lesley-Ann Huggins, Adam E Mullick, Mark J Graham, Tomasz A Wietecha, Shelley L Barnhart, Allison Mogul, Katharina Pfeiffer, Andreas Zirlik, Edward A Fisher, Karin E Bornfeldt, Florian Willecke, Ira J Goldberg
Rationale: Animal models have been used to explore factors that regulate atherosclerosis. More recently, they have been used to study the factors that promote loss of macrophages and reduction in lesion size after lowering of plasma cholesterol levels. However, current animal models of atherosclerosis regression require challenging surgeries, time-consuming breeding strategies, and/or methods that block liver lipoprotein secretion.Objective: We sought to develop a more direct and time-effective method to create and then reverse hypercholesterolemia as well as atherosclerosis via transient knockdown of the hepatic LDL receptor (LDLR) followed by its rapid restoration.Methods and Results: We used antisense oligonucleotides directed to LDLR mRNA to create hypercholesterolemia in wild type C57BL/6 mice fed an atherogenic diet. This led to the development of lesions in the aortic root, aortic arch, and brachiocephalic artery. Use of a sense oligonucleotide replicating the targeted sequence region of the LDLR mRNA rapidly reduced circulating cholesterol levels due to recovery of hepatic LDLR expression. This led to a decrease in macrophages within the aortic root plaques and brachiocephalic artery, i.e. regression of inflammatory cell content, after a period of 2-3 weeks.Conclusions: We have developed an inducible and reversible hepatic LDLR knockdown mouse model of atherosclerosis regression. While cholesterol reduction decreased early en-face lesions in the aortic arches, macrophage area was reduced in both early and late lesions within the aortic sinus after reversal of hypercholesterolemia. Our model circumvents many of the challenges associated with current mouse models of regression. The use of this technology will potentially expedite studies of atherosclerosis and regression without use of mice with genetic defects in lipid metabolism.
Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100 Circ. Res. (IF 13.965) Pub Date : 2018-01-04 Jaume Amengual, Liang Guo, Alanna Strong, Julio Madrigal-Matute, Haizhen Wang, Susmita Kaushik, Jeffrey L Brodsky, Daniel J Rader, Ana Maria Cuervo, Edward A Fisher
Rationale: Genome-Wide Association Studies identified single nucleotide polymorphisms (SNPs) near the SORT1 locus strongly associated with decreased plasma low-density lipoprotein cholesterol (LDL-C) levels and protection from atherosclerotic cardiovascular disease and myocardial infarction. The minor allele of the causal SORT1 SNP locus creates a putative C/EBPα binding site in the SORT1 promoter, thereby increasing sortilin expression by 12-fold in liver, which is rich in this transcription factor. Our previous studies in mice have showed reductions in plasma LDL-C and its principal protein component, apolipoprotein B (apoB) with increased SORT1 expression, and in vitro studies suggested that sortilin promoted the presecretory lysosomal degradation of apoB associated with the LDL precursor, very-low density lipoprotein (VLDL).Objective: To determine directly that SORT1 overexpression results in apoB degradation and to identify the mechanisms by which this reduces apoB and VLDL secretion by the liver, thereby contributing to understanding the clinical phenotype of lower LDL-C levels.Methods and Results: Pulse-chase studies directly established that SORT1 overexpression results in apoB degradation. As noted above, previous work implicated a role for lysosomes in this degradation. Through in vitro and in vivo studies, we now demonstrate that the sortilin-mediated route of apoB to lysosomes is unconventional and intersects with autophagy. Increased expression of sortilin diverts more apoB away from secretion, with both proteins trafficking to the endosomal compartment in vesicles that fuse with autophagosomes to form amphisomes. The amphisomes then merge with lysosomes. Furthermore, we show that sortilin itself is a regulator of autophagy and that its activity is scaled to the level of apoB synthesis.Conclusions: These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin, and provide a mechanism contributing to the reduced LDL-C found in individuals with SORT1 overexpression.
In This Issue Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Ruth Williams
### Excess lipids meddle with mitochondrial function in the heart, report Tsushima et al. Obesity and diabetes are 2 major risk factors for heart disease and can lead to myocardial lipotoxicity—cardiac dysfunction caused by excessive fatty acid accumulation. At a pathological level, lipotoxicity has been associated with mitochondrial dysfunction, but exactly how excess lipids affect mitochondria is unclear. To find out, Tsushima and colleagues studied mice that were genetically engineered to accumulate excess fatty acids specifically in their cardiac myocytes. These animals ultimately developed heart failure, but not until they are ≈4 months old, giving the team the opportunity to study pathological progression of lipotoxicity. In early weeks of life, excess lipids were associated with an increase in mitochondrial activity. Prolonged excess, however, …
Meet the First Authors Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Lippincott Williams & Wilkins
Dr Francesco Spallotta is a senior postdoctoral fellow at Goethe University, Frankfurt am Main (Germany), working in Dr Gaetano’s lab in the Division of Cardiovascular Epigenetics. He earned his MSc in Medical Biotechnology and his PhD in Experimental Medicine at Sapienza University, Rome (Italy). Since 2005, he is actively working in the field of epigenetics to elucidate new molecular mechanisms involved in human diseases. Recently, he started broadening his scientific horizons, attempting to characterize the link between metabolic alterations and epigenetic enzyme function in the context of metabolically altered environments and in the presence of the so-called “hyperglycemic memory.” To this aim, he took advantage of integrative bioinformatics analysis of multi-OMIC data derived from cardiac mesenchymal cells isolated from type 2 diabetic donors. For this study, the Functional Genomics Translational Biology (FGTB) council awarded him the FGTB Young Investigator Award during American Heart Association Scientific Session 2016 in New Orleans. His research goal is to shed light on novel epi-metabolic mechanisms underpinning human disease. During his leisure time, he enjoys wine tasting. He loves travelling around the world, going to vinyl shops looking for rarities, and supporting his Italian soccer team, “AS Roma.” Dr Wared Nour-Eldine earned an MS in Molecular Biology from the Lebanese University, Lebanon, in 2013, and a PhD in Immunology from Paris Descartes University, Paris, in 2017. …
Anthology of Images Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Roberto Bolli
The popular adage “a picture is worth a thousand words” is an undeniable truth. It is estimated that more than half of the information we gather from our environment comes through our vision. Images have extraordinary power. Some of them can remain etched …
Natural Killer Cells at Ease Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Holger Winkels, Klaus Ley
Atherosclerosis is a lipid-driven, chronic inflammatory disorder that is characterized by the formation of leukocyte-rich plaques in large- and medium-sized arteries. Plaque macrophages form lipid-laden foam cells and eventually fail to clear the overwhelming number of apoptotic cells (failure of efferocytosis), forming a necrotic core. Other immune cells like T- and B-cell subsets contribute to atheroprogression by controlling the inflammatory milieu. The subject of the present work1 concerns the role of natural killer (NK) cells in atherosclerosis progression. Article, see p 47 NK cells are found at an average of 1 to 2 cells per lesion section.1 NK cells are potent immune cells protecting the host from viral infections and tumor formation. If a host cell lacks surface MHC-I (major histocompatibility complex I), being in a state of missing self, NK cells will kill this cell. NK cells also display immune-regulatory features and are capable of influencing antigen-specific T-cell responses. In the course of cardiovascular disease, the number of NK cells decreases in patients with stable angina or non–ST-segment–elevation myocardial infarction without affecting their cytokine expression profile.2 Until now,1 the role of NK cells in atherosclerosis had remained unclear and controversial. In this issue of Circulation Research , Nour-Eldine et al1 show that NK cells are not involved in atherosclerosis. A first study investigating NK cell activity in atherosclerosis assessed beige mice. Beige mice carry a mutation of the Lyst gene impairing NK …
What You Eat Affects Your Shape Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Elizabeth Murphy, Brian Glancy, Charles Steenbergen
Mitochondria are no longer considered to be static structures that just make ATP. Emerging data show that mitochondrial form or shape is intimately related to mitochondrial function.1,2 It, therefore, follows that changes in mitochondrial substrate selection and metabolism might lead to altered mitochondrial dynamics. A recent study in Circulation Research examines this issue3 Article, see p 58 Diabetic cardiomyopathy is associated with cardiac lipotoxicity and mitochondrial dysfunction,4 and a better understanding of the mechanisms involved are needed. To examine the mechanisms linking lipid overload and diabetic cardiomyopathy, Tsushima et al3 studied a mouse model with overexpression of ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes (ACS-transgenic [Tg]). ACSL1 was under the control of α-myosin heavy chain promoter, and the gene was, therefore, turned on shortly before birth. Wild-type (WT) hearts had little or no ACSL1 mRNA expression at postnatal day zero (P0), whereas ACS-Tg hearts expressed mRNA but no protein at this time (P0). An increase in ACSL1 protein was observed in the ACS-Tg hearts at ≈1 week, and by 12 weeks, there was >10-fold increase in ACSL1 in the transgenic hearts. Normally, after birth, there is an increase in mitochondrial dimensions, and the mitochondria become larger. Interestingly, the postnatal increase in mitochondrial dimensions is blunted in the ACS-Tg hearts. Two-dimensional electron microscopy showed that in WT hearts, mitochondrial dimensions doubled by 3 weeks after birth; however, this postnatal increase was not observed in ASC-Tg mice. To better assess mitochondrial differences, 3-dimensional transmission electron microscopy tomography was performed, and data collected at 8 weeks showed that ACS-Tg mitochondria were narrower and more elongated than mitochondria from WT hearts. Thus, a role for alterations in proteins that regulate mitochondrial dynamics, the mitochondrial fission and fusion proteins, were considered. As indicated by their names, these proteins regulate …
Failed Power Plant Turns Into Mass Murder Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Chi Fung Lee, Yang Cao, Rong Tian
Mitochondria are known as the powerhouse of the cell. For a high-energy–consuming organ, such as the heart, continuous ATP production via oxidative metabolism in the mitochondria is essential. Apart from ATP generation, mitochondria are also key to the regulation of cellular metabolism, calcium homeostasis, and reactive oxygen species (ROS) generation.1 Mitochondrial dysfunction has been strongly implicated in a variety of cardiovascular diseases including ischemic heart disease and heart failure. Furthermore, a large portion of mitochondrial disease patients, a condition caused by mutation of genes for mitochondrial proteins, develop cardiomyopathy indicating a causal role of mitochondria in cardiac dysfunction. Given its significant role in the pathogenesis and the current lack of effective therapy for mitochondrial dysfunction, there is a clear need for discovery and innovation in mitochondrial medicine.2,3 Article, see p 74 It is well established that the fetal heart relies heavily on glycolysis for energy metabolism. A switch from glycolysis to oxidative metabolism in the early postnatal period is associated with explosive mitochondrial biogenesis.4,5 The switch is critical for the postnatal maturation of the heart. Loss of PGC-1α/β (peroxisome proliferator–activated receptor gamma coactivator), the powerful transcriptional regulators of mitochondrial biogenesis, in perinatal and postnatal periods, results in lethal cardiomyopathy.6,7 The role of mitochondria in the embryonic cardiomyocytes is, however, less explored. Recent studies using pluripotent cell–derived cardiomyocytes have suggested intriguing functions of mitochondria beyond energy provision in the regulation of cardiomyocytes maturation.6,8–10 …
Cardiac Cell Cycle Activation as a Strategy to Improve iPSC-Derived Cardiomyocyte Therapy Circ. Res. (IF 13.965) Pub Date : 2018-01-05 June-Wha Rhee, Joseph C. Wu
Over the past 2 decades, scientists and clinicians have strived to leverage stem cell therapy as a treatment for heart failure. However, a myriad of clinical trials investigating the potential of adult stem cells to restore damaged myocardium showed inconsistent effectiveness.1 A subsequent paradigm shift emerged with evidence that the benefits of such treatment, if any, were derived from cardioprotective paracrine factors released by stem cells as opposed to direct myocardial regeneration. As a result, researchers have attempted to regenerate the lost myocardium by delivering cardiac cells to the sites of myocardial damage. Article, see p 88 With recent advances in induced pluripotent stem cell (iPSC) technology, cardiomyocytes can be efficiently and reproducibly generated from iPSCs.2 The use of iPSCs in cell therapy is particularly attractive for the following reasons. First, iPSCs have extensive self-renewal and differentiation potential, which enables generation of a large number of iPSC-derived cardiomyocytes (iPSC-CMs) required for successful cell therapy. Second, this self-renewal property of iPSCs makes them amenable to desired genetic modification before differentiation.3 Third, iPSC-CMs exhibit properties of beating cardiomyocytes and have been shown to engraft in the host myocardium and electromechanically couple to neighboring native cardiomyocytes.4 Finally, because iPSCs are derived from patients’ own somatic cells, the use of autologous iPSC-CMs may help circumvent potential immunogenicity of the transplanted cells.5 Despite these beneficial characteristics of iPSCs, poor survival and engraftment of the transplanted cells remain major obstacles for efficient myocardial regeneration.1 In this issue of Circulation Research , Zhu et al6 sought to test whether the use of genetically engineered, cell cycle–activated iPSC-CMs could improve cardiac cell therapy. Recognizing that only a small fraction of transplanted iPSC-CMs survive and engraft into the myocardium, they hypothesized that if iPSC-CMs could retain proliferative capacity, then even a small …
Sex Differences in Sex Hormones, Carotid Atherosclerosis, and Stroke Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Kathryn Rexrode
There are notable sex differences in cardiovascular disease. Although the cumulative incidence of cardiovascular disease in women lags behind that of men by ≈7 to 10 years, strokes comprise a larger proportion of cardiovascular events in women than in men.1 In terms of clinical impact, aspirin used for primary prevention is associated with a significance reduction in stroke women but not myocardial infarction in men.2 Differences in endogenous sex hormones have been hypothesized to underlie these substantial sex differences, but clinical data are limited on the relationship between endogenous levels and cardiovascular disease occurrence. Article, see p 97 In this issue, Glisic et al3 examine the relationship of endogenous sex hormone levels and carotid plaque composition, as well as incident stroke, in >2100 older men and women in the Rotterdam Study. Notably, presence of carotid atherosclerosis (carotid intimal–medial thickness of >2.0 mm on carotid screening) was more common among men than women in the study. Among those with established atherosclerosis, the prevalence of calcified plaques was similar in men and women, whereas women were less likely to have a lipid core (36.9% of women; 49.5% of men) and less likely to have intraplaque hemorrhage than men (29.0% of women; 40.0% of men). Endogenous hormones, specifically estradiol and testosterone, were correlated with carotid plaque composition. Higher estradiol levels were associated with increased odds of a lipid core in carotid plaque in both men and women. Women with detectable estradiol levels had a 58% increased odds of having intraplaque hemorrhage compared with women with low estradiol, whereas higher total testosterone levels were associated with decreased odds. No relationship was observed for total testosterone and carotid plaque composition features in men.3 Endogenous hormones were also related to incident stroke in women. Among women with carotid plaque, …
David Polhemus Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Pam Goldberg-Smith
Baseball aficionado, David Polhemus, is not one to let a strike avert a home run, nor does he allow a temporary setback in science prevent him from accomplishing the task at hand. David double majored in Chemistry and Economics at Emory University. He recently graduated with a PhD in Pharmacology and Experimental Therapeutics. David currently works in the Lefer lab at Louisiana State University’s Health Sciences Center in New Orleans. David Polhemus I’m from San Francisco, California, born and raised. When I was young, what I cared about most was playing baseball on the street with my friends. I enjoyed sports and being outdoors. Neither of my parents had a scientific background; dad is in finance and mom works in human resources. My parents were incredibly supportive of my education and encouraged me to pursue my interests, not theirs. When I attended Emory University in Atlanta, Georgia, I studied economics for its practical applications, but also studied chemistry. My passion for science further developed during summer vacations when I worked in anesthesia and neuroscience labs as a student intern. I applied for a lab tech position in a cardiovascular research lab at Emory and I immediately fell in love with the field, so much so that a couple of years later I entered a PhD program within the same lab. I have an outstanding mentor, Dr David Lefer, whom I credit for my success. His love for science is inspirational. During my young career, I have had the unique opportunity to play a role in translating a discovery that we made in mice into clinical trials in humans. We found that in mice, hydrogen sulfide improves cardiac remodeling and function during heart failure. Currently, the same hydrogen sulfide drug that we tested in …
Teasing Apart Heart Failure With Preserved Ejection Fraction Phenotypes With Echocardiographic Imaging Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Edgar Argulian, Y. Chandrashekhar, Sanjiv J. Shah, Olivier Huttin, Bertram Pitt, Faiez Zannad, Robert O. Bonow, Jagat Narula
Phenotyping heart failure represents a major challenge for both research studies and clinical practice. Large-scale clinical trials have failed to achieve meaningful improvement in clinical outcomes with different pharmacological agents in patients with heart failure and preserved left ventricular ejection fraction. Therefore, an alternative scheme for phenotyping heart failure is needed, which is both pathophysiologically distinct and practical for routine clinical application. Heart failure is a syndromic diagnosis broadly based on clinical features, physical findings, and serum biomarkers. Although the assessment of exercise hemodynamics and invasive estimation of filling pressures may be necessary, it is typically confirmed and phenotyped by the imaging data. Phenotyping heart failure represents a major challenge despite decades of ongoing research, vast clinical experience in the field, and multiple iterations of published guidelines. Left ventricular ejection fraction (LVEF) remains the major phenotyping tool endorsed by multiple cardiology societies. However, it has multiple limitations especially in patients with heart failure with preserved LVEF (HFpEF), and many have questioned the current approach to phenotyping of heart failure but no alternative, widely accepted, scheme (which is both clinically relevant and practical) has been offered.1 The existing phenotyping approach to heart failure is based on the premise of LVEF as a surrogate marker for left ventricular systolic performance and, in turn, prognosis. Heart failure patients with reduced LVEF (HFrEF) are assumed to have systolic heart failure, whereas many heart failure patients have preservation of LVEF and are commonly labeled as HFpEF. This assumption makes LVEF the primary marker of heart failure and excludes other important abnormalities that can create the heart failure syndrome. Furthermore, LVEF is an imperfect marker even for assessment of systolic function: it has high interobserver variability, it mainly reflects radial shortening, it is load dependent, and it does not reflect the remodeling pattern of the …
Lessening the Burden of Familial Hypercholesterolemia Using Health Information Technology Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Maya S. Safarova, Iftikhar J. Kullo
Despite advances in our understanding of heritable lipid disorders and the availability of highly effective lipid-lowering drugs, the awareness, detection, and control of familial hypercholesterolemia (FH) remain suboptimal. 1 A major reason for the low detection rate in the United States is the lack of a widely accepted screening strategy, despite the recommendations for universal or targeted lipid screening by several expert panels. Although the use of universal lipid screening remains a matter of debate, cascade screening (a form of targeted screening of family members of affected individuals) is acknowledged as the most cost-effective screening strategy for FH. In the Netherlands >26 000 new cases were identified over 2 decades by genotyping family members of FH probands, and it is estimated that genetic cascade screening, coupled with statin therapy for diagnosed patients, could save $92 million per year in the European Union. 1 Several factors lead to the low rates of cascade screening for FH in the United States. First, no nationwide strategy for the early detection of FH exists. Second, the low acceptance of genetic testing for FH in the United States is an impediment to unambiguous diagnosis and cascade screening. Third, patients and family members are often concerned about the stigma associated with genetic diagnoses. Fourth, because of the Health Insurance Portability and Accountability Act, disclosing the risk of genetic disease to family members can incur liability, even if this knowledge leads to early detection and treatment. Fifth, …
Cell Therapy for Nonischemic Cardiomyopathy Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Bojan Vrtovec
Currently, noni schemic dilated cardiomyopathy (NICM) represents the leading cause of advanced heart failure, accounting for >50% of all heart transplantation procedures. We propose that when compared with patients with ischemic heart failure (IHF), patients with NICM demonstrate a more favorable clinical response to cell therapy, which offers a potential novel promising treatment approach for this patient population. Chronic heart failure represents one of the most important healthcare problems worldwide. Although survival after diagnosis of heart failure has improved, overall mortality remains high.1 In the recent years, several novel approaches for heart failure management have been tested in clinical trials, with cell therapy representing one of potentially more promising treatment modalities. The majority of clinical trials of cell therapy in chronic heart failure have been focusing on patients with IHF. In this cohort, early trials demonstrated clinical benefits and an improvement in left ventricular function after cell therapy; however, subsequent larger trials failed to confirm these findings. Furthermore, a recent meta-analysis of 38 randomized controlled trials in IHF found only low-quality evidence that treatment with bone marrow-derived cells reduces mortality and improves left ventricular ejection fraction (LVEF).2 Although the reasons for the inconsistent results remain poorly defined, they could be partially explained by the fact that despite the potential beneficial effects on the myocardium, cell therapy does not affect the progression of atherosclerosis, which may limit the clinical efficacy of this approach in patients with IHF. In the last decade, NICM has become the leading cause of advanced heart failure, accounting for >50% of all heart transplantations.1 These trends indicate that patients with NICM may represent the largest subpopulation of heart failure patients with a particular need for alternative treatment modalities, including cell therapy. The disease progression …
Stable Oxidative Cytosine Modifications Accumulate in Cardiac Mesenchymal Cells From Type2 Diabetes PatientsNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Francesco Spallotta, Chiara Cencioni, Sandra Atlante, Davide Garella, Mattia Cocco, Mattia Mori, Raffaella Mastrocola, Carsten Kuenne, Stefan Guenther, Simona Nanni, Valerio Azzimato, Sven Zukunft, Angela Kornberger, Duran Sürün, Frank Schnütgen, Harald von Melchner, Antonella Di Stilo, Manuela Aragno, Maarten Braspenning, Wim van Criekinge, Miles J. De Blasio, Rebecca H. Ritchie, Germana Zaccagnini, Fabio Martelli, Antonella Farsetti, Ingrid Fleming, Thomas Braun, Andres Beiras-Fernandez, Bruno Botta, Massimo Collino, Massimo Bertinaria, Andreas M. Zeiher, Carlo Gaetano
Rationale: Human cardiac mesenchymal cells (CMSCs) are a therapeutically relevant primary cell population. Diabetes mellitus compromises CMSC function as consequence of metabolic alterations and incorporation of stable epigenetic changes. Objective: To investigate the role of α-ketoglutarate (αKG) in the epimetabolic control of DNA demethylation in CMSCs. Methods and Results: Quantitative global analysis, methylated and hydroxymethylated DNA sequencing, and gene-specific GC methylation detection revealed an accumulation of 5-methylcytosine, 5-hydroxymethylcytosine, and 5-formylcytosine in the genomic DNA of human CMSCs isolated from diabetic donors. Whole heart genomic DNA analysis revealed iterative oxidative cytosine modification accumulation in mice exposed to high-fat diet (HFD), injected with streptozotocin, or both in combination (streptozotocin/HFD). In this context, untargeted and targeted metabolomics indicated an intracellular reduction of αKG synthesis in diabetic CMSCs and in the whole heart of HFD mice. This observation was paralleled by a compromised TDG (thymine DNA glycosylase) and TET1 (ten–eleven translocation protein 1) association and function with TET1 relocating out of the nucleus. Molecular dynamics and mutational analyses showed that αKG binds TDG on Arg275 providing an enzymatic allosteric activation. As a consequence, the enzyme significantly increased its capacity to remove G/T nucleotide mismatches or 5-formylcytosine. Accordingly, an exogenous source of αKG restored the DNA demethylation cycle by promoting TDG function, TET1 nuclear localization, and TET/TDG association. TDG inactivation by CRISPR/Cas9 knockout or TET/TDG siRNA knockdown induced 5-formylcytosine accumulation, thus partially mimicking the diabetic epigenetic landscape in cells of nondiabetic origin. The novel compound (S)-2-[(2,6-dichlorobenzoyl)amino]succinic acid (AA6), identified as an inhibitor of αKG dehydrogenase, increased the αKG level in diabetic CMSCs and in the heart of HFD and streptozotocin mice eliciting, in HFD, DNA demethylation, glucose uptake, and insulin response. Conclusions: Restoring the epimetabolic control of DNA demethylation cycle promises beneficial effects on cells compromised by environmental metabolic changes.
Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis DevelopmentNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Wared Nour-Eldine, Jérémie Joffre, Kazem Zibara, Bruno Esposito, Andréas Giraud, Lynda Zeboudj, José Vilar, Megumi Terada, Patrick Bruneval, Eric Vivier, Hafid Ait-Oufella, Ziad Mallat, Sophie Ugolini, Alain Tedgui
Rationale: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. Objectives: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl−DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. Methods and Results: No difference in atherosclerotic lesion size was found in Ldlr−/− (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl−DTA, Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ–producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti–asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti–asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr−/− mice transplanted with Ncr1iCreR26Rlsl−DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr−/− mice reconstituted with either wild-type or Ncr1iCreR26Rlsl−DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell–deficient chimeric mice. Conclusions: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs.
Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial FissionNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose McGlauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel
Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. Conclusions: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.
Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte ProliferationNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Donghui Zhang, Yifei Li, Danielle Heims-Waldron, Vassilios Bezzerides, Silvia Guatimosim, Yuxuan Guo, Fei Gu, Pingzhu Zhou, Zhiqiang Lin, Qing Ma, Jianming Liu, Da-Zhi Wang, William T. Pu
Rationale: Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. Objective: To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Methods and Results: Tfam inactivation by Nkx2.5Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Conclusions: Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.
CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell–Derived CardiomyocytesNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Wuqiang Zhu, Meng Zhao, Saidulu Mattapally, Sifeng Chen, Jianyi Zhang
Rationale: The effectiveness of transplanted, human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) for treatment of ischemic myocardial injury is limited by the exceptionally low engraftment rate. Objective: To determine whether overexpression of the cell cycle activator CCND2 (cyclin D2) in hiPSC-CMs can increase the graft size and improve myocardial recovery in a mouse model of myocardial infarction by increasing the proliferation of grafted cells. Methods and Results: Human CCND2 was delivered to hiPSCs via lentiviral-mediated gene transfection. In cultured cells, markers for cell cycle activation and proliferation were ≈3- to 7-folds higher in CCND2-overexpressing hiPSC-CMs (hiPSC-CCND2OECMs) than in hiPSC-CMs with normal levels of CCND2 (hiPSC-CCND2WTCMs; P<0.01). The pluripotent genes (Oct 4, Sox2, and Nanog) decrease to minimal levels and undetectable levels at day 1 and 10 after differentiating to CMs. In the mouse myocardial infarction model, cardiac function, infarct size, and the number of engrafted cells were similar at week 1 after treatment with hiPSC-CCND2OECMs or hiPSC-CCND2WTCMs but was about tripled in hiPSC-CCND2OECM–treated than in hiPSC-CCND2WTCM–treated animals at week 4 (P<0.01). The cardiac function and infarct size were significantly better in both cell treatment groups’ hearts than in control hearts, which was most prominent in hiPSC-CCND2OECM–treated animals (P<0.05, each). No tumor formation was observed in any hearts. Conclusions: CCND2 overexpression activates cell cycle progression in hiPSC-CMs that results in a significant enhanced potency for myocardial repair as evidenced by remuscularization of injured myocardium. This left ventricular muscle regeneration and increased angiogenesis in border zone are accompanied by a significant improvement of left ventricular chamber function.
Associations of Endogenous Estradiol and Testosterone Levels With Plaque Composition and Risk of Stroke in Subjects With Carotid AtherosclerosisNovelty and Significance Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Marija Glisic, Blerim Mujaj, Oscar L. Rueda-Ochoa, Eralda Asllanaj, Joop S.E. Laven, Maryam Kavousi, M. Kamran Ikram, Meike W. Vernooij, M. Arfan Ikram, Oscar H. Franco, Daniel Bos, Taulant Muka
Rationale: Sex steroids may play a role in plaque composition and in stroke incidence. Objectives: To study the associations of endogenous estradiol and testosterone with carotid plaque composition in elderly men and postmenopausal women with carotid atherosclerosis, as well as with risk of stroke in this population. Methods and Results: Data of 1023 postmenopausal women and 1124 men (≥45 years) with carotid atherosclerosis, from prospective population-based RS (Rotterdam Study), were available. At baseline, total estradiol (TE) and total testosterone (TT) were measured. Carotid atherosclerosis was assessed by ultrasound, whereas plaque composition (presence of calcification, lipid core, and intraplaque hemorrhage) was assessed by magnetic resonance imaging. TE and TT were not associated with calcified carotid plaques in either sex. TE was associated with presence of lipid core in both sexes (in women odds ratio, 1.48 [95% confidence interval [CI], 1.02–2.15]; in men odds ratio, 1.23 [95% CI, 1.03–1.46]), whereas no association was found between TT and lipid core in either sex. Higher TE (odds ratio, 1.58 [95% CI, 1.03–2.40]) and lower TT (odds ratio, 0.82 [95% CI, 0.68–0.98]) were associated with intraplaque hemorrhage in women but not in men. In women, TE was associated with increased risk of stroke (hazard ratio, 1.98 [95% CI, 1.01–3.88]), whereas no association was found in men. TT was not associated with risk of stroke in either sex. Conclusions: TE was associated with presence of vulnerable carotid plaque as well as increased risk of stroke in women, whereas no consistent associations were found for TT in either sex.
Trials and Tribulations of CETP Inhibitors Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Alan R. Tall, Daniel J. Rader
The development of CETP (cholesteryl ester transfer protein) inhibitors has had a long and difficult course with 3 compounds failing in phase III clinical trials. Finally, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid modification) trial has shown that the CETP inhibitor anacetrapib decreased coronary heart disease when added to statin therapy. Although the result is different to earlier studies, this is likely related to the size and duration of the trial. The benefit of anacetrapib seems to be largely explained by lowering of non-HDL-C (high-density lipoprotein cholesterol), rather than increases in HDL-C. Although the magnitude of benefit for coronary heart disease appeared to be moderate, in part this may have reflected aspects of the trial design. Anacetrapib treatment was associated with a small increase in blood pressure, but was devoid of major side effects and was also associated with a small reduction in diabetes mellitus. Treatment with CETP inhibitors, either alone or in combination with statins, could provide another option for patients with coronary disease who require further reduction in LDL (low-density lipoprotein) and non-HDL-C.
Resident and Monocyte-Derived Macrophages in Cardiovascular Disease Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Lisa Honold, Matthias Nahrendorf
Macrophages are ubiquitous cells that reside in all major tissues. Counter to long-held beliefs, we now know that resident macrophages in many organs are seeded during embryonic development and self-renew independently from blood monocytes. Under inflammatory conditions, those tissue macrophages are joined and sometimes replaced by recruited monocyte-derived macrophages. Macrophage function in steady state and disease depends on not only their developmental origin but also the tissue environment. Here, we discuss the ontogeny, function, and interplay of tissue-resident and monocyte-derived macrophages in various organs contributing to the development and progression of cardiovascular disease.
Elixir of Life Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte
All living beings undergo systemic physiological decline after ontogeny, characterized as aging. Modern medicine has increased the life expectancy, yet this has created an aged society that has more predisposition to degenerative disorders. Therefore, novel interventions that aim to extend the healthspan in parallel to the life span are needed. Regeneration ability of living beings maintains their biological integrity and thus is the major leverage against aging. However, mammalian regeneration capacity is low and further declines during aging. Therefore, modalities that reinforce regeneration can antagonize aging. Recent advances in the field of regenerative medicine have shown that aging is not an irreversible process. Conversion of somatic cells to embryonic-like pluripotent cells demonstrated that the differentiated state and age of a cell is not fixed. Identification of the pluripotency-inducing factors subsequently ignited the idea that cellular features can be reprogrammed by defined factors that specify the desired outcome. The last decade consequently has witnessed a plethora of studies that modify cellular features including the hallmarks of aging in addition to cellular function and identity in a variety of cell types in vitro. Recently, some of these reprogramming strategies have been directly used in animal models in pursuit of rejuvenation and cell replacement. Here, we review these in vivo reprogramming efforts and discuss their potential use to extend the longevity by complementing or augmenting the regenerative capacity.
Epithelial Properties of the Second Heart Field Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Claudio Cortes, Alexandre Francou, Christopher De Bono, Robert G. Kelly
The vertebrate heart tube forms from epithelial progenitor cells in the early embryo and subsequently elongates by progressive addition of second heart field (SHF) progenitor cells from adjacent splanchnic mesoderm. Failure to maximally elongate the heart results in a spectrum of morphological defects affecting the cardiac poles, including outflow tract alignment and atrioventricular septal defects, among the most common congenital birth anomalies. SHF cells constitute an atypical apicobasally polarized epithelium with dynamic basal filopodia, located in the dorsal wall of the pericardial cavity. Recent studies have highlighted the importance of epithelial architecture and cell adhesion in the SHF, particularly for signaling events that control the progenitor cell niche during heart tube elongation. The 22q11.2 deletion syndrome gene Tbx1 regulates progenitor cell status through modulating cell shape and filopodial activity and is required for SHF contributions to both cardiac poles. Noncanonical Wnt signaling and planar cell polarity pathway genes control epithelial polarity in the dorsal pericardial wall, as progenitor cells differentiate in a transition zone at the arterial pole. Defects in these pathways lead to outflow tract shortening. Moreover, new biomechanical models of heart tube elongation have been proposed based on analysis of tissue-wide forces driving epithelial morphogenesis in the SHF, including regional cell intercalation, cell cohesion, and epithelial tension. Regulation of the epithelial properties of SHF cells is thus emerging as a key step during heart tube elongation, adding a new facet to our understanding of the mechanisms underlying both heart morphogenesis and congenital heart defects.
Long Noncoding RNA Discovery in Cardiovascular Disease Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Tamer Sallam, Jaspreet Sandhu, Peter Tontonoz
Despite significant improvements during the past 3 decades, cardiovascular disease remains a leading worldwide health epidemic. The recent identification of a fascinating group of mediators known as long noncoding RNAs (lncRNAs) has provided a wealth of new biology to explore for cardiovascular risk mitigation. lncRNAs are expressed in a highly context-specific fashion, and multiple lines of evidence implicated them in diverse biological processes. Indeed, abnormalities of lncRNAs have been directly linked with human ailments, including cardiovascular biology and disease. Of particular interest to the cardiovascular research community, dysregulation in lncRNA regulatory circuits have been associated with cardiac pathological hypertrophy, vascular disease, cell fate programming and development, atherosclerosis, dyslipidemia, and metabolic syndrome. Although techniques in interrogating noncoding RNAs are rapidly evolving, a major challenge in studying lncRNAs remains navigating through multiple technical constraints. In this review, we provide a road map for lncRNA discovery and interrogation in biological systems relevant to cardiovascular disease and highlight approaches to decipher their modes of action.
Physiologic, Pathologic, and Therapeutic Paracrine Modulation of Cardiac Excitation-Contraction Coupling Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Joshua Mayourian, Delaine K. Ceholski, David M. Gonzalez, Timothy J. Cashman, Susmita Sahoo, Roger J. Hajjar, Kevin D. Costa
Cardiac excitation–contraction coupling (ECC) is the orchestrated process of initial myocyte electrical excitation, which leads to calcium entry, intracellular trafficking, and subsequent sarcomere shortening and myofibrillar contraction. Neurohumoral β-adrenergic signaling is a well-established mediator of ECC; other signaling mechanisms, such as paracrine signaling, have also demonstrated significant impact on ECC but are less well understood. For example, resident heart endothelial cells are well-known physiological paracrine modulators of cardiac myocyte ECC mainly via NO and endothelin-1. Moreover, recent studies have demonstrated other resident noncardiomyocyte heart cells (eg, physiological fibroblasts and pathological myofibroblasts), and even experimental cardiotherapeutic cells (eg, mesenchymal stem cells) are also capable of altering cardiomyocyte ECC through paracrine mechanisms. In this review, we first focus on the paracrine-mediated effects of resident and therapeutic noncardiomyocytes on cardiomyocyte hypertrophy, electrophysiology, and calcium handling, each of which can modulate ECC, and then discuss the current knowledge about key paracrine factors and their underlying mechanisms of action. Next, we provide a case example demonstrating the promise of tissue-engineering approaches to study paracrine effects on tissue-level contractility. More specifically, we present new functional and molecular data on the effects of human adult cardiac fibroblast conditioned media on human engineered cardiac tissue contractility and ion channel gene expression that generally agrees with previous murine studies but also suggests possible species-specific differences. By contrast, paracrine secretions by human dermal fibroblasts had no discernible effect on human engineered cardiac tissue contractile function and gene expression. Finally, we discuss systems biology approaches to help identify key stem cell paracrine mediators of ECC and their associated mechanistic pathways. Such integration of tissue-engineering and systems biology methods shows promise to reveal novel insights into paracrine mediators of ECC and their underlying mechanisms of action, ultimately leading to improved cell-based therapies for patients with heart disease.
Letter by Bestetti et al Regarding Article, “Inflammatory Cardiomyopathic Syndromes” Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Reinaldo B. Bestetti, Renata Dellalibera-Joviliano, Lucélio B. Couto
We have read with great interest the superb review by Trachtemberg and Hare1 on inflammatory cardiomyopathies. Among other interesting scientific points, in that article, the authors summarize the knowledge about chronic Chagas disease, a disease caused by the protozoan Trypanosoma cruzi. This disease is the cause of a cardiomyopathy that primarily plagues Latin America, but nowadays is globalized to the point to affect ≈400 000 people in the United States, and to cause chronic heart failure in 19% of patients with nonischemic cardiomyopathy in Los Angeles.2 Trachtemberg and Hare1 correctly pointed out that Chagas disease runs 2 forms: the acute and the chronic stage. Whereas the acute stage lasts up …
Response by Trachtenberg and Hare to Letter Regarding the Article, “Inflammatory Cardiomyopathic Syndromes” Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Barry Trachtenberg, Joshua Hare
Thank you Bestetti et al for your interest in our article1 and for your important letter. Indeed, although antiparasital therapy is clearly recommended for acute Chagas disease and is not recommended for chronic Chagas associated with cardiomyopathy, antiparasital therapy for those with the indeterminate form is controversial. This is largely because of a lack of large, randomized trials in this population. As Bestetti et al point out, most patients have …
Correction to: Circulating Growth Differentiation Factor 11/8 Levels Decline With Age Circ. Res. (IF 13.965) Pub Date : 2018-01-05 Lippincott Williams & Wilkins
In the article by Poggioli et al, “Circulating Growth Differentiation Factor 11/8 Levels Decline with Age,” which published in the January 8, 2016 issue of the journal ( Circ Res . 2016;118:29–37. DOI: 10.1161/CIRCRESAHA.115.307521), corrections were needed to the Online Supplement. In Online Table I, we reported values that demonstrate an effect of GDF11/8 on heart weight and body mass. Since then, we have discovered multiple errors present in Online Table I, primarily from spreadsheet errors by one trainee. Specifically, the “Body weight values for Day 0 and 9” for old saline and old GDF11 (0.5mg), Delta body weight Day 0–9 (%) for old saline and HW/BW ratio for old GDF11 (0.5 mg) that we presented in Online Table I in that article, did not reflect the raw data that we originally collected. In this corrigendum, we present the data that we intended to report in Poggioli et al, and explain how the errors occurred. We have also included two columns providing additional data of tibia length and heart weight to tibia length ratio, to show the tibia versus body weight normalization. The errors below occurred in the Lee Laboratory. Online Table I shows the mean±SD of the heart weight (HW) and body …
(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice from Diet-Induced Obesity and Hepatosteatosis Circ. Res. (IF 13.965) Pub Date : 2018-01-04 Liwei Ren, Yuan Sun, Hong Lu, Dien Ye, Lijuan Han, Na Wang, Alan Daugherty, Furong Li, Miaomiao Wang, Fengting Su, Wenjun Tao, Jie Sun, Noam Zelcer, Adam E Mullick, AH J Danser, Yizhou Jiang, Yongcheng He, Xiongzhong Ruan, Xifeng Lu
Rationale: An elevated level of plasma low-density lipoprotein (LDL) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDL receptor (LDLR) and SORT1, independently of the renin-angiotensin system.Objective: To investigate the physiological role of [P]RR in lipid metabolism in vivo.Methods and Results: We used N-Acetylgalactosamine (GalNAc) modified antisense oligonucleotides (ASO) to specifically inhibit hepatic [P]RR expression in C57BL/6J mice, and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic [P]RR silencing increased plasma LDL cholesterol. Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6J mice fed a normal or high fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that [P]RR inhibition decreased protein abundance of acetyl-CoA carboxylase (ACC) and pyruvate dehydrogenase (PDH). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic [P]RR inhibition attenuated diet-induced obesity and hepatosteatosis.Conclusions: Collectively, our study suggests that [P]RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.
Yes-Associated Protein Promotes Angiogenesis Via Signal Transducer and Activator of Transcription 3 in Endothelial Cells Circ. Res. (IF 13.965) Pub Date : 2018-01-03 Jinlong He, Qiankun Bao, Yan Zhang, Mingming Liu, Huizhen Lv, Yajin Liu, Liu Yao, Bochuan Li, Chenghu Zhang, Shuang He, Guijin Zhai, Yan Zhu, Xin Liu, Kai Zhang, Xiujie Wang, Ming-Hui Zou, Yi Zhu, Ding Ai
Rationale: Angiogenesis is a complex process regulating endothelial cell (EC) functions. Emerging lines of evidence support that Yes-associated protein (YAP) plays an important role in regulating the angiogenic activity of ECs.Objective: To specify the effect of EC YAP on angiogenesis and its underlying mechanisms.Methods and Results: In ECs, vascular endothelial growth factor reduced YAP phosphorylation time- and dose-dependently and increased its nuclear accumulation. Using Tie2Cre-mediated YAP transgenic (Tie2Cre-YAPTg) mice, we found that YAP promoted angiogenesis in the postnatal retina and tumor tissues. Mass spectrometry revealed signal transducer and activator of transcription 3 (STAT3) as a potential binding partner of YAP in ECs. Western blot and immunoprecipitation assays indicated that binding with YAP prolonged interleukin 6-induced STAT3 nuclear accumulation by blocking chromosomal maintenance 1-mediated STAT3 nuclear export without affecting its phosphorylation. Moreover, angiopoietin-2 (Ang2) expression induced by STAT3 was enhanced by YAP overexpression in ECs. Finally, a selective STAT3 inhibitor or Ang2 blockage partly attenuated retinal angiogenesis in Tie2Cre-YAPTgmice.Conclusions: YAP binding sustained STAT3 in the nucleus to enhance the latter's transcriptional activity and promote angiogenesis via regulation of Ang2.
Kidney Transplantation in a Patient Lacking Cytosolic Phospholipase A2 Proves Renal Origins of Urinary PGI-M and TX-M Circ. Res. (IF 13.965) Pub Date : 2018-01-03 Jane Mitchell, Rebecca B Knowles, Nicholas S Kirkby, Daniel M Reed, Matthew L Edin, William E White, Melissa V Chan, Hilary Longhurst, Magdi Yaqoob, Ginger L Milne, Darryl C Zeldin, Timothy D Warner
Rationale: The balance between vascular prostacyclin which is anti-thrombotic and platelet thromboxane A2 which is pro-thrombotic is fundamental to cardiovascular health. Prostacyclin and thromboxane A2 are formed following the concerted actions of cytosolic phospholipase A2 (cPLA2α) and cyclooxygenase. Urinary 2,3-dinor-6-keto PGF1α (PGI-M) and 11-dehydro-TXB2 (TX-M) have been taken as biomarkers of prostacyclin and thromboxane A2 formation with the circulation and used to explain cyclooxygenase biology and patient phenotypes, despite concerns that urinary PGI-M and TX-M originate in the kidney.Objective: We report data from a remarkable patient carrying an extremely rare genetic mutation in cPLA2α, causing almost complete loss of prostacyclin and thromboxane A2, who was transplanted with a normal kidney resulting in an experimental scenario of 'whole body cPLA2α knockout, kidney specific knock-in'. By studying this patient, we can determine definitively the contribution of the kidney to the productions of PGI-M and TX-M and test their validity as markers of prostacyclin and thromboxane A2 in the circulation.Methods and Results: Metabolites were measured using LC-MS/MS. Endothelial cells were grown from blood progenitors. Before kidney transplantation the patient's endothelial cells and platelets released negligible levels of prostacyclin (measured as 6-ketoPGF1α) and thromboxane A2 (measured as TXB2), respectively. Likewise, the urinary levels of PGI-M and TX-M were very low. Following transplantation and the establishment of normal renal function the levels of PGI-M and TX-M in the patient's urine rose to within normal ranges while endothelial production of prostacyclin and platelet production of thromboxane A2 remained negligible.Conclusions: This data shows that PGI-M and TX-M can be derived exclusively from the kidney without contribution from prostacyclin made by endothelial cells or thromboxane A2 by platelets in the general circulation. Previous work relying upon urinary metabolites of prostacyclin and thromboxane A2 as markers of whole body endothelial and platelet function now requires re-evaluation.
A-To-I Editing of Microrna-487b Alters Target Gene Selection After Ischemia and Promotes Neovascularization Circ. Res. (IF 13.965) Pub Date : 2017-12-28 Reginald V van der Kwast, Eva van Ingen, Laura Parma, Hendrika A Peters, Paul H Quax, A Y Nossent
Rationale: Adenosine-to-inosine (A-to-I) editing of microRNAs has the potential to cause a shift in target-site selection. 2'-O-ribose-methylation (2'OMe) of adenosine residues however, has been shown to inhibit A-to-I-editing.Objective: To investigate whether angiomiR miR487b is subject to A-to-I-editing and/or 2'OMe during neovascularization.Methods and Results: cDNA was prepared from C57BL/6-mice subjected to hindlimb ischemia. Using Sanger-sequencing and endonuclease digestion, we identified and validated A-to-I-editing of the miR487b seed-sequence. In the gastrocnemius muscle, pri-miR487b editing increased from 6.7±0.4% before to 11.7±1.6% (P=0.02) 1 day after ischemia. Edited pri-miR487b is processed into a novel microRNA, miR487b-ED, which is also upregulated following ischemia. We confirmed editing of miR487b in multiple human primary vascular cell-types. siRNA-mediated knockdown demonstrated that editing is ADAR1&2-dependent. Using 'Reverse-Transcription at Low dNTP concentrations followed by Quantitative-PCR' (RTL-Q), we found that the same adenosine-residue is methylated in mice and human primary cells. In the murine gastrocnemius, the estimated methylation fraction increased from 32.8±14% before to 53.6±12% 1 day after ischemia. siRNA knockdown confirmed that methylation is Fibrillarin-dependent. Although we could not confirm that methylation directly inhibits editing, we do show that ADAR1&2 and Fibrillarin negatively influence each other's expression. Using multiple luciferase reporter gene assays, we could demonstrate that editing results in a complete switch of target-site selection. In human primary cells, we confirmed the shift in miR487b targeting after editing, resulting in a miR487b-ED targetome that is enriched for multiple pro-angiogenic pathways. Furthermore, overexpression of miR-487b-ED, but not miR-487b-WT, stimulates angiogenesis in both in vitro and ex vivo assays.Conclusions: MiR487b is edited in the seed-sequence in mice and humans, resulting in a novel, pro-angiogenic microRNA with a unique targetome. The rate of miR487b editing, as well as 2'OMe, is increased in murine muscle tissue during post-ischemic neovascularization. Our findings suggest miR487b editing plays an intricate role in post-ischemic neovascularization.
AMPKα2 Protects Against the Development of Heart Failure by Enhancing Mitophagy via PINK1 Phosphorylation Circ. Res. (IF 13.965) Pub Date : 2017-12-28 Bei Wang, Jiali Nie, Lujin Wu, Yangyang Hu, Zeng Wen, Lingli Dong, Ming-Hui Zou, Chen Chen, Dao Wen Wang
Rationale: Mitochondrial dysfunction plays an important role in heart failure (HF). However, the molecular mechanisms regulating mitochondrial functions via selective mitochondrial autophagy (mitophagy) are poorly understood.Objective: We sought to determine the role of AMP-activated protein kinase (AMPK) in selective mitophagy during HF.Methods and Results: An isoform shift from AMPKα2 to AMPKα1 was observed in failing-heart samples from HF patients and transverse aortic constriction (TAC)-induced mice, accompanied by decreased mitophagy and mitochondrial function. The recombinant adeno-associated virus Serotype 9-mediated overexpression of AMPKα2 in mouse hearts prevented the development of TAC-induced chronic HF by increasing mitophagy and improving mitochondrial function. In contrast, AMPKα2−/− mutant mice exhibited an exacerbation of the early progression of TAC-induced HF via decreases in cardiac mitophagy. In isolated adult mouse cardiomyocytes (CMs), AMPKα2 overexpression mechanistically rescued the impairment of mitophagy after phenylephedrine (PE) stimulation for 24 h. Genetic knockdown of AMPKα2, but not AMPKα1, by short interfering RNA suppressed the early phase (6 h) of PE-induced compensatory increases in mitophagy. Furthermore, AMPKα2 specifically interacted with phosphorylated PTEN-induced putative kinase 1 (PINK1) at Ser495 after PE stimulation. Subsequently, phosphorylated PINK1 recruited the E3 ubiquitin ligase, Parkin, to depolarized mitochondria, and then enhanced the role of the PINK1-Parkin-sequestosome-1 pathway involved in cardiac mitophagy. This increase in cardiac mitophagy was accompanied by the elimination of damaged mitochondria, improvement in mitochondrial function, decrease in reactive oxygen species (ROS) production, and apoptosis of CMs. Finally, Ala mutation of PINK1 at Ser495 partially suppressed AMPKα2 overexpression-induced mitophagy and improvement of mitochondrial function in PE-stimulated CMs, whereas Asp (phosphorylation-mimic) mutation promoted mitophagy after PE stimulation.Conclusions:In failing hearts, the dominant AMPKα isoform switched from AMPKα2 to AMPKα1, which accelerated HF. The results show that phosphorylation of Ser495 in PINK1 by AMPKα2 was essential for efficient mitophagy to prevent the progression of HF.
Late Ca2+ Sparks and Ripples During the Systolic Ca2+ Transient in Heart Muscle Cells Circ. Res. (IF 13.965) Pub Date : 2017-12-27 Ewan D Fowler, Cherrie H Kong, Jules Hancox, Mark B Cannell
Rationale: The development of a refractory period for Ca2+ spark initiation after Ca2+ release in cardiac myocytes, should inhibit further Ca2+ release during the action potential (AP) plateau. However, Ca2+ release sites that did not initially activate, or which have prematurely recovered from refractoriness might release Ca2+ later during the AP and alter the cell-wide Ca2+ transient.Objective: To investigate the possibility of late Ca2+ spark (LCS) activity in intact isolated cardiac myocytes using fast confocal line scanning with improved confocality and signal to noise.Methods and Results: We recorded Ca2+ transients from cardiac ventricular myocytes isolated from rabbit hearts. APs were produced by electrical stimulation and rapid solution changes were used to modify the L-type Ca2+ current. After the upstroke of the Ca2+ transient, late Ca2+ sparks (LCS) were detected which had increased amplitude compared to diastolic Ca2+ sparks. LCS are triggered by both L-type Ca2+ channel activity during the action potential plateau, as well as by the increase of cytosolic Ca2+ associated with the Ca2+ transient itself. Importantly, a mismatch between SR load and L-type Ca2+ trigger can increase the number of LCS. The likelihood of triggering a LCS also depends on recovery from refractoriness that appears after prior activation. Consequences of LCS include a reduced rate of decline of the Ca2+ transient and, if frequent, formation of microscopic propagating Ca2+ release events (Ca2+ ripples). Ca2+ ripples resemble Ca2+ waves in terms of local propagation velocity but spread for only a short distance due to limited regeneration.Conclusions: These new types of Ca2+ signalling behaviour extend our understanding of Ca2+ mediated signalling. LCS may provide an arrhythmogenic substrate by slowing the Ca2+ transient decline as well as by amplifying maintained Ca2+ current effects on intracellular Ca2+ and consequently Na+/Ca2+ exchange current.
MUSCLEMOTION: A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo Circ. Res. (IF 13.965) Pub Date : 2017-12-27 Luca Sala, Berend J van Meer, Leon T Tertoolen, Jeroen Bakkers, Milena Bellin, Richard P Davis, Chris N Denning, Michel A Dieben, Thomas Eschenhagen, Elisa Giacomelli, Catarina Grandela, Arne Hansen, Eduard Holman, Monique R Jongbloed, Sarah M Kamel, Charlotte D Koopman, Quentin Lachaud, Ingra Mannhardt, Mervyn P Mol, Diogo Mosqueira, Valeria V Orlova, Robert Passier, Marcelo C Ribeiro, Umber Saleem, Godfrey Smith, Francis L L Burton, Christine L Mummery
Rationale: There are several methods to measure cardiomyocyte (CM) and muscle contraction but these require customized hardware, expensive apparatus and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming and only specialist researchers can quantify data.Objective: Here we describe and validate an automated, open source software tool (MUSCLEMOTION) adaptable for use with standard laboratory- and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes and pharmacological responses.Methods and Results: MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in: (i) 1-dimensional in vitro models such as isolated adult and human pluripotent stem cell-derived CMs (hPSC-CMs); (ii) 2-dimensional in vitro models, such as beating CM monolayers or small clusters of hPSC-CMs; (iii) 3-dimensional multicellular in vitro or in vivo contractile tissues such as cardiac "organoids", engineered heart tissues (EHT), zebrafish- and human hearts. MUSCLEMOTION was effective under different recording conditions (bright field microscopy with simultaneous patch clamp recording, phase contrast microscopy and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement such as optical flow, pole deflection, edge-detection systems or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses.Conclusions: Using a single open source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell-, animal- and human models.
Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation Circ. Res. (IF 13.965) Pub Date : 2017-12-26 Chenglai Fu, Richa Tyagi, Alfred C Chin, Tomas Rojas, Ruo-jing Li, Prasun Guha, Isaac A Bernstein, Feng Rao, Risheng Xu, Jiyoung Y Cha, Jing Xu, Adele M Snowman, Gregg L Semenza, Solomon H Snyder
Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored.Objective: We have investigated the role of IPMK in regulating angiogenesis.Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of vascular endothelial growth factor (VEGF), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. Hypoxia inducible factor 1α (HIF1α) is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF1α protein and thus VEGF. HIF1α is constitutively ubiquitinated by von Hippel-Lindau protein (pVHL) followed by proteasomal degradation under normal conditions. However, HIF1α is not recognized and ubiquitinated by pVHL in IPMK knock out cells. IP5 reinstates the interaction of HIF1α and pVHL. HIF1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK deleted cells. IP5 promotes HIF1α prolyl hydroxylation and thus pVHL dependent degradation of HIF1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KOs disrupts blood-brain barrier and enhances brain blood vessel permeability.Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL dependent degradation of HIF-1α.
Deficiency of Natriuretic Peptide Receptor 2 Promotes Bicuspid Aortic Valves, Aortic Valve Disease, Left Ventricular Dysfunction, and Ascending Aortic Dilatations in Mice Circ. Res. (IF 13.965) Pub Date : 2017-12-22 Mark C Blaser, Kuiru Wei, Rachel L Adams, Yu-Qing Zhou, Laura-lee Caruso, Zahra Mirzaei, Alan Lam, Richard K Tam, Hangjun Zhang, Scott P Heximer, Mark Henkelman, Craig A Simmons
Rationale: Aortic valve disease is a cell-mediated process without effective pharmacotherapy. C-type natriuretic peptide (CNP) inhibits myofibrogenesis and osteogenesis of cultured valve interstitial cells (VICs), and is downregulated in stenotic aortic valves. However, it is unknown whether CNP signaling regulates aortic valve health in vivo.Objective: To determine whether a deficient CNP signaling axis in mice causes accelerated progression of aortic valve disease.Methods and Results: In cultured porcine VICs, CNP inhibited pathological differentiation via the guanylate cyclase natriuretic peptide receptor 2 (NPR2) and not the G-protein-coupled clearance receptor NPR3. We used Npr2+/- and Npr2+/-;Ldlr-/- mice and wild-type littermate controls to examine the valvular effects of deficient CNP/NPR2 signaling in vivo, in the context of both moderate and advanced aortic valve disease. Myofibrogenesis in cultured Npr2+/- fibroblasts was insensitive to CNP treatment, while aged Npr2+/- and Npr2+/-;Ldlr-/- mice developed cardiac dysfunction and ventricular fibrosis. Aortic valve function was significantly impaired in Npr2+/- and Npr2+/-;Ldlr-/- mice vs. wild-type littermates, with increased valve thickening, myofibrogenesis, osteogenesis, proteoglycan synthesis, collagen accumulation, and calcification. 9.4% of mice heterozygous for Npr2 had congenital bicuspid aortic valves (BAVs), with worse aortic valve function, fibrosis, and calcification than those Npr2+/- with typical tricuspid aortic valves or all wild-type littermate controls. Moreover, cyclic guanosine monophosphate-dependent protein kinase (cGK) activity was downregulated in Npr2+/- valves, and CNP triggered synthesis of cGMP and activation of cGK1 in cultured porcine VICs. Finally, aged Npr2+/-;Ldlr-/- mice developed dilatation of the ascending aortic, with greater aneurysmal progression in Npr2+/- mice with BAVs than those with tricuspid valves.Conclusions: Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease, and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.
Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages Circ. Res. (IF 13.965) Pub Date : 2017-12-21 Thomas Moore-Morris, Paola Cattaneo, Nuno Guimarães-Camboa, Julius Bogomolovas, Marta Cedenilla, Indroneal Banerjee, Mercedes Ricote, Tatiana Kisseleva, Lunfeng Zhang, Yusu Gu, Nancy D Dalton, Kirk L Peterson, Ju Chen, Michel Puceat, Sylvia M Evans
Rationale: Myocardial infarction (MI) is a major cause of adult mortality worldwide. The origin(s) of cardiac fibroblasts that constitute the post-infarct scar remain controversial, in particular the potential contribution of bone marrow lineages to activated fibroblasts within the scar.Objective:To establish the origin(s) of infarct fibroblasts using lineage tracing and bone marrow transplants, and a robust marker for cardiac fibroblasts, the Collagen1a1-GFP reporter.Methods and Results: Using genetic lineage tracing or bone marrow transplant, we found no evidence for Collagen-producing fibroblasts derived from hematopoietic or bone marrow lineages in hearts subjected to permanent left anterior descending (LAD) coronary artery ligation. In fact, fibroblasts within the infarcted area were largely of epicardial origin. Intriguingly, collagen-producing fibrocytes from hematopoietic lineages were observed attached to the epicardial surface of infarcted and sham-operated hearts in which a suture was placed around the LAD.Conclusions: In this controversial field, our study demonstrated that the vast majority of infarct fibroblasts were of epicardial origin and not derived from bone marrow lineages, endothelial-to-mesenchymal transition (EndoMT) or blood. We also noted the presence of collagen-producing fibrocytes on the epicardial surface that resulted at least in part from the surgical procedure.
Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: Blood-and-Muscle Model Circ. Res. (IF 13.965) Pub Date : 2017-12-14 Athanase Benetos, Simon Toupance, Sylvie Gautier, Carlos Labat, Masayuki Kimura, Pascal M Rossi, Nicla Settembre, Jacques Hubert, Luc Frimat, Baptiste Bertrand, Mourad Boufi, Xavier Flecher, Nicolas Sadoul, Pascal Eschwege, MichÃ¨le Kessler, Irene P Tzanetakou, Ilias P Doulamis, Panagiotis S Konstantopoulos, Aspasia I Tzani, Laskarina-Maria Korou, Anastasios Gkogkos, Konstantinos G Perreas, Evangelos Menenakos, George Samanidis, Michail Vasiloglou-Gkanis, Jeremy D Kark, Sergueï Malikov, Simon Verhulst, Abraham Aviv
Rationale: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth and/or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, while TL in skeletal muscle (M) represents a minimally replicative tissue.Objective: We measured LTL and MTL in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD.Methods and Results: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTLA (MTL adjusted for muscle biopsy site) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (p=0.005), but not MTLA (p=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (p=0.0003) and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (p=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals.Conclusions: This first study to apply the 'blood-and-muscle' TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients.Clinical Trial Registration: NCT02176941
Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone Circ. Res. (IF 13.965) Pub Date : 2017-12-13 Miranda E Good, Yu-Hsin Chiu, Ivan K Poon, Christopher B Medina, Joshua T Butcher, Suresh K Mendu, Leon J DeLalio, Alexander W Lohman, Norbert Leitinger, Eugene J Barrett, Ulrike M Lorenz, Bimal N Desai, Iris Z Jaffe, Douglas Bayliss, Brant E Isakson, Kodi S Ravichandran
Rationale: Resistant hypertension is a major health concern with unknown etiology. Spironolactone is an effective anti-hypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization (WHO) as an "essential" medication. Although spironolactone can act at the mineralocorticoid receptor (NR3C2), there is increasing evidence of mineralocorticoid receptor (MR)-independent effects of spironolactone.Objective: Here, we detail the unexpected discovery that pannexin 1 (Panx1) channels could be a relevant in vivo target of spironolactone.Methods and Results: First, we identified spironolactone as a potent inhibitor of Panx1 in an unbiased small molecule screen, which was confirmed by electrophysiological analysis. Next, spironolactone inhibited α-adrenergic vasoconstriction in arterioles from mice and hypertensive humans, an effect dependent upon smooth muscle Panx1, but independent of the mineralocorticoid receptor NR3C2. Lastly, spironolactone acutely lowered blood pressure, which was dependent on smooth muscle cell expression of Panx1 and independent of NR3C2. This effect, however, was restricted to steroidal MR antagonists as a non-steroidal MR antagonist failed to reduced blood pressure.Conclusions: These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition.
VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression Circ. Res. (IF 13.965) Pub Date : 2017-12-12 Marco F Morini, Costanza Giampietro, Monica Corada, Federica Pisati, Elisa Lavarone, Sara I Cunha, Lei L Conze, Nicola J O'Reilly, Dhira Joshi, Svend Kjaer, Roger George, Emma Nye, Anqi Ma, Jian Jin, Richard Mitter, Michela Lupia, Ugo Cavallaro, Diego Pasini, Dinis P Calado, Elisabetta Dejana, Andrea Taddei
Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumours, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular inter-endothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, vascular endothelial (VE)-cadherin (VEC), upregulate genes with key roles in endothelial differentiation and stability.Objective: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization.Methods and Results: We compared a VEC-null cell line with the same line reconstituted with VEC wild type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) and von Willebrand factor (vWf). Mechanistically VEC exerts this effect by inhibiting Polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 and β-catenin, which contribute to Polycomb repressive complex-2 (PRC2) binding to promoter regions of claudin-5, VE-PTP and vWf. VE-cadherin/β-catenin complex also sequesters a core subunit of PRC2 (Ezh2) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VE-cadherin association increases Ezh2 recruitment to claudin-5, VE-PTP and vWf promoters, causing gene downregulation. RNA-seq comparison of VEC-null and VEC-positive cells suggested a more general role of VE-cadherin in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of Claudin-5 and VE-PTP.Conclusions: These data extend the knowledge of Polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the Polycomb-mediated repression system.
Physiologic Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand Circ. Res. (IF 13.965) Pub Date : 2017-12-12 Michael Coronado, Giovanni Fajardo, Kim Nguyen, Mingming Zhao, Kristina B Kooiker, Gwanghyun jung, Dong-Qing Hu, Sushma Reddy, Erik Sandoval, Aleksandr Stotland, Roberta A Gottlieb, Daniel Bernstein
Rationale: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiologic stress such as exercise.Methods and Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, "physiologic" mitochondrial fragmentation results in enhanced, rather than impaired mitochondrial function, and is mediated in-part by β1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 or in mice with cardiac specific Drp1 ablation, significantlyConclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
In This Issue Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Ruth Williams
### Parikh et al develop a protocol for promoting t-tubule formation in human iPSC-derived cardiomyocytes. Cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are useful for modeling a variety of heart diseases and potentially for repairing injured hearts. But the process of in vitro hiPSC-CM differentiation generally fails to produce fully mature cells. For example, they tend to lack t-tubules—membranous invaginations that transverse the cell and are essential for normal cellular electrophysiology. Previous strategies for improving hiPSC-CM maturation include growing the cells on a matrix of physiological stiffness (matrigel mattress) and adding thyroid and glucocorticoid hormones to the media. However, neither of these approaches promote fully fledged t-tubule development. Parikh and colleagues have now discovered that by …
Meet the First Authors Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Lippincott Williams & Wilkins
Shan Parikh is an aspiring physician-scientist training under Dr Bjorn Knollmann at the Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART). Prior to beginning his MD/PhD, Shan completed his undergraduate studies at the University of Connecticut, where he studied Physiology and Neurobiology. His interest in studying heart disease originated while working at Temple University School of Medicine, where he joined the laboratory of Dr Thomas Force to explore in vivo models of heart failure. He is fascinated by the potential of pluripotent stem cell-derived cardiomyocytes for repair of the failing heart and is focused on enhancing his understanding of their biology and developing expertise for their use in disease modeling. After completing his MD/PhD, Shan intends to pursue a clinical and research career devoted to the investigation and treatment of heart disease. While at home, Shan enjoys riding his bike, hiking, spending time with his family, and filling his home with plants. Guizhen Zhao is a PhD candidate in an 8-year Bachelor–PhD program in Physiology and Pathophysiology at Peking University in Beijing, China. She earned a BS in Basic Medicine in …
A Recipe for T-Tubules in Human iPS Cell–Derived Cardiomyocytes Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Jean Scotty Cadet, Timothy J. Kamp
Human pluripotent stem cell–derived cardiomyocytes (hPSC-CMs) provide a powerful tool for investigating human cardiac biology, drug screening, and potentially therapeutic applications; however, these applications are limited by the relative immaturity of hPSC-CMs. In other words, the in vitro differentiated hPSC-CMs are more akin to early fetal cardiomyocytes than adult cardiomyocytes, which means they are structurally and functionally distinct in certain properties. One feature notably absent from immature hPSC-CMs relative to adult cardiomyocytes are T-tubules. The T-tubule system forms around the time of birth and is a complex network of interconnecting tubules and membranes contiguous with the extracellular space referred to as T-tubules for the predominant transverse components aligned with the z lines. Because ventricular cardiomyocytes are remarkably large cells, the T-tubule network enables the rapid spread of the electric impulse throughout the cardiomyocyte. This is critical for the synchronized onset of contraction given that key components of excitation–contraction coupling are present in dyads where L-type Ca2+ channels in the T-tubules provided the triggering influx of Ca2+ during the action potential leading to intracellular Ca2+ release from the closely apposed ryanodine receptors of the junctional sarcoplasmic reticulum which together produce the Ca2+ transient activating contraction of the myofilaments. Thus, to investigate properties of adult cardiac excitation–contraction coupling and alterations in diseases, such as inherited cardiomyopathies or Ca2+-triggered arrhythmias, an hPSC-CM model with more mature features including a functional T-tubule network and adult-like Ca2+ cycling is desirable. Furthermore, the improved contractile performance and reduced spontaneous automaticity of mature ventricular-like …
Arrhythmogenic Cardiomyopathy Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Silvia G. Priori, Demetrio J. Santiago
In the current issue of the Circulation Research, Karmouch et al1 present a provocative study attributing a pivotal role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) to the loss of DSP (desmoplakin) gene in a subpopulation of the cells of the conduction system. This hypothesis is in sharp departure from the current view on the disease, and it opens the question on whether the data reported in mice with a selective expression of the genetic defects in the specialized cells of the conduction system replicate the clinical phenotype found in patients. Article, see p 1346 ACM is a genetic disease of the heart muscle caused, in most instances, by mutations in genes encoding for desmosomal proteins that is predominantly inherited as an autosomal dominant trait.1 Two syndromic recessive forms of the disease have been described and both present abnormalities in skin2 and heart. Carvajal Syndrome3 presents a striate type of keratoderma, is associated with a cardiomyopathy with preferred involvement of the left ventricle, and is associated with DSP mutations. Occasionally, Carvajal is inherited as a dominant disease that also presents hypodontia.4 Naxos disease5 is associated with mutations in the plakoglobin gene and manifests diffuse keratoderma and right ventricular cardiomyopathy. Occasionally, Naxos disease with dominant inheritance has been reported. Karmouch et al1 investigate the recessive form of ACM caused by mutations in the DSP gene that manifests with palmo-plantar keratosis, wooly hair, and dilatation of both ventricular chambers with fibro-fatty infiltration and life-threatening arrhythmias.3 There is general consensus that cardiac manifestations of the disease are the consequence of DSP mutations that alter the function of cardiac myocytes (CMs). The assumption that mutations in cardiac genes affect CMs is not unique to ACM; rather, it is the paradigm in the study of most …
Decreased Maternal Cardiac Glucose Oxidation Circ. Res. (IF 13.965) Pub Date : 2017-12-08 John R. Ussher, Gary D. Lopaschuk
During pregnancy, there are several coordinated and dynamic maternal adaptations that take place to meet the demands of the growing and developing fetus. This includes significant physiological, endocrine, and metabolic adaptations that produce a diabetogenic state of progressive insulin resistance.1,2 It is thought that these metabolic adaptations occur so that nutrients, such as glucose, are conserved and directed toward the fetus to sustain its constant nutritional and oxygen requirements. Pregnancy is also associated with significant physiological remodeling of the cardiovascular system, which includes increases in ventricular wall mass, ventricular hypertrophy, myocardial contractility, and cardiac compliance.1,2 These cardiac adaptations combined with an increase in heart rate and cardiac output further ensure the optimization of nutrient and oxygen delivery to the growing fetus. Although the maternal cardiovascular and metabolic adaptations that allow for optimal nutrient delivery to the fetus during pregnancy are well understood, one particular area where knowledge is lacking in pregnancy relates to maternal cardiac energy metabolism profiles. Because pregnancy results in an increased maternal cardiac hypertrophy, and both physiological and pathophysiological cardiac hypertrophy are associated with several alterations in myocardial energy metabolism,3,4 it is likely that pregnancy-associated cardiac hypertrophy is also accompanied by altered myocardial metabolism. In support of this, in this issue of Circulation Research, Liu et al5 provide evidence that the cardiac hypertrophy associated with late pregnancy is associated with reductions in myocardial glucose oxidation rates and increases in fatty acid oxidation rates (Figure). Article, see p 1370 Cardiac energy metabolism during pregnancy. The study by Liu et al demonstrates that pregnancy-induced cardiac hypertrophy is associated with alterations in myocardial energy metabolism mimicking that observed in the heart during obesity and diabetes mellitus with an increase in fatty acid oxidation rates and a decrease in …
United We Stand; Divided We Fibrillate? Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Barry London
The heart is an electric and biochemical syncytium with its cardiac myocytes coupled by gap junctions that allow the passage of both ionic current and small molecules.1 Electric coupling allows the rapid spread of depolarization through the atrium, ventricle, and specialized conduction system that is required for coordinated and efficient mechanical function. In addition, these low-resistance intercellular connections help to prevent arrhythmias in several ways. First, tight coupling leads to synchronization of repolarization across the cardiac chambers that decreases dispersion of repolarization and refractoriness and prevents functional reentry.2 Second, the flow of ions and metabolites minimizes the differences at the single cell level that could result from variations in ion channel expression and metabolic state, stabilizing electric propagation and preventing triggered activity. Third, if an aberrant action potential is triggered in a cell or small group of cells, the source–sink mismatch of the electric syncytium will often prevent propagation. In fact, both theoretical and experimental studies have estimated the number of synchronized myocytes required to initiate a premature ventricular beat.3,4 Article, see p 1379 Although coupling between cardiac myocytes is important, the absence of coupling is also critical in some circumstances. Electric isolation is required …
Circulating Thyroxine Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Jeffrey L. Anderson
Thyroid dysfunction has long been known to affect certain cardiovascular conditions. Measuring thyroid function to discover occult hyperthyroidism is recommended to evaluate causal factors for new-onset atrial fibrillation.1 Similarly, thyroid function testing is advocated to exclude hypothyroidism as a secondary cause of dyslipidemia before initiating lipid-lowering therapy.2 However, the effect of thyroid hormone on atherothrombosis, the major cause of cardiovascular morbidity and mortality, remains controversial, with various studies showing no effect on cardiovascular risk,3,4 increased risk associated with low thyroid function,5,6 and greater risk associated with high thyroid function,7–9 in some cases within the reference range. Thus, whether variations in thyroid function both without and within the normal reference range can impact atherosclerotic cardiovascular disease (ASCVD) risk is unresolved. Article, see p 1392 In this issue of Circulation Research, Bano et al10 examine the relationship of 3 metrics of thyroid function to 3 measures of atherosclerosis, spanning its spectrum from preclinical disease (defined by coronary artery calcification), to clinical ASCVD events, to ASCVD-related mortality. To examine this association, they turned to the well-known prospective population-based Rotterdam Cohort Study—an ongoing investigation of the determinants of chronic disease occurrence and progression in middle-aged and older adults. The Rotterdam Study enrolled its first cohort in 1989 and added a second cohort in 2000 and a third in 2006, with clinical follow-up for health outcomes every 3 to 5 years. The present study included 9420 subjects, including those seen at the third visit for cohort 1 and the first visits for cohorts 2 and 3, who had complete baseline thyroid function measurements for thyroid-stimulating hormone (TSH), free thyroxine (FT4), and thyroid peroxidase antibodies, and who also had complete information on ASCVD. Over a mean follow-up of 8.8 …
Shine on, Young Physician-Scientist Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Giovanni Davogustto
Physician-scientists have been recognized as an important piece for the advancement of medicine by being translators of medical research.1 Despite this recognized role, physician-scientists in the United States have decreased from 5% of all physician workforce in 1987 to 1.5% in 2014.2 Why, in spite of their relevance, have physician-scientists become a rara avis in medical research? It is a complex matter, and I don’t expect to provide a universal answer in this short column. However, I hope to raise awareness of this subject from a trainee’s perspective by scrutinizing the hurdles that I (and some of my young colleagues) have to surpass during graduate medical education to become a physician-scientist in cardiovascular research. I have decided to dissect the obstacles in the graduate medical education system, which in my experience, dampen the recruitment (and success) of young physician-scientists into trainee-related, program/institutional support and funding. a. Debt and salary: During informal discussions with my classmates, debt and salary has a great weight on their decision to not pursue further training. According to the Association of American Medical Colleges, 2015’s graduates from medical school had a mean debt of …
Bradford C. Berk Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Sandra J. Ackerman
As Brad Berk sees it, “All the work I do can pretty much fit under the heading of signal transduction in blood vessels.” This deceptively short phrase, however, covers decades of research into the cellular and genetic mechanisms that produce some of cardiovascular medicine’s most stubborn challenges: atherosclerosis, aneurysms, and pulmonary hypertension. Berk’s academic career has led him from the University of Rochester to Harvard Medical School, Emory University, and the University of Washington before circling back to Rochester. Currently, he holds the post of Distinguished University Professor in medicine, neurology, pathology, and pharmacology and physiology. He has founded and directed 2 multidepartment institutes: the Aab Cardiovascular Research Institute (CVRI; from 1999 to 2006) and the University of Rochester Neurorestoration Institute (URNI; from 2015 to the present). Bradford C. Berk While at the University of Washington, in 1998, he published with Oren Traub a review1 of what was then known about how changes in blood-flow profile (steady versus disturbed) influence vascular disease. Berk went on to develop a highly reproducible model2 for vascular remodeling of the carotid as mediated by blood-flow profile. The disturbed flow region shows the formation of intima—a pathological thickening of the vessel wall. Because this thickening is predictive for cardiovascular events, the identification of genetic factors that played a role in the process3 marked a significant advance in cardiovascular research. Together with Korshunov et al, Berk studied 3 disease processes that contribute to intima: endothelial dysfunction, inflammation, and smooth muscle growth. By performing a genetic linkage study to home in on regions of the mouse genome that contribute to the intima,4 Berk and Korshunov identified a specific gene (RpL17) that accounts for smooth muscle cell growth. With Smolock et al,5,6 they found a key link to inflammation now identified …
2017 Lucian Award Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Susan Ince
The 2017 Louis and Artur Lucian award for research in circulatory disease, established by a bequest to McGill University in 1965, has been awarded to John J.J.V. McMurray, MD, of the University of Glasgow. McMurray has dedicated much of his career to heart failure, with more than 900 publications ranging from basic research and epidemiology to the design and completion of numerous clinical trials that have altered our understanding of the condition and its treatment and prognosis. “He’s done a tremendous amount that is clinically relevant and has resulted in new medications for heart failure. He was head and shoulders above the other applicants this year, with an incredible track record and extensive publications,” says James Martin, MD, chair of the McGill University department of medicine and chair of the Lucian Committee. As McMurray was completing medical school, American and European investigators were beginning to understand the disease mechanisms of heart failure and to identify targets for treatment other than digoxin and diuretics. At that time, there was no way to directly influence the weakness in cardiac contraction underlying heart failure, but inappropriate and sustained activation of the renin–angiotensin–aldosterone system (RAAS) helped explain why the function of blood vessels, kidneys, and heart muscle deteriorated over time. Shortly after the introduction of the angiotensin-converting enzyme (ACE) inhibitor captopril, McMurray witnessed the Lazarus-like recovery and discharge from the hospital of an extremely ill woman with heart failure after she was given the new drug—spurring a career-long interest in heart failure. After 2 years of residency training, McMurray obtained a cardiovascular research fellowship in Dundee, Scotland, where physician scientist Allan Struthers was studying cardiac natriuretic peptides, newly described hormones produced by the heart, which helped that organ protect itself and the whole body from volume and pressure overload by, among other things, …
Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai Translational Mission Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Roger J. Hajjar, Kiyotake Ishikawa, Jason C. Kovacic, Valentin Fuster
The Cardiovascular Research Center (CVRC) at Icahn School of Medicine at Mount Sinai was established in 2007 and is focused on advancing our knowledge of cardiovascular diseases and translating these discoveries into effective therapies. The CVRC is currently housed in The Leon and Norma Hess Center for Science and Medicine, a state-of-the-art clinical and research facility in New York’s Upper East Side. The Center is part of the Mount Sinai Health System, comprised of the Icahn School of Medicine at Mount Sinai and 7 other hospital campuses throughout the New York Metropolitan Area. Since its inception, the CVRC has grown to include ≈75 members composed of physicians, physician-scientists, postdoctoral fellows, research scientists, and technicians. Our team of lead investigators and researchers work across platforms to investigate cardiac and stem cell biology, tissue engineering, vector biology, cardiac physiology, electrophysiology, vascular diseases, metabolic disorders, imaging, and clinical trials. Close collaboration and shared vision among the investigators glean fundamental insights into cardiovascular physiology and pathobiology, which illuminate potential avenues for therapeutic treatment. The Center currently has 2 full professors, 5 associate professors, 10 assistant professors, and 4 instructors in medicine/cardiology. In 2017, total National Institutes of Health funding increased to >14 million dollars. In addition to 15 R01s, 3 K awards, and an F30, the CVRC is home to 3 Transatlantic Leducq Foundation grants, 4 American Heart Association postdoctoral fellowships, 4 American Heart Association Scientist Development grants, an American Heart Association Strategically Focused Research Network, a Department of Defence Concept Award, and a National Institutes of Health S10 Shared Instrument grant. We have also recently acquired funding from 2 biotechnology companies. Figure shows the junior and senior investigators at the Cardiovascular Research Center. Junior and senior investigators at the Cardiovascular Research Center. Front row (left to right): Anthony Fargnoli, Irene Turnbull, Ah …
CANTOS Circ. Res. (IF 13.965) Pub Date : 2017-12-08 Borja Ibañez, Valentin Fuster
Cumulative evidence links inflammation with atherothrombotic disease. Conversely, the role of modulating the inflammatory process as a therapeutic target has remain an unproven hypothesis until the execution of the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). On the one hand, this trial provides robust evidence that interleukin-1β (IL-1β) inhibition by canakinumab reduces the incidence of repetitive atherothrombotic events in patients with postmyocardial infarction already on state-of-the-art treatment but with a residual inflammatory risk. On the other hand, the absolute antiatherothrombotic effect size of this intervention seems small (189 patients had to be intervened during 1 year to prevent 1 myocardial infarction episode) and associated with a mild increase in the incidence of serious adverse events (≈1 in 750 patients intervened during 1 year developed a fatal infection or sepsis). Beyond all these considerations, CANTOS represents a gigantic (10 000 patients) proof-of-concept trial. Atherosclerosis is a systemic disease with a long clinically silent phase. Arterial wall lipid deposition, the hallmark of atherosclerosis, begins early in life. Atherosclerotic plaques grow gradually for several years, the disease becoming clinically overt only when the plaque is large enough to restrict blood flow or becomes unstable and ruptures, causing a thrombus. From its earliest asymptomatic phase through to the late clinical manifest stages, atherosclerosis is predominantly an inflammatory disease, featuring leukocyte activation, cytokine release, and infiltration by eosinophils, neutrophils, and macrophages. Epidemiological studies have revealed that circulating inflammatory biomarkers, especially C-reactive protein (CRP) measured by a high sensitivity (hs) assay, are associated with a higher incidence of atherothrombotic events (myocardial infarction, stroke, etc.).1 All these observations suggested that strategies to reduce inflammation would lead to a reduction in atherothrombotic events. However, it is important to note that the evidence linking inflammation to atherosclerosis is associative, and evidence for a causal role of inflammation in atherothrombotic …
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
- Acc. Chem. Res.
- ACS Appl. Mater. Interfaces
- ACS Biomater. Sci. Eng.
- ACS Catal.
- ACS Cent. Sci.
- ACS Chem. Biol.
- ACS Chem. Neurosci.
- ACS Comb. Sci.
- ACS Earth Space Chem.
- ACS Energy Lett.
- ACS Infect. Dis.
- ACS Macro Lett.
- ACS Med. Chem. Lett.
- ACS Nano
- ACS Omega
- ACS Photonics
- ACS Sens.
- ACS Sustainable Chem. Eng.
- ACS Synth. Biol.
- Acta Biomater.
- Acta Mater.
- Adv. Colloid Interface Sci.
- Adv. Electron. Mater.
- Adv. Energy Mater.
- Adv. Funct. Mater.
- Adv. Healthcare Mater.
- Adv. Mater.
- Adv. Mater. Interfaces
- Adv. Opt. Mater.
- Adv. Sci.
- Adv. Synth. Catal.
- AlChE J.
- Anal. Bioanal. Chem.
- Anal. Chem.
- Anal. Chim. Acta
- Anal. Methods
- Angew. Chem. Int. Ed.
- Annu. Rev. Anal. Chem.
- Annu. Rev. Biochem.
- Annu. Rev. Food Sci. Technol.
- Annu. Rev. Mater. Res.
- Annu. Rev. Phys. Chem.
- Appl. Catal. A Gen.
- Appl. Catal. B Environ.
- Appl. Clay. Sci.
- Appl. Energy
- Aquat. Toxicol.
- Arab. J. Chem.
- Asian J. Org. Chem.
- Atmos. Environ.
- Carbohydr. Polym.
- Catal. Commun.
- Catal. Sci. Technol.
- Catal. Today
- Cell Chem. Bio.
- Cem. Concr. Res.
- Ceram. Int.
- Chem. Asian J.
- Chem. Bio. Drug Des.
- Chem. Biol. Interact.
- Chem. Commun.
- Chem. Educ. Res. Pract.
- Chem. Eng. J.
- Chem. Eng. Sci.
- Chem. Eur. J.
- Chem. Mater.
- Chem. Phys.
- Chem. Phys. Lett.
- Chem. Phys. Lipids
- Chem. Rev.
- Chem. Sci.
- Chem. Soc. Rev.
- Combust. Flame
- Compos. Part A Appl. Sci. Manuf.
- Compos. Sci. Technol.
- Compr. Rev. Food Sci. Food Saf.
- Comput. Chem. Eng.
- Constr. Build. Mater.
- Coordin. Chem. Rev.
- Corros. Sci.
- Crit. Rev. Food Sci. Nutr.
- Crit. Rev. Solid State Mater. Sci.
- Cryst. Growth Des.
- Curr. Opin. Chem. Eng.
- Curr. Opin. Colloid Interface Sci.
- Curr. Opin. Environ. Sustain
- Curr. Opin. Solid State Mater. Sci.
- Ecotox. Environ. Safe.
- Electrochem. Commun.
- Electrochim. Acta
- Energy Environ. Sci.
- Energy Fuels
- Environ. Impact Assess. Rev.
- Environ. Int.
- Environ. Model. Softw.
- Environ. Pollut.
- Environ. Res.
- Environ. Sci. Policy
- Environ. Sci. Technol.
- Environ. Sci. Technol. Lett.
- Environ. Sci.: Nano
- Environ. Sci.: Processes Impacts
- Environ. Sci.: Water Res. Technol.
- Eur. J. Inorg. Chem.
- Eur. J. Med. Chem.
- Eur. J. Org. Chem.
- Eur. Polym. J.
- J. Acad. Nutr. Diet.
- J. Agric. Food Chem.
- J. Alloys Compd.
- J. Am. Ceram. Soc.
- J. Am. Chem. Soc.
- J. Am. Soc. Mass Spectrom.
- J. Anal. Appl. Pyrol.
- J. Anal. At. Spectrom.
- J. Antibiot.
- J. Catal.
- J. Chem. Educ.
- J. Chem. Eng. Data
- J. Chem. Inf. Model.
- J. Chem. Phys.
- J. Chem. Theory Comput.
- J. Chromatogr. A
- J. Chromatogr. B
- J. Clean. Prod.
- J. CO2 UTIL.
- J. Colloid Interface Sci.
- J. Comput. Chem.
- J. Cryst. Growth
- J. Dairy Sci.
- J. Electroanal. Chem.
- J. Electrochem. Soc.
- J. Environ. Manage.
- J. Eur. Ceram. Soc.
- J. Fluorine Chem.
- J. Food Drug Anal.
- J. Food Eng.
- J. Food Sci.
- J. Funct. Foods
- J. Hazard. Mater.
- J. Hydrol.
- J. Ind. Eng. Chem.
- J. Inorg. Biochem.
- J. Magn. Magn. Mater.
- J. Mater. Chem. A
- J. Mater. Chem. B
- J. Mater. Chem. C
- J. Mater. Process. Tech.
- J. Mech. Behav. Biomed. Mater.
- J. Med. Chem.
- J. Membr. Sci.
- J. Mol. Catal. A Chem.
- J. Mol. Liq.
- J. Nat. Gas Sci. Eng.
- J. Nat. Prod.
- J. Nucl. Mater.
- J. Org. Chem.
- J. Photochem. Photobiol. C Photochem. Rev.
- J. Phys. Chem. A
- J. Phys. Chem. B
- J. Phys. Chem. C
- J. Phys. Chem. Lett.
- J. Porphyr. Phthalocyanines
- J. Power Sources
- J. Solid State Chem.
- J. Taiwan Inst. Chem. E.
- Macromol. Rapid Commun.
- Mass Spectrom. Rev.
- Mater. Chem. Front.
- Mater. Des.
- Mater. Horiz.
- Mater. Lett.
- Mater. Sci. Eng. A
- Mater. Sci. Eng. R Rep.
- Mater. Today
- Meat Sci.
- Med. Chem. Commun.
- Microchem. J.
- Microchim. Acta
- Micropor. Mesopor. Mater.
- Mol. Biosyst.
- Mol. Cancer Ther.
- Mol. Catal.
- Mol. Nutr. Food Res.
- Mol. Pharmaceutics
- Mol. Syst. Des. Eng.
- Nano Energy
- Nano Lett.
- Nano Res.
- Nano Today
- Nano-Micro Lett.
- Nanoscale Horiz.
- Nat. Catal.
- Nat. Chem.
- Nat. Chem. Biol.
- Nat. Commun.
- Nat. Energy
- Nat. Mater.
- Nat. Med.
- Nat. Methods
- Nat. Nanotech.
- Nat. Photon.
- Nat. Prod. Rep.
- Nat. Protoc.
- Nat. Rev. Chem.
- Nat. Rev. Drug. Disc.
- Nat. Rev. Mater.
- Neurochem. Int.
- New J. Chem.
- NPG Asia Mater.
- npj 2D Mater. Appl.
- npj Comput. Mater.
- npj Flex. Electron.
- npj Mater. Degrad.
- npj Sci. Food
- Pharmacol. Rev.
- Pharmacol. Therapeut.
- Photochem. Photobiol. Sci.
- Phys. Chem. Chem. Phys.
- Phys. Life Rev.
- PLOS ONE
- Polym. Chem.
- Polym. Degrad. Stabil.
- Polym. J.
- Polym. Rev.
- Powder Technol.
- Proc. Combust. Inst.
- Prog. Cryst. Growth Ch. Mater.
- Prog. Energy Combust. Sci.
- Prog. Mater. Sci.
- Prog. Photovoltaics
- Prog. Polym. Sci.
- Prog. Solid State Chem.