European Journal of Heart Failure (2015) 17, 235–236 doi:10.1002/ejhf.257

March 2015 at a glance Marco Metra

Starting with this issue, it is my intention to write a brief summary of the articles published. My perspective is that of an interested, curious, though very busy, reader who wishes to have a first look at what’s new this month in our journal. Articles are grouped according to the main topics that we use.

Pathophysiology Cardiac remodelling Liver X receptors belong to the nuclear receptor superfamily and regulate inflammation, metabolism, and immunity. In this issue of the journal, Cannon et al. show the protective effects of the new, high-affinity, liver X factor receptor agonist, AZ876, on pathological cardiac hypertrophy and fibrosis in an experimental model of heart failure (HF) induced by pressure overload. Favourable effects of this X receptor agonist were independent from blood pressure lowering and were achieved without adverse lipogenic effects.1

Heart failure with preserved ejection fraction Skeletal muscle abnormalities and the beneficial effects of physical training are well established in subjects with HF with reduced ejection fraction (HFrEF). In this issue of the journal, molecular, mitochondrial, histological, and functional alterations of the skeletal muscles are demonstrated in an experimental model of HF with preseved ejection fraction (HFpEF) and these were attenuated by exercise training, confirming the potential role of this non-pharmacological intervention for HFpEF treatment.2

Cocaine cardiomyopathy Frustaci et al. have analysed endomyocardial biopsies from 10 patients with dilated cardiomyopathy attributed to cocaine. Compared with biopsies from patients with idiopathic dilated cardiomyopathy and from normal controls, biopsies from patients with cocaine cardiomyopathy showed larger cardiomyocytes, more pronounced myocardial fibrosis, more apoptosis and necrosis, signs of contraction band necrosis, greater expression of inducible nitric oxide synthase and nitrotyrosine, and reduced superoxide


Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy

© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

dismutase and catalase activity. These last changes correlated with cell death and severity of LV dysfunction. These results show the role of oxidative stress as a major mechanism of myocardial damage in human cocaine cardiomyopathy.3

Pulmonary vascular resistance in heart failure with reduced ejection fraction Verbrugge et al. have studied the pulmonary vascular response to exercise in 40 consecutive patients with HFrEF and pulmonary hypertension.4 All subjects underwent invasive haemodynamic assessment, at rest and during exercise, during infusions of i.v. diuretics and sodium nitroprusside (SNP), and, on the following day, after up-titration of oral treatment with renin–angiotensin system antagonists and hydralazine. The proportion of patients who had an increase in pulmonary vascular resistance to >3.5 Woods units at peak exercise increased from only 5 patients (13%) during i.v. therapy to 19 patients (48%) on oral therapy. This exercise-induced rise in pulmonary vascular resistance was associated with right ventricular dysfunction and a reduced right ventricular stroke work. This study shows that an increase in pulmonary vascular resistance may persist during oral therapy in patients with HFrEF and pulmonary hypertension. This exercise-induced increase in pulmonary vascular resistance can be ascribed to an impairment in nitric oxide (NO) release as it is blunted by the administration of NO donors, such as i.v. SNP. Consistent with other recent studies,5 – 7 this study also shows the utility of invasive exercise haemodynamic assessment for better categorization of patients with HF.8

Clinical assessment and prognosis Gender differences Carolyn Lam et al. compared 4570 women and 10 133 men enrolled in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Compared with men, women were older, had more co-morbidities, and were more likely to have post-infarction angina or HF. They had smaller LV volumes but a similar EF. After adjusting for baseline differences, women had a similar risk of fatal or non-fatal outcomes, with the exception of a higher risk of HF hospitalizations.9


Biological age Biological age, measured by the leucocyte telomere length, was not superior to chronological age for the prediction of outcomes in 3275 patients with HF enrolled in the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA) study.11

Treatment Neprilysin inhibition The PARADIGM-HF (Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin-converting-enzyme inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure] trial is a major step forward in the treatment of the patients with HFrEF. How we have come to study LCZ696, an angiotensin receptor neprilysin inhibitor in patients with HF, a ‘tale of science, serendipity, and second chances’, is the topic of John McMurray’s enthralling review in this issue of the journal.12

Iron therapy Both a review13 and a research article14 are focused on iron therapy in this issue. Iron deficiency affects up to 50% of HF patients and is associated with poor quality of life, impaired exercise tolerance, and mortality, independent of serum haemoglobin levels. Iron absorption from oral iron preparations is generally low and variable, and is further impaired in HF patients. Accordingly, there is no evidence for the clinical benefits of oral iron therapy in HF. In contrast, i.v. iron has been shown to have beneficial effects in recent trials.15,16 Ponikowski et al. have analysed the effects of i.v. iron on renal function in iron-deficient HF patients enrolled in the Ferinject® Assessment in Patients With IRon Deficiency and Chronic Heart Failure (FAIR-HF) trial. Treatment with ferric carboxymaltose was associated with an increase in the estimated glomerular filtration rate, and the efficacy and safety were independent of baseline renal function.14 An indication to look for iron deficiency and treat it with i.v. iron is reinforced by these articles.13,14

References 1. Cannon MV YH, Candido WM, Dokter MM, Lindstedt E-L, Silljé HHW, van Gilst WH, de Boer RA. The liver X receptor agonist AZ876 protects against


Hollander et al. showed gender-specific plasma protein biomarker panels in patients with Anderson–Fabry disease suggesting gender-specific differences in the pathophysiology and prognosis of this disease.10







7. 8.




12. 13. 14.



pathological cardiac hypertrophy and fibrosis without lipogenic side effects. Eur J Heart Fail 2015;17:273–282. Bowen TS, Rolin NP, Fischer T, Bækkerud FH, Medeiros A, Werner S, Bronstad E, Rognmo O, Mangner N, Linke A, Schuler G, Silva GJJ, Wisloff U, Adams V; on behalf of the Optimex Study Group. Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle. Eur J Heart Fail 2015;17:263–272. Frustaci ARM, Morgante E, Scopelliti F, Aquilano K, Ciriolo MR, Grande C, Verardo R, Chimenti C. Oxidative myocardial damage in human cocaine-related cardiomyopathy. Eur J Heart Fail 2015;17:283–290. Verbrugge FH, Dupont M, Bertrand PB, Nijst P, Grieten L, Dens J, Verhaert D, Janssens S, Tang WH, Mullens W. Pulmonary vascular response to exercise in symptomatic heart failure with reduced ejection fraction and pulmonary hypertension. Eur J Heart Fail 2015;17:320–328. Santos M, Opotowsky AR, Shah AM, Tracy J, Waxman AB, Systrom DM. A central cardiac limit to aerobic capacity in patients with exertional pulmonary venous hypertension: implications for heart failure with preserved ejection fraction. Circ Heart Fail 2015;in press. Dorfs S, Zeh W, Hochholzer W, Jander N, Kienzle RP, Pieske B, Neumann FJ. Pulmonary capillary wedge pressure during exercise and long-term mortality in patients with suspected heart failure with preserved ejection fraction. Eur Heart J 2014;35:3103–3112. Borlaug BA. Heart failure with preserved and reduced ejection fraction: different risk profiles for different diseases. Eur Heart J 2013;34:1393–135. Kenneth D. Increased pulmonary vascular resistance, right ventricular dysfunction and reversible pulmonary vasoconstriction in type 2 pulmonary hypertension: who has it and are we missing a potential therapeutic target in patients with heart failure? Eur J Heart Fail 2015;17:237–238. Lam CSP MM, Claggett B, Liu J, Skali H, Lewis E, Køber L, Rouleau J, Velazquez E, Califf R, McMurray JJ, Pfeffer M, Solomon S. Sex differences in clinical characteristics and outcomes after myocardial infarction: insights from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Eur J Heart Fail 2015;17:301–312. Hollander Z, Dai DL, Putko BN, Yogasundaram H, Wilson-McManus JE, Thompson RB, Khan A, West ML, McManus BM, Oudit GY. Gender-specific plasma proteomic biomarkers in patients with Anderson–Fabry disease. Eur J Heart Fail 2015;17:291–300. Haver VG, Mateo Leach I, Kjekshus J, Fox JC, Wedel H, Wikstrand J, de Boer RA, van Gilst WH, McMurray JJ, van Veldhuisen DJ, van der Harst P. Telomere length and outcomes in ischaemic heart failure: data from the COntrolled ROsuvastatin multiNAtional Trial in Heart Failure (CORONA). Eur J Heart Fail 2015;17:313–319. McMurray JJV. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail 2015;17:242–247. McDonagh T, Macdougall IC. Iron therapy for the treatment of iron deficiency in chronic heart failure: intravenous or oral? Eur J Heart Fail 2015;17:248–262. Ponikowski P, Filippatos G, Comin Colet J, Willenheimer R, Dickstein K, Lüscher T, Gaudesius G, von Eisenhart Rothe B, Mori C, Greenlaw N, Ford I, Macdougall I, Anker SD; for the FAIR-HF Trial Investigators. The impact of intravenous ferric carboxymaltose on renal function: an analysis of the FAIR-HF study. Eur J Heart Fail 2015;17:329–339. Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–2448. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD; for the CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2014; doi: [Epub ahead of print].

© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology

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March 2015 at a glance.

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