Alexandra Le Bras

Exosome-based therapy to repair the injured heart

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Cardiology Pharmacological and surgical interventions after myocardial infarction (MI) improve clinical outcome but do not restore the function of the damaged tissue. Investigators are therefore exploring new strategies for cardiac repair after MI, including the delivery of stem cells or cardiac muscle cells to the injured heart; however, the cells tend to cause arrhythmias, and their effects and mode of action remain unclear. A study describes a new cellfree therapy that improves cardiac recovery after MI in rats through the delivery of exosomes isolated from cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCMs). “We asked ourselves if we could achieve the benefits of the cell therapy of the heart without using the cells,” explains lead investigator Gordana VunjakNovakovic. Cell transplantations improve cardiac function after MI despite low cell retention in the heart, a ‘hitandrun’ mechanism that suggests that the cell secretome mediates cardiac repair. Previous studies have shown that extracellular vesicles (EVs) secreted by stem or progenitor cells can improve cardiac repair; VunjakNovakovic and colleagues hypothesized that EVs from iPSCMs (iCMEVs) would be more therapeutic than EVs from iPS cells (iPSEVs), given their cardiacspecific components. Bioactive molecules in EVs include microRNAs (miRNAs), and miRNA profiling confirmed that iCMEVs are enriched in miRNAs that target genes involved in cardiac processes and hypertrophy compared with iPSEVs. Human iPSEVs and iCMEVs were packaged into hydrogel patches and placed on the myocardium of rats after MI. iCMEVs reduced cardiac dilatation and improved function compared with iPSEVs or no treatment at 2 weeks after MI. Additionally, delivery of iCMEVs but not iPSEVs significantly reduced infarct size and cardiomyocyte hypertrophy compared with no treatment at 4 weeks after MI. iCMEVs were also not arrhythmogenic and reduced apoptosis in the injured heart. “We are very excited about the prospects of this treatment. An advantage of this cellfree approach would be the largely simplified FDA regulatory procedure,” concludes VunjakNovakovic.

Cardiac lymphatics mediate the resolution of inflammation

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Cardiology Cardiac lymphatics expand in mouse hearts after myocardial infarction (Mi); treatment with vascular endothelial growth factor C (veGFC) increases this lymphangiogenic response, which improves cardiac function. according to a new study, the expansion of lymphatic vessels after Mi promotes heart repair by increasing immune cell clearance. a previous study suggested that veGFC-induced lymphangiogenesis improves cardiac outcome after Mi by restoring interstitial fluid equilibrium. Paul riley and colleagues hypothesized that lymphatic vessels in the heart might also influence the immune response after injury, a phenomenon already described in peripheral tissues during wound healing. “this is an entirely novel finding that was not previously appreciated in the context of heart injury,” says riley. in mice treated with veGFC, the number of immune cells in cardiac tissue was reduced 7 days after Mi compared with vehicletreated mice, but unchanged at earlier time points, when lymphatic sprouting had not yet occurred, suggesting that lymphangiogenesis accelerates the resolution of inflammation after Mi. the constitutive deletion of lymphatic vessel endothelial hyaluronic acid receptor 1 (LYve1) did not affect cardiac lymphangiogenesis at day 7 after Mi, but Lyve1─/─ mice had an increased number of leukocytes in the heart compared with wildtype mice, whereas the number was reduced in mediastinal lymph nodes. at day 21 after Mi, Lyve1─/─ mice showed reduced cardiac function and increased scarring compared with wildtype mice. together, these results indicate that the clearance of immune cells by the lymphatics is dependent on LYve1 and regulates cardiac outcome after Mi. “this study highlights the cardiac lymphatics as a potential therapeutic target in ischaemic heart disease, but also demonstrates the need to condition the local inflammatory environment in the context of cardiovascular injury as an essential parallel strategy to cellbased repair or regeneration,” explains riley, adding that future studies include the screening of smallmolecule inducers of lymphangiogenesis and immune cell clearance as the first stage of a drugdiscovery pipeline. Alexandra Le Bras AC U T E C O R O N A RY S Y N D R O M E S

Dynamics of fibroblast activation in the infarcted heart

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Cardiology After myocardial infarction (MI), which causes a substantial loss of cardiomyocytes, fibroblasts are activated, proliferate, and differentiate into extracellular matrix (ECM)-producing myofibroblasts that contribute to the formation of a fibrotic scar in the wounded area. In the non-regenerative heart, the scar persists, stabilized by fibroblasts that revert to a quiescent state. A new study provides further insights into the phenotypic changes of cardiac fibroblasts during scar formation. “Fibroblasts are absolutely critical for acute healing of the heart after injury,” explains lead study investigator Jeffery Molkentin, “yet at the same time, overzealous long-term activation of fibroblasts in more chronic heart disease states can hasten the demise of the heart.” Molkentin remarks that studies into heart diseases have now started to focus on fibroblasts, with the recent advent of new genetic tools to investigate this cell type. In this study, Molkentin and colleagues used three inducible, lineage-tracing mouse models, Tcf21–MerCreMer, Postn– MerCreMer, and Acta2–CreER, to reliably identify fibroblast dynamics and differentiated stages in the heart after MI. Analysis of the Tcf21–MerCreMer reporter system, which targets the majority of the tissue-resident cardiac fibroblasts, showed that fibroblast proliferation occurred in the first week after MI in the infarct and border regions, reaching a peak of 3.5-fold expansion at 2–4 days compared with uninjured areas. The fibroblast content in injured regions persisted for weeks, suggesting that these new fibroblasts are robust and do not undergo cell turnover. Activated fibroblasts, labelled using the Postn– MerCreMer system, were shown to derive from Tcf21-traced cells 4 days after MI. Postn-traced cells had similar proliferation dynamics as Tcf21-labelled cells, expressed smooth muscle α-actin (αSMA) — a myofibroblast marker encoded by Acta2 — at 4–7 days after MI, and showed no significant proliferation rates or αSMA expression 2 weeks after MI. Acta2–lineage tracing confirmed that myofibroblasts appear at day 3–4 after MI, and lose αSMA expression by 10 days after MI. Altogether, these findings demonstrate that myofibroblasts are not a long-lasting differentiated state of fibroblasts, and that fibroblasts transition to an alternate stage refractory to proliferation by 10–14 days after MI. Histological analysis of the scar also revealed that the loss of αSMA expression and myofibroblast phenotype preceded the reorganization of the ECM associated with scar maturation, suggesting that myofibroblasts are a transient cellular support network that preserves ventricular wall integrity before collagen accumulation. mRNA profiling of Tcf21-lineage traced cells at different time points revealed that the greatest differences in gene expression between fibroblasts from infarcted hearts and fibroblasts from healthy hearts occurred 3 days after MI. Fibroblasts isolated 4 weeks after MI were the most related to the quiescent, uninjured fibroblast phenotype, but differentially expressed a unique panel of genes, including Comp, Chad, and Clip2, that is usually expressed by chondroblasts and osteoblasts. The investigators referred to this unique fibroblast phenotype as the matrifibrocyte. “We propose that the matrifibrocyte is a MI scar-specific differentiated state of the cardiac fibroblast that underlies the long-term stability of the fibrotic scar itself,” explains Molkentin. “Our hopes are that better molecular characterization of the specific stages of fibroblast differentiation, along with an understanding of their nodal regulatory pathways, will permit better targeted therapies to control these cells in the heart,” he concludes. “This is a very well executed study that confirms the existing conceptual paradigm on the cell biological dynamics of fibroblast activation in the infarcted myocardium using robust new genetic tools,” says Nikolaos Frangogiannis, who was not involved in the study. Frangogiannis explains that several questions remain unanswered, including whether different functional fibroblast subsets regulate different processes in the heart, such as ECM remodelling, inflammation, angiogenesis, or repair. “Answers to these questions are critical to design interventions that target detrimental effects of fibroblasts while preserving their reparative functions,” he adds. Alexandra Le Bras A C U T E C O R O N A R Y S Y N D R O M E

Targeting the gut to protect the heart

production as a therapeutic strategy to reduce the risk of cardiovascular disease (CVD). In 2015, the group reported that a natural product found in cold-pressed extra-virgin olive oil, 3,3-dimethyl-1-butanol (DMB), inhibits microbiotal choline TMA lyase activity, leading to reductions in plasma TMAO level and in atherosclerotic lesion development in mice. In the past 3 years, additional studies have demonstrated that TMAO can also increase platelet hyperactivity and the risk of thrombosis; Hazen and his group therefore thought to investigate the effects of DMB on platelet responsiveness in mice fed with a choline-supplemented diet. Exposure to DMB significantly reduced TMAO plasma level and stimulus-dependent platelet aggregation, but despite the high doses of DMB administered, TMAO plasma level could not be reduced to the level of TMAO observed in chow-fed mice. In an effort to develop a generation of more potent choline TMA lyase inhibitors, a new class of suicide substrates, including choline analogues iodomethylcholine (IMC) and fluoromethylcholine (FMC), were designed to irreversibly inactivate choline TMA lyase activity. In vitro, the potency of IMC was 10,000-times greater than that of DMB. In mice receiving a choline-supplemented diet, a single dose of IMC or FMC resulted in >95% reduction in plasma TMAO levels (P < 0.0001) after 24 h compared with no treatment. Functionally, the inhibitors completely suppressed the effects of choline supplementation on platelet responsiveness and, in a model of carotid artery injury, reduced the time to thrombus formation in choline-fed mice beyond that observed in chow-fed

GWAS identifies new blood lipid-associated genetic variants

Transcatheter mitral valve repair improves outcomes in patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation compared with medical therapy alone, according to data from the COAPT trial, presented at the 2018 TCT conference. A total of 614 patients were randomly assigned to receive a MitraClip device (Abbott) plus medical therapy or medical therapy alone. During 24 months of follow-up, the rate of the primary end point (hospitalizations for heart failure) was 35.8% per patient-year in the device group versus 67.9% per patient-year in the control group (HR 0.53, 95% CI 0.40–0.70, P < 0.001). The rate of the primary safety end point (freedom from device-related complication at 12 months) in the device group was 96.6%, which exceeded the prespecified objective performance goal of 88.0% (P < 0.001). All-cause mortality within 24 months was 29.1% and 46.1% in each group, respectively (HR 0.62, 95% CI 0.46–0.82, P < 0.001).

Ticagrelor not superior to DAPT after PCI

The weightloss drug lorcaserin is safe and not associated with an increased rate of cardiovascularu200bevents,u200baccordingu200btou200bdatau200b presented at the 2018 eSC Congress. Lorcaserinu200bisu200bau200bselectiveu200bagonistu200bofu200btheu200b 5-hydroxytryptamine receptor 2C, which is involvedu200binu200btheu200bregulationu200bofu200bappetite.u200b Theu200bdrugu200bwasu200bshownu200binu200bpreviousu200btrialsu200btou200bbeu200b effectiveu200bforu200bpromotingu200bweightu200blossu200bandu200bwasu200b consequentlyu200bapprovedu200bbyu200btheu200bFDAu200binu200b2012u200b as an adjunct to a reducedcalorie diet andu200bincreasedu200bphysicalu200bactivityu200bforu200blongtermu200bweightu200bmanagement.u200bHowever,u200botheru200b weight-lossu200bdrugsu200bhaveu200bhadu200banu200badverseu200b cardiovascularu200brisku200bprofile,u200bsou200btheu200b CAMELLIA-TIMIu200b61u200btrialu200bwasu200binitiatedu200btou200b testu200btheu200bcardiovascularu200bsafetyu200bandu200befficacyu200b of lorcaserin. A total of 12,000 patients who were overweightu200boru200bobeseu200b(BMIu200b≥27) with establishedu200batheroscleroticu200bcardiovascularu200b diseaseu200boru200bmultipleu200bcardiovascularu200brisku200bfactorsu200b wereu200brandomlyu200bassignedu200btou200breceiveu200beitheru200b lorcaserin (10 mg twice daily) or placebo. At 1 year, weight loss of ≥5% had occurred in 38.7% of patients in the lorcaserin group and inu200b17.4%u200bofu200bpatientsu200binu200btheu200bplacebou200bgroupu200b (ORu200b3.01,u200b95%u200bCIu200b2.74–3.30,u200bP < 0.001). During followup (median 3.3 years), the rate of the primary safety outcome (au200bcompositeu200bofu200bcardiovascularu200bdeath,u200b myocardial infarction, or stroke) was 2.0% andu200b2.1%u200bperu200byearu200binu200beachu200bgroup,u200brespectivelyu200b (HRu200b0.99,u200b95%u200bCIu200b0.85–1.14,u200bP < 0.001 for noninferiority). The rate of the primary cardiovascularu200befficacyu200bendu200bpointu200b(extendedu200b majoru200bcardiovascularu200bevents)u200bwasu200bnotu200b significantly different between the two groupsu200b(4.1%u200bversusu200b4.2%u200bperu200byear). Theu200bratesu200bofu200badverseu200beventsu200bwereu200bgenerallyu200b similaru200binu200bbothu200bgroups;u200bhowever,u200bmoreu200bpatientsu200b in the lorcaserin group than in the placebo groupu200bdevelopedu200bseriousu200bhypoglycaemiau200b (13u200bversusu200b4;u200bP =u200b0.04).u200b“Liraglutideu200b[au200bGLP1u200b receptoru200bagonist]u200bwouldu200bprovideu200bau200bsimilaru200b degree of weight loss but a lower risk of diabetesu200b[mellitus],”u200bcommentu200bJulieu200b Ingelfinger and Clifford Rosen in an accompanying editorial. Accordingly, they adviseu200bthatu200blorcaserinu200b“mayu200bbeu200bbestu200busedu200bonu200bau200b cautious basis according to the needs of individualu200bpatients”. Gregory B. Lim The presence of secondary mitral regurgitation, characterizedu200bbyu200bau200bstructurallyu200bnormalu200bvalveu200b with regurgitation resulting from a dilated leftu200bventricleu200bwithu200bpooru200bfunction,u200bisu200bau200bpredictoru200b of poor clinical outcomes for patients with heart failure. Reducing the regurgitation with surgeryu200boru200bpercutaneousu200binterventionu200bhasu200b beenu200bproposedu200btou200bimproveu200boutcomesu200binu200btheseu200b patients;u200binu200bparticular,u200bpercutaneousu200brepairu200b with a mitraClip (Abbott vascular) is becoming moreu200bfrequent.u200bHowever,u200bonlyu200blow-levelu200b evidenceu200bisu200bavailableu200btou200bsupportu200btheseu200b approaches. A randomized clinical trial presented at the eSC Congress now shows that inu200bpatientsu200bwithu200bchronicu200bheartu200bfailureu200bandu200bsevereu200b secondary mitral regurgitation, percutaneous mitralu200bvalveu200brepairu200bwithu200bau200bMitraClipu200binu200badditionu200b tou200bmedicalu200btherapy,u200balthoughu200beffectiveu200binu200b reducingu200bregurgitation,u200bdoesu200bnotu200bimproveu200b survivalu200boru200bsymptomsu200bcomparedu200bwithu200bmedicalu200b therapy alone. Theu200btrialu200bincludedu200b304u200bpatientsu200bwithu200bsevereu200b secondary mitral regurgitation and symptomatic heartu200bfailureu200bwithu200bleftu200bventricularu200bejectionu200b fractionu200b15–40%u200bwhou200bwereu200brandomlyu200bassignedu200b tou200bpercutaneousu200bmitralu200bvalveu200brepairu200bwithu200bau200b mitraClip in addition to optimal medical treatment or to optimal medical therapy alone. The mitraClip was safe and significantly reduced mitral regurgitation, with a procedural successu200brateu200bofu200b95.8%.u200bHowever,u200bafteru200b1u200byear,u200b the rate of the primary end point (all-cause death or unplanned hospitalization for heartu200bfailure)u200bandu200btheu200bratesu200bofu200btheu200bindividualu200b components were similar in both groups. “Theseu200bresultsu200bshouldu200bencourageu200bau200bmoreu200b accurate selection of patients with heart failure beforeu200bconsideringu200bmitralu200bvalveu200brepair,”u200bremarksu200b leadu200binvestigatoru200bJean-Françoisu200bObadia.u200b“Moreu200b randomized studies are necessary to define possible subgroups of patients who could really benefitu200bfromu200bmitralu200bvalveu200brepair,”u200bheu200bconcludes.

Radial-artery versus saphenous-vein grafts

The majority of patients undergoing CABG surgery receive a saphenousvein graft, but a new study provides evidence that use of radialartery grafts improves clinical outcomes after CABG surgery compared with use of saphenousvein grafts. A total of 1,036 patients were included in this analysis of six randomized controlled trials that compared radialartery grafting (534 patients) with saphenousvein grafting (502 patients). At 5 years of followup, the risks of myocardial infarction (HR 0.72; P = 0.04) and of repeat vascularization (HR 0.50; P < 0.001) were significantly lower in the radialartery graft group than in the saphenousvein graft group. Use of radialartery grafts was also associated with a lower risk of occlusion. These findings support the current guidelines, which recommend the use of arterial grafts for CABG surgery.

Publisher Correction: Exosome-based therapy to repair the injured heart

The article originally published online contained an error in the figure in which the scale bar was incorrectly associated with a value of 100u2009µm. This error has been corrected in the HTML and PDF versions of the article to associate the scale bar with the correct value of 1u2009mm.The article originally published online contained an error in the figure in which the scale bar was incorrectly associated with a value of 100u2009µm. This error has been corrected in the HTML and PDF versions of the article to associate the scale bar with the correct value of 1u2009mm.

Genetic variation explains residual CHD risk with statin therapy

Statins decrease the incidence of coronary heart disease (CHD) by reducing the levels of plasma LDL cholesterol (LDLC), but some individuals still have CHD events despite receiving statin therapy. New research provides a genetic explanation to this interindividual variability. Genotyping of 3,099 individuals with CHD events and 7,681 individuals without CHD events, both groups on statin therapy, identified seven single nucleotide polymorphisms (SNPs) that were associated with CHD and were located in the LPA gene, which encodes apolipoprotein(a) (Lp(a)). The SNP rs10455872 showed the strongest association with CHD, and individuals carrying this risk variant had a 58% increased risk of CHD events compared with noncarriers. This association was independent of LDLC changes in response to statin therapy and persisted in individuals with LDLC ≤70 mg/dl. A previous study also showed that rs10455872 is associated with increased plasma Lp(a) levels, an indicator of high risk of CHD. Thus, strategies to lower Lp(a) levels might reduce CHD incidence in patients receiving statin therapy.

Basic research: Visceral adipose tissue regulates cardiac ageing

Pu bl is he rs L im it ed Osteopontin (OPN) is a matricellular protein that is upregulated in models of pathological cardiac fibrosis and remodelling. OPN plasma levels also increase with age, and a new study published in Circulation reveals that OPN secreted by visceral adipose tissue (VAT) promotes age-associated interstitial fibrosis in the heart. Ageing induces structural changes in the heart, notably fibrotic remodelling, which impairs cardiac function. Several matricellular proteins have previously been implicated in fibrotic cardiomyopathy in ageing individuals but the role and source of OPN during cardiac ageing are unknown. Sawaki and colleagues analysed OPN expression in tissues from young and aged mice and showed that VAT is the main source of OPN during ageing, whereas the myocardium expresses a low, stable level of OPN. Surgical removal of VAT in aged mice reduced levels of OPN and the profibrotic cytokine transforming growth factor-β1 in the circulation, decreased cardiac fibrosis, and improved myocardial function. Knocking out Opn abolished the increase in myocardial interstitial fibrosis and the reduction in myocardial contractility associated with ageing. B A S I C R E S E A R C H