Use your head and your heart: a brain injury biomarker shows promise in assessing myocarditis Research published in the Journal of Cardiovascular Translational Research has highlighted the use of a brain injury biomarker, translocator protein 18 kDa (TSPO), in assessing the severity of myo­ carditis. It is proposed that this marker may lead to the design of a novel noninvasive test for inflammation of the heart. Myocarditis, heart inflammation, can lead to heart failure and mortality, yet currently there is no noninvasive test to diagnose the condition. Confirmation of diagnosis requires a biopsy, which can put the patient at risk and does not always pick up the condition, meaning many patients may be unaware that they are suffering from myocarditis at all. Investigators from Columbia Univer­ sity’s Mailman School of Public Health (NY, USA), Johns Hopkins (MD, USA) and the Mayo Clinic (MN, USA) aimed to tackle these current pitfalls by evaluat­ ing whether a marker for brain inflam­ mation could be translated to the heart. Once physicians have determined the damage to the brain after injury, a PET scan is used to iden­ tify whether levels of the marker in question, TSPO, which is present through­ out the body in immune cells, are elevated. The present research involved the assessment of TSPO in biopsied tissue from both humans and mice with myocarditis by singlephoton emission computed tomography imaging. Single-photon emission computed tomography findings indicated TSPO levels were higher in male mice when

10.2217/FCA.14.11 © 2014 Future Medicine Ltd

compared with controls, further genetic testing highlighted elevated TSPO in men with myocarditis also. Levels of CD11b (a marker for TSPO-containing immune cells) were also assessed and revealed to be increased in these individuals. The inves­ tigators state that the gender differences are dye to sex hormones with TSPO play­ ing an important part in their metabolism. “Testosterone amplifies inflammation in a bad way that leads to permanent damage in the heart and heart failure,” comments DeLisa Fairweather (Johns Hopkins). “This is why men are at greater risk for myocarditis and all heart conditions related to inflammation.” Fairweather also states, “We should be able to detect the acute stage of inflammation in women and determine if they are at a risk to progress to heart failure.” Further strengthening TSPO’s role as a biomarker the researchers propose that it may impact a patients prognosis. Fairweather reports “TSPO is directly related to whether patients are going to develop severe myocar­ ditis and hea rt

in the news... • Lead story: Use your head and your

heart: a brain injury biomarker shows promise in assessing myocarditis

• Milestone in pacemaker history:

first postapproval implantation of Nanostim™ in UK pg 162 

• Riociguat recommended by CHMP

for approval in the EU for use in two forms of pulmonary hypertension pg 163

• Promising results for future

predicative test of myocardial infarction pg 163

• High-density lipoproteins may offer

a more promising route to statin therapy pg 164

• PROGNOSIS looking good for a

possible serum test for preeclampsia pg 164

• Priority Paper Alerts pg 165

part of

Future Cardiol. (2014) 10(2), 161–165

ISSN 1479-6678


BULLETIN BOARD failure. That means it’s important to look at for its prognostic value.” The future of this research will likely involve the completion of a small trial at Mayo Clinic. This would aim to determine if inflammation in myocarditis patients could be detected by TSPO. Following this, larger studies with noninf lamed patients would be necessary to identify a threshold for the TSPO level, which would

diagnose myocarditis and in the long term may lead to a noninvasive method for confirming a myocarditis diagnosis. Tomas Guilarte (Columbia’s Mailman School) who is a key figure in TSPO research concludes, “Our latest study is a major milestone because it demonstrates that we can take what we learned about TSPO in the brain and draw lessons for the heart. Indeed, TSPO will likely have

implications for other organ systems. At the same time, we should be able to take what we are learning about TSPO in the heart and apply it to our continuing TSPO research in the brain.” – Written by Elizabeth Webb Illustration by Amy O’Donnell Source: Columbia University Mailman School of Public Health press release: www.mailman.columbia.edu/ news/brain-biomarker-shows-promise-heart

Milestone in pacemaker history: first postapproval implantation of Nanostim™ in UK January 2014 saw the first postapproval implant of the Nanostim™ leadless pacemaker (St Jude Medical, MN, USA) in the UK. The world’s first retrievable leadless pacemaker was implanted at St Bartholomew’s Hospital (London) by Professor Richard Schilling.

“...the Nanostim leadless pacemaker is designed to be placed directly in the heart without the visible surgical pocket, scar and leads required for conventional pacemakers.” The patient, a 77-year-old female, became the first person in the UK to receive the device. Having dealt with persistent atrial fibrillation for over a decade, the patient experienced periods of dizziness and fatigue often, which pre­ vented the undertaking of routine activi­ ties. In some extreme cases, the patient’s abnormal heart rhythm resulted in epi­ sodes where her heart would stop beat­ ing for up to 5 s at a time. The procedure took just 8 min to perform. As reported in the ‘News and Views’ in sister journal Interventional Cardiology in December 2013 shortly after CE approval of the device, the Nanostim leadless pacemaker is designed to be placed directly in the heart without the visible surgical pocket, scar and leads required for conventional pacemakers. Implanted via the femoral vein with a


steerable catheter, the device offers a lessinvasive approach for physicians com­ pared to traditional pacemaker proce­ dures that require more invasive surgery. The device is designed to be fully retriev­ able so that it can be readily repositioned throughout the implant procedure and later retrieved if necessary. Commenting on the new pacemaker technology, Schilling said, “This min­ iaturized, minimally invasive car­ diac pacemaker offers my patients the potential for reduced complications like infection and aesthetic benefits over con­ ventional pacemakers, in addition to quicker recovery times. We are delighted to have conducted the first implants of this ground-breaking technology at St Bartholomew’s Hospital in the UK.”

“...the removal of patient activity restrictions that may prevent the dislodgement or damage to a conventional lead, will potentially improve the quality of life for patients with this technology...” There are numerous advantages with the new device over conventional pacemakers, including the smaller size (Nanostim is less than 10% of the size of conventional pacemakers), which along with the lack of a surgical pocket, coupled with the exclusion of a lead, improves patient comfort and can reduce compli­ cations, including device pocket-related

Future Cardiol. (2014) 10(2)

infection and lead failure. The elimi­ nation of the visible lump and scar at a conventional pacemaker’s implant site, in addition to the removal of patient activ­ ity restrictions that may prevent the dis­ lodgement or damage to a conventional lead, will potentially improve the quality of life for patients with this technology by allowing most to continue living active, uninhibited lifestyles. Initial results from the LEADLESS study, a prospective, single-arm, multi­ center study evaluating patients with the Nanostim leadless pacemaker, were pre­ sented earlier this year and demonstrated overall device performance comparable to conventional pacemakers. Total implant procedure times averaged 28 min. Even with miniaturization, the device battery is expected to have an average lifespan of more than 9 years at 100% pacing, or more than 13 years at 50% pacing. The Nanostim leadless pacemaker recently received CE mark approval and is now available in select European mar­ kets. The Nanostim leadless pacemaker is not available for sale in the USA. – Written by Michael Dowdall Sources: Dowdall M. World’s first leadless pacemaker receives CE mark approval and is acquired by St Jude Medical. Interv. Cardiol. 5(6), 605–606 (2013); St Jude Medical announces implant of world’s first leadless pacemaker in the UK: www.sjm.com/~/ media/SJM/corporate/Media%20Kits/nanostim/ Nanostim%20First%20Implant%20Press%20Release_UK_FINAL.ashx

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Riociguat recommended by CHMP for approval in the EU for use in two forms of pulmonary hypertension The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval for riociguat tablets (Bayer Healthcare, Leverkusen, Germany) for use in two forms of pulmonary hyper­ tension: the treatment of adult patients with inoperable chronic thromboembolic pulmo­ nary hypertension (CTEPH) or persistent or recurrent CTEPH after surgical treatment to improve exercise capacity and the treat­ ment of adult patients with pulmonary arte­ rial hypertension (PAH) to improve exercise capacity. Riociguat is a soluble guanylate cyclase (sGC) stimulator and is the first member of a novel class of compounds targeting a key molecular mechanism underlying PH. Due to its novel mode of action, it is hoped that riociguat could overcome a number of limitations currently associated with the approved PAH therapies, includ­ ing nitric oxide dependence and is the first drug that has demonstrated clinical ben­ efits in CETPH, where no pharmacological treatment is approved. Principal investigator Ardeschir Ghofrani, University Hospital Giessen and Marburg (Germany) commented “Riociguat has demonstrated significant and sustained clin­ ical efficacy and safety in treatment naive PAH patients and patients pretreated with endothelin-receptor antagonists or pros­ tanoid monotherapy, as well as in patients with inoperable CTEPH or persistent or recurrent CTEPH after surgery. So far, no other pharmacological treatment has shown significant effect in CETPH. For both PAH and CTEPH patients and their treating phy­ sicians, the clinical improvements across multiple end points are of high relevance.” The recommendation from the CHMP is based on the results from the two rand­ omized, double-blind, placebo-controlled, global Phase III studies CHEST-1 and

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PATENT-1, as well as on interim results of the long-term extension studies CHEST-2 and PATENT-2. The studies assessed the efficacy and safety of oral riociguat in the treatment of CTEPH and PAH, respec­ tively. PAH and CTEPH are two rare and life-threatening forms of pulmonary hypertension characterized by significantly increased pressure in the pulmonary arteries. CHEST-1 and PATENT-1, both Phase III studies of riociguat met their primary end­ points, a change in exercise capacity, after

16 and 12 weeks, respectively. Riociguat also demonstrated consistent improve­ ments across multiple, relevant secondary end points, and was generally well-tolerated, with a good safety profile. The Phase III trial programs CHEST and PATENT are ongoing with the long-term extension stud­ ies, CHEST-2 and PATENT-2, showing in first interim analyses a good safety profile and sustained efficacy over 1 year. Riociguat was approved under the name Adempas® in the USA for use in CTEPH and PAH in October 2013 and in Canada and Switzerland in the CTEPH indication in September and November 2013, as well as in Japan in CTEPH in January 2014. – Written by Michael Dowdall Source: Press release: Bayer’s Riociguat recommended for approval in the EU in two forms of pulmonary hypertension: www.arraydiagnostica.com/bayersriociguat-recommended-approval-eu-two-formspulmonary-hypertension

Promising results for future predicative test of myocardial infarction A group of scientists from The Scripps Research Institute (CA, USA) have adapted a fluid-phase biopsy technology platform, termed ‘high-definition circu­ lating endothelial cell’ assay, which could be used to indicate patients that are at a high risk of myocardial infarction. The assay detects circulating endothelial cells (CECs), as increased levels of CECs are seen in a variety of pathological con­ ditions, including myocardial infarction. The assay is able to distinguish CECs from other white blood cells due to their distinct morphological structure. According to the report, the team ana­ lyzed blood samples from 79 myocardial infarction patients, 25 healthy controls and six patients undergoing vascular surgery. The results indicated that CEC levels are significantly increased in patients who had recently had a myocardial infarction com­ pared with healthy controls. In addition,

the assay demonstrated higher specificity than the current US FDA-approved assay CellSearch®, which is used to detect CECs in cancer patients. Lead researcher, Peter Kuhn commented, “The goal of this paper was to establish evidence that these CECs can be detected reliably in patients following a heart attack and do not exist in healthy controls, which we have achieved.” Kuhn continued, “Our results were so significant relative to the healthy controls that the obvious next step is to assess the usefulness of the test in iden­ tifying patients during the early stages of a heart attack.” – Written by Jessica Thorne Sources: Bethel K, Luttgen MS, Damani S et al. Fluid phase biopsy for detection and characterization of circulating endothelial cells in myocardial infarction. Phys. Biol. 11(1), 016002 (2014); Researchers develop test to predict early onset of heart attacks: www. scripps.edu/news/press/2014/20140109kuhn.html




High-density lipoproteins may offer a more promising route to statin therapy In a collaborative effort, researchers have developed an injectectable recon­ stituted HDL nanoparticle carrier vehi­ cle capable of delivering statins to treat atherosclerotic plaque inflammation. Although statins have potent antiinflammatory properties, they suffer from low systemic bioavailability if adminis­ tered by the conventional oral route, thereby reducing the overall effectiveness of this therapy. By formulating synthetic versions of HDLs, a key component in the transpor­ tation of molecules such as cholesterol and fats in the body, the team was able to successfully deliver anti-inflammatory drugs to the heart, potentially enabling the prevention of repeat heart attacks or stroke. The group demonstrated the effective­ ness of this approach with two different treatment regimens in an apoE-knockout mouse model of atherosclerosis. Leader of

the study, Willem Mulder, a researcher at Mount Sinai School of Medicine (NY, USA), commented, “A 3-month lowdose nanotherapy regimen was found to inhibit plaque inflammation progression, while a 1-week high dose lowered inflam­ mation burden by 90% in advanced in advanced atherosclerotic lesions.”

“...this novel approach represents an alternative and effective treatment paradigm for atherosclerotic disease, which may be employed to swiftly stabilize subjects and reduce the high recurrence rates.” In terms of the current standard of care, recurrence rates after myocardial infarc­ tion or stroke are as high as 30%. With this in mind, Mulder concluded that, “this novel approach represents an alternative

and effective treatment paradigm for atherosclerotic disease, which may be employed to swiftly stabilize subjects and reduce the high recurrence rates.” With regard to future work, the team now intends to evaluate the HDL statin nanotherapy in more clinically relevant animal models, in addition to investi­ gating the incorporation of different anti-inflammatory compounds to poten­ tially achieve a more potent formulation. According to Mulder, “The group’s ulti­ mate ambition is to perform trials with our clinical partners at the Academic Medical Center in Amsterdam (The Netherlands).” – Written by Hannah Coaker Source: Duivenvoorden R, Tang J, Cormode DP et al. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat. Commun. 5, 3065 (2014).

PROGNOSIS looking good for a possible serum test for preeclampsia Preeclampsia is the second most common cause of maternal death, affecting one in 20 pregnancies. It can be life-threatening for mother and baby, especially if diagnosed late. PROGNOSIS aims to address the prediction of preeclampsia as an important unmet medical need. Initial data from the PROGNOSIS study presented at the 18th World Congress on Controversies in Obstetrics, Gynaecology & Infertility (COGI) held in Vienna in October 2013 indicate the potential for a serum-based test to improve the conventional diagnostics of preeclampsia (currently based on the clinical parameters hypertension and pro­ teinuria). It is hoped this could allow the easy identification of patients at highest risk, thus improving clinical outcome and healthcare resource allocation. PROGNOSIS is a multicenter, pro­ spective, double-blind and noninter­ ventional trial evaluating the short-term


prediction of preeclampsia, eclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome in pregnant women with suspected preec­ lampsia. The study started enrolling in December 2010 at nine sites in western Europe and was expanded to 31 sites worldwide across Australia, Canada, New Zealand and Latin America in 2012. PROGNOSIS is investigating the corre­ lation between the ratio of two proteins sFlt-1 and PlGF in maternal blood and the risk of developing preeclampsia over the subsequent 4 weeks. Principal investigator Harald Zeisler, form Medica l Universit y Vienna

Future Cardiol. (2014) 10(2)

(Austria) explained “The PROGNOSIS study will expand the use of these pow­ erful markers for preeclampsia from the very good performance for aid in diag­ nosis towards the area of prediction and early risk stratification. We hope that early identification of women at high risk of developing preeclampsia will allow healthcare professionals to prevent the most serious effects of the disease and avoid unnecessary expenditure by healthcare systems on excessive medical treatment or unnecessary hospital admis­ sion prompted by inadvertently positive diagnoses based on current standard of clinical practice.”

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BULLETIN BOARD It was back in 2010 that Roche intro­ duced Elecsys® to the UK market which provides healthcare professionals with a reliable tool for the diagnosis of preec­ lampsia. It is possible that if PROGNOSIS yields its anticipated results, there is the potential of using a fully automated test to predict preeclampsia. A predictive test would enable healthcare professionals

to focus on patients at highest need of appropriate and timely clinical and those patients who are identified as unlikely to develop the disease could be safely discharged from hospital. Interim analysis of the data from the first 500 patients included in the study have demonstrated promising results with an approximately 20% prevalence of

preeclampsia in the target population. Full results are expected to be reported in 2014. – Written by Michael Dowdall Sources: Press release: PROGNOSIS study to determine whether serum test predicts preeclampsia: www.roche.co.uk/portal/uk/2013_press_ releases?siteUuid=re7208002&paf_gear_id=41800 051&pageId=re7734007&synergyaction=show&p af_dm=full&nodeId=1415-e8cf5f0f5bfb11e3b54defe0 692339e3¤tPage=0

Priority Paper Alerts Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women. PLoS ONE 9(1), e84698 (2014). Progesterone is effective treatment for hot flushes/night sweats, however, the cardiovascular effects of progesterone therapy are unknown, but evidence suggests that premenopausal normal estradiol with normal progesterone levels may provide later cardiovascular protection. In this study, the authors compared the effects of progesterone with placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. The study results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL cholesterol and the statistically significant decrease in HDL cholesterol levels was not clinically important (based on lack of cardiovascular risk profile change). Suncion VY, Ghersin E, Fishman J et al. Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally? An analysis from the POSEIDON randomized trial. Circ. Res. doi:10.1161/CIRCRESAHA.114.302854 (2014) (Epub ahead of print). Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy; however, the impact of the injection site remains unknown. To address whether TESI exerts its effects at the site of injection only or also in remote areas, the authors hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in non-injected segments. The authors findings illustrated a dichotomy in regional responses to TESI. Although scar reduction was evident at the site of TESI and remotely, ventricular functional responses occurred preferentially at the sites of TESI. In addition, the authors found that improvement was greatest when segmental left ventricular dysfunction was severe.

About the Bulletin Board

The News highlights some of the most important events and research. If you have newsworthy information, please contact: Michael Dowdall, Managing Commissioning Editor, Future Cardiology, Future Medicine Ltd, Unitec House, 2 Albert Place, London, N3 1QB, UK; [email protected]

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Use your head and your heart: a brain injury biomarker shows promise in assessing myocarditis.

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