ViewpointLast Word on Viewpoint: Anemia contributes to cardiovascular disease through reductions in nitric oxideFelicita Andreotti, Giulio Coluzzi, Teodosio Pafundi, Teresa Rio, Eliano Pio Navarese, Filippo Crea, Massimo Pistolesi, Attilio Maseri, and Charles H. HennekensFelicita AndreottiInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Giulio ColuzziInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Teodosio PafundiInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Teresa RioInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Eliano Pio NavareseDepartment of Cardiology, Dusseldorf, Germany; , Filippo CreaInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Massimo PistolesiSection of Respiratory Medicine, Department of Experimental and Clinical Medicine, University of Florence, Italy; , Attilio MaseriHeart Care Foundation, Florence, Italy; and , and Charles H. HennekensCharles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FloridaPublished Online:15 Feb 2017https://doi.org/10.1152/japplphysiol.01095.2016MoreSectionsPDF (55 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: Allen, Debevec, Millet, and Madsen (see Ref. 1) provide Commentaries on our Viewpoint (2) that anemia may contribute to cardiovascular disease through reduced nitric oxide (NO). Physiologic hypoxic vasodilatation by NO derived from S-nitroso-hemoglobin (SNO-Hb) has been demonstrated in animals, in whom mutations preventing SNO-Hb formation cause impaired basal blood flow, impaired tissue oxygenation, and increased rates of myocardial infarction, heart failure, and death (6).Allen (see Ref. 1) highlights the challenges of setting up rigorous accurate animal models to investigate potential mechanisms linking anemia to reduced NO bioavailability and of testing the effects of different amounts, sites and times of NO replenishment on cardiovascular events in patients with anemia. Given the potential therapeutic benefits, Allen encourages further research and we concur about the importance of confirming or refuting our hypothesis.Debevec and Millet (see Ref. 1) discuss the concept that exercise, by potentiating NO synthase activity, may counterbalance anemia-related NO deficiency. We believe Debevec and Millet’s hypothesis could be formally tested in humans with and without anemia undergoing, or not, an exercise training program. Indeed, in animal models of sickle cell anemia, physical activity did enhance NO synthesis (3).In his own studies, showing an inverse relation between Hb concentrations and radial (but not brachial) artery diameter increase during hyperemia (so called flow-mediated dilatation or FMD) in healthy (but not diabetic) subjects, Madsen (see Ref. 1) states that Hb and basal artery diameters were not related (5). Madsen interprets the inverse relation of Hb with FMD as indicating Hb’s scavenging of NO. Of note, high affinity binding of NO to the deoxygenated heme iron of intracellular Hb in the peripheral hypoxic milieu is a crucial step according to our hypothesis; in the oxygenated lungs, this heme-bound NO moves to Cysβ93 to form SNO-Hb and is later propelled, in the periphery, into the hypoxic capillary bloodstream; at the same time, newly generated NO is “scavenged” by Hb’s deoxy-heme-iron. In the context of FMD, higher compared with lower Hb concentrations flowing through the ultrahypoxic milieu determined by a 5-min suprasystolic cuff occlusion is likely to fleetingly release more oxygen and in parallel to “scavenge” an equally greater number of NO molecules onto the deoxy-heme-iron (relatively greater than the NO molecules propelled outwards from Cysβ93), fleetingly limiting both local peripheral vasodilatation and the upstream shear that stimulates endothelial NO and directly affects FMD. Thus we believe our hypothesis and Madsen’s interpretations are not in conflict. Given that FMD measures a ratio between peak and basal artery diameters, we believe the precise mechanism behind the inverse relation of Hb concentrations with FMD remains unclear.We concur with Madsen that, in patients with flow-limiting vascular disease, ischemic mediators may cause maximal compensatory vasodilation. In such cases, NO released from SNO-Hb in peripheral capillaries would not lead to further dilatation, but could still offer significant vasculoprotection through anti-platelet, anti-inflammatory, insulin-sensitizing, and progenitor-cell stimulating effects (2).Zhang et al. (6) state: “the delivery of SNO-based NO bioactivity by Hb redefines the respiratory cycle as a triune system (NO/O2/CO2).” We firmly believe the relation between anemia, NO, and cardiovascular disease merits investigation. Based on the current totality of evidence, our hypothesis may turn out to be true but could also turn out to be, to paraphrase Thomas Huxley, “another beautiful hypothesis slain by ugly facts” (4).DISCLOSURESF.A. reports receiving lecture/consultation fees from Amgen, Bayer, Boehringer Ingelheim, BMS-Pfizer, Daiichi Sankyo and International Menarini Foundation. C.H.H. reports that he is funded by the Charles E. Schmidt College of Medicine at Florida Atlantic University; serves as an independent scientist in an advisory role to investigators and sponsors as: Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, Sanofi, Sunovion and the Wellcome Foundation; to Aralez/Pozen, the United States (U.S.) Food and Drug Administration, UpToDate, and legal counsel for Pfizer and Takeda; receives royalties for authorship or editorship of 3 textbooks and as coinventor on patents for inflammatory markers and CV disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the West-Bacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.AUTHOR CONTRIBUTIONSF.A., G.C., and A.M. conceived and designed research; F.A. analyzed data; F.A., M.P., and C.H.H. drafted manuscript; F.A., G.C., T.R., E.P.N., F.C., M.P., A.M., and C.H.H. edited and revised manuscript; F.A., G.C., T.P., T.R., E.P.N., F.C., M.P., A.M., and C.H.H. approved final version of manuscript; G.C., T.P., T.R., E.P.N., F.C., and C.H.H. interpreted results of experiments.REFERENCES1. Allen BW, Debevec T, Millet GP, Madsen PL. Commentaries on Viewpoint: Anemia contributes to cardiovascular disease through reductions in nitric oxide. J Appl Physiol. doi:10.1152/japplphysiol.01047.2016.Link | Google Scholar2. Andreotti F, Coluzzi G, Pafundi T, Rio T, Navarese EP, Crea F, Pistolesi M, Maseri A, Hennekens CH. Viewpoint: Anemia contributes to cardiovascular disease through reductions in nitric oxide. J Appl Physiol (1985). doi:10.1152/japplphysiol.00995.2016. Link | ISI | Google Scholar3. Charrin E, Aufradet E, Douillard A, Romdhani A, Souza GD, Bessaad A, Faes C, Chirico EN, Pialoux V, Martin C. Oxidative stress is decreased in physically active sickle cell SAD mice. Br J Haematol 168: 747–756, 2015. doi:10.1111/bjh.13207. Crossref | PubMed | ISI | Google Scholar4. Huxley TH. President’s Address to the British Association for the Advancement of Science. Liverpool, 14 Sept 1870.Google Scholar5. Madsen PL, Scheuermann Freestone M, Neubauer S, Channon K, Clarke K. Haemoglobin and flow-mediated vasodilation. Clin Sci (Lond) 110: 467–473, 2006. doi:10.1042/CS20050291. Crossref | PubMed | ISI | Google Scholar6. Zhang R, Hess DT, Qian Z, Hausladen A, Fonseca F, Chaube R, Reynolds JD, Stamler JS. Hemoglobin βCys93 is essential for cardiovascular function and integrated response to hypoxia. Proc Natl Acad Sci USA 112: 6425–6430, 2015. doi:10.1073/pnas.1502285112. Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: F. Andreotti, Institute of Cardiology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy (e-mail: felicita.[email protected]it). Download PDF Previous Back to Top FiguresReferencesRelatedInformation More from this issue > Volume 122Issue 2February 2017Pages 420-421 Copyright & PermissionsCopyright © 2017 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01095.2016PubMed28202536History Received 19 December 2016 Accepted 19 December 2016 Published online 15 February 2017 Published in print 1 February 2017 Metrics

AIMS:Radiofrequency (RF) catheter ablation (CA) is superior to standard medical therapy in controlling recurrent ventricular tachycardia (VT). The majority of procedures have been performed in a middle-aged population. The outcome of VT ablation in the elderly has not been described.METHODS AND RESULTS:We retrospectively studied the outcome and safety of CA of VT in octogenarians performed in four European centres. The population consisted of patients presenting with recurrent VT refractory to medical therapy. Patients aged over 80 years were compared with younger patients undergoing CA. Clinical characteristics, procedural data, complications, and outcomes were examined. Implantable cardioverter-defibrillator (ICD) therapy data were collected. A total of 54 consecutive octogenarian patients underwent RF CA of VT and represented the study group (42 males, age 82.8 ± 2.7 years) compared with a control group of 104 younger patients (85 males, age 66.7 ± 8.9 years). Mean follow-up was 33 ± 48 months. Implantable cardioverter-defibrillators were present in 81 and 86% of patients, respectively (P = 0.93). Left ventricular ejection fraction was 29% ± 8.2 in octogenarians vs. 34% ± 10.2 in the younger group (P < 0.01). More major complications occurred in octogenarians (18 vs. 2%, P < 0.01). During follow-up, there were more ICD shocks in the octogenarians (28 vs. 15%, P < 0.01). The Kaplan-Meier curve of survival after VT ablation confirms comparable survival rates at 1 year, but the elderly have poor survival in the mid-term. Survival in the elderly post VT ablation is comparable with that in an age-matched cohort with ICDs but no VT storm.CONCLUSION:Octogenarians undergoing CA of VT have more risk factors, higher risk of complications and ICD shocks, but demonstrate comparable short-term survival rates.

ViewpointAnemia contributes to cardiovascular disease through reductions in nitric oxideFelicita Andreotti, Giulio Coluzzi, Teodosio Pafundi, Teresa Rio, Eliano Pio Navarese, Filippo Crea, Massimo Pistolesi, Attilio Maseri, and Charles H. HennekensFelicita AndreottiInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Giulio ColuzziInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Teodosio PafundiInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Teresa RioInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Eliano Pio NavareseDepartment of Cardiology, Dusseldorf, Germany; , Filippo CreaInstitute of Cardiology, Catholic University Hospital, Rome, Italy; , Massimo PistolesiSection of Respiratory Medicine, Department of Experimental and Clinical Medicine, University of Florence, Italy; , Attilio MaseriHeart Care Foundation, Florence, Italy; and , and Charles H. HennekensCharles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FloridaPublished Online:15 Feb 2017https://doi.org/10.1152/japplphysiol.00995.2015This is the final version - click for previous versionMoreSectionsPDF (302 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat anemia is significantly associated with cardiovascular disease (CVD) after adjustment for other risk factors in patients with established disease as well as in the general population (21, 23). The main proposed mechanisms linking anemia to CVD involve the reduction of oxygen delivery to myocardial as well as systemic tissues, the compensatory increase in stroke volume/heart rate to maintain adequate oxygen delivery, the development of secondary left ventricular remodeling/hypertrophy, and the presence of underlying kidney or inflammatory diseases (21, 23). During acute myocardial infarction, anemia affects up to 20–35% of patients, in whom each 1 g/dl decrement in Hb increases the risk of cardiovascular death at 30 days by 20% independently of other risk factors (21). In a prospective cohort study of apparently healthy men and women aged 45–64 yr, the Atherosclerosis Risk in Communities study, those with anemia experienced a 41% increased risk of CVD during a 6-yr follow-up after adjustment for other risk factors (23).Of the several mechanisms that have been proposed (21, 23), to the best of our knowledge, none has considered nitric oxide (NO). NO is a labile diatomic gas that diffuses rapidly in tissues. Its production is catalyzed by a family of NO synthases that facilitate the reaction of l-arginine with oxygen to yield NO and citrulline (3, 15, 30). NO synthases are activated by several cofactors, including tetrahydrobiopterin and calmodulin, and are present in many tissues, including erythrocytes (29, 30). NO synthesis is inhibited experimentally by l-n-methylarginine and endogenously by asymmetric dimethylarginine (9, 30). Other sources of NO include S-nitrosothiols and nitrate/nitrite(NO2−) (30). The best characterized pathway of NO bioactivity is its binding to soluble guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP in turn activates protein kinases and phosphodiesterases that mediate vascular smooth muscle relaxation, platelet and leucocyte inhibition, and cell growth and differentiation (Fig. 1). Through these mechanisms, NO provides protection against CVD (2, 11, 15, 30). Intracellular Hb is an oxygen carrier and donor, but also a circulating reservoir of NO (3). In this manuscript we propose the viewpoint that anemia contributes to CVD through reductions in NO as well as oxygen. Specifically, when Hb declines, the donation of NO into the tissues is compromised, thereby adversely affecting the fundamental physiologic process of erythrocyte-mediated NO systemic hypoxic vasodilatation (3, 7, 15, 22, 24, 29).Fig. 1.Nitric oxide generation and physiological effects. Nitric oxide activates soluble guanylyl cyclase, leading to generation of cyclic GMP, responsible for vascular smooth muscle relaxation, platelet inhibition, and suppression of leucocyte recruitment. Nitric oxide also generates S-nitrosoproteins that promote sarco/endoplasmic reticulum calcium ATPase (SERCA), calcium depletion, and relaxation.Download figureDownload PowerPointFig. 2.Erythrocyte-mediated NO-dependent systemic hypoxic vasodilatation. As Hb is deoxygenated in the systemic microcirculation, it switches to a tense structure that triggers the release of nitric oxide (NO) from the cysteine thiols of S-nitroso-Hb to the erythrocyte membrane and surrounding tissues. Unloaded deoxyHb reloads local NO through high affinity heme iron binding, renewing the NO cycle.Download figureDownload PowerPointHb as NO Carrier and DonorDuring inspiration, oxygen enters the pulmonary microcirculation and saturates Hb. Specifically, the Hb tetramer loads oxygen on its heme iron atoms and assumes a relaxed (R) conformation; in parallel, the NO bound to heme iron or deriving from nitrite (NO2−) is transferred to inwardly oriented cysteine residues in position 93 (Cysβ93) to form S-nitroso-Hb (3, 7, 25, 29). As blood deoxygenates in the systemic microcirculation, Hb switches to a tense (T) structure that orients Cysβ93 toward the protein surface and triggers NO release from S-nitroso-Hb (24) (Fig. 2). In parallel, the heme iron atoms reload NO with high affinity (Fig. 2). In the normally ventilated lungs, the iron-bound NO moves again within seconds to produce S-nitroso-Hb (7), thus renewing the NO cycle within the red cell. Erythrocyte-mediated NO-dependent systemic hypoxic vasodilatation has been demonstrated in vivo in the coronary circulation of dogs and mice (20, 29).The export of NO out of erythrocytes may involve reduction of nitrite (NO2−) to NO by deoxyHb itself (7, 22, 30)—particularly at the erythrocyte submembrane as it traverses the arteriole (26)—generating intermediate species from nitrite (NO2−) that diffuse out to form extracellular NO or S-nitrosothiols (SNOs) (7, 22, 26, 30). In addition or alternatively, there may be binding of S-nitroso-Hb to the cytoplasmic domain of transmembrane band 3 protein (or anion exchanger AE1) (30), favoring NO transfer to other SNOs, such as low mass S-nitrosoglutathione and AE1 itself (25). The role of S-nitroso-Hb as a primary transport mechanism for NO has been debated, because mice expressing human Hb in which the Cysβ93 residue had been replaced by alanine seemed to maintain erythrocyte-mediated hypoxic vasodilatation (25). More recent evidence, however, confirms the essential role of Cysβ93 in response to hypoxia (13, 29). Of note, Cysβ93 is one of three amino acids in Hb strictly conserved in all mammals and birds (29). Other heme-containing proteins such as myoglobin, neuroglobin, and cytoglobin also react with nitrite to form NO (14).Systemic Vasodilatation vs. Pulmonary Vasoconstriction in Response to HypoxiaSystemic microcirculatory dilatation occurs physiologically under multiple stimuli that include metabolites (e.g., bradykinin, histamine, ACh, substance P), physical forces (shear stress, exercise), growth factors, hormones, and hypoxia (30). Hypoxic vasoconstriction in the pulmonary circulation seems in apparent contrast to systemic hypoxic vasodilatation. The former, however, is a direct response of pulmonary vascular smooth muscle cells to alveolar hypoxia, through increased intracellular calcium and rho kinase-mediated calcium sensitization, independently of Hb-NO interactions; such vasoconstriction prevents gas in poorly ventilated alveoli from lowering the arterial oxygen pressure (1, 27). In the microcirculation of poorly ventilated hypoxic alveoli, Hb is not subjected to oxygenation and NO remains bound to the high affinity iron of the heme group. Conversely, in the normoxic well-ventilated lung, Hb is exposed to oxygen and the latter, given the even higher affinity of heme for oxygen than for NO, displaces NO from the heme group onto Cysβ93.Vascular and Metabolic Effects of NONO released by deoxyHb in systemic capillary beds can diffuse across several cell diameters into arteriolar smooth muscle cells, platelets, and endothelial cells. Therein, NO binds to the heme group of soluble guanylyl cyclase inducing this cyclase to generate cGMP, activate protein kinase G, and reduce intracellular calcium concentrations (30) (Fig. 1). Smooth muscle relaxation, suppression of platelet adhesion/degranulation/aggregation, downregulation of endothelial and platelet P-selectin expression, and prevention of leukocyte rolling ensue (2, 11, 15, 24, 30) (Fig. 1).Moreover, independently of cGMP, NO may modify protein cysteine thiols (S-nitrosylation) in endothelium, lymphocytes, cardiomyocytes, platelets, and vascular smooth muscle cells, causing, among other effects, delayed apoptosis, proangiogenesis, anti-inflammatory effects, and platelet inhibition (7, 15, 30). NO pathways are also involved in insulin, insulin-like growth factor 1, and erythropoietin signaling, as well as in progenitor cell production required for vascular/myocardial repair (9, 10, 15, 18). Activation of phosphoinositol-3-kinase by insulin increases endothelial NO-synthase gene expression (10).Clinical Evidence of Hb-Mediated VasodilatationData in humans support the role of Hb-related NO vasodilatation. For example, systemic hypoxic vasodilatation is impaired with transfused blood and is reversed by S-nitroso-Hb repletion (20). Adverse effects of blood transfusion have been attributed to depletion of NO bioactivity in banked blood (20). Although rigorous reversibility studies in humans are lacking, considerable circumstantial evidence is available.In patients with stable IHD, low Hb concentrations are associated with reduced NO bioavailability, assessed as plasma nitrites/nitrates (5), and with reduced circulating progenitor cells, assessed as CD34+ cells (4), independently of age, sex, or indices of inflammation (5). The CD34 surface antigen identifies bone marrow progenitor cells, including endothelial progenitors that are considered relevant to vascular regeneration and repair (4, 9). Reduced numbers of circulating CD34+ cells predict CVD outcomes (4).Impaired tissue blood flow in patients with diabetes mellitus or in patients with sickle cell anemia has been associated with altered levels of erythrocyte S-nitroso-Hb. Altered S-nitroso-Hb was related to glycated Hb in diabetes and to HbS in sickle cells and was considered relevant to the microcirculatory complications of these disorders (29).On the other hand, high-altitude polycythemic individuals, compared with sea-level subjects, have increased basal cardiac output and forearm blood flow as well as increased blood concentrations of Hb, S-nitroso-Hb, and NO products (12, 16).Among patients with chronic obstructive pulmonary disease (COPD), those with polycythemia show increased baseline brachial artery diameters, with similar wall shear stress despite increased viscosity, compared with normocythemic COPD patients (8). The increased baseline arterial diameters, cardiac output, and systemic blood flow in the polycythemic patients are attributed to the greater amounts of NO released by the higher Hb concentrations (6).Both flow-mediated dilatation (FMD) and ACh-induced vasodilatation have been consistently inversely related to Hb concentrations (17, 19, 28). Indeed increased Hb concentration may upregulate baseline Hb-NO dilatation with diminished further dilator potential. This view is consistent with the close inverse relation found in healthy subjects between baseline radial artery diameter and radial FMD (17).ConclusionsHb is among the most abundant blood proteins, with concentrations greater than two times those of albumin and ~40 times those of fibrinogen. NO is a highly diffusible short-lived vasculoprotective gas with a high affinity reaction with Hb’s heme. Rate limiting steps of the Hb-NO interaction are likely the Hb concentration itself, as well as the NO generation and NO diffusing capacities. By limiting Hb’s potential to release bioactive NO in the systemic microcirculation, reduced Hb levels may contribute to CVD.Our hypothesis does not clash with any of the other proposed mechanisms linking anemia to CVD, but rather illustrates an additional potential mechanism, intimately associated with Hb’s function in the respiratory cycle, as carrier and donor of both oxygen and NO. Given the crucial role of the microcirculation, the elusive nature of NO, and the uncertainties surrounding the actual clinical role of Hb as carrier and donor of NO, further research is necessary. For example, relevant information may derive from the assessment of forearm blood flow adjusted to changes in blood pressure, heart rate, and viscosity in blood donors before and after donation or in polycythemic patients before and after phlebotomy in the presence and absence of the NO synthase inhibitor l-n-methylarginine. In the meanwhile, it is our viewpoint that a plausible interpretation of the data is that anemia contributes to CVD through reduced NO as well as reduced oxygen bioavailability.DISCLOSURESF.A. reports receiving lecture/consultation fees from Amgen, Bayer, Boehringer Ingelheim, BMS-Pfizer, and Daiichi Sankyo. C.H.H. reports that he is funded by the Charles E. Schmidt College of Medicine at Florida Atlantic University; serves as an independent scientist in an advisory role to investigators and sponsors as: Chair or Member of Data and Safety Monitoring Boards for Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, Sanofi, Sunovion and the Wellcome Foundation; to Aralez/Pozen, the United States (U.S.) Food and Drug Administration, UpToDate, and legal counsel for Pfizer and Takeda; receives royalties for authorship or editorship of 3 textbooks and as coinventor on patents for inflammatory markers and CV disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the West-Bacon Group within SunTrust Investment Services, which has discretionary investment authority and does not own any common or preferred stock in any pharmaceutical or medical device company.AUTHOR CONTRIBUTIONSF.A., A.M., and G.C. conceived and designed research; F.A., T.P., and T.R. prepared figures; F.A. and G.C. drafted manuscript; F.A., T.P., T.R., F.C., M.P., and C.H.H. edited and revised manuscript; F.A., G.C., T.P., T.R., E.P.N., F.C., M.P., A.M., and C.H.H. approved final version of manuscript.REFERENCES1. 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Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByCommentaries on Viewpoint: Anemia contributes to cardiovascular disease through reductions in nitric oxide15 February 2017 | Journal of Applied Physiology, Vol. 122, No. 2 More from this issue > Volume 122Issue 2February 2017Pages 414-417 Copyright & PermissionsCopyright © 2017 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00995.2015PubMed27687564History Received 30 November 2015 Accepted 27 September 2016 Published online 15 February 2017 Published in print 1 February 2017 Metrics

In December 2011, a 39-year-old man resuscitated from out-of-hospital cardiac arrest caused by ventricular fibrillation received the diagnosis of Brugada syndrome on the basis of a spontaneous Brugada type 1 ECG pattern (Figure 1A). Before implantation of a cardioverter-defibrillator, the patient, after providing written informed consent, underwent a 3-dimensional electroanatomic mapping of the right ventricle (RV) as part of a clinical research study approved by ethics committee of our institution. A localized low-voltage area with delayed and fragmented potentials was evident in both bipolar and unipolar voltage maps in the anterior RV outflow tract. The patient was discharged with no antiarrhythmic medication and was free of arrhythmic events at implantable cardioverter-defibrillator interrogation for 1 year.Figure 1. A , A 12-lead rest ECG obtained in 2011 showing a spontaneous type 1 Brugada pattern in leads V1 and V2. B , Continuous ECG monitoring (in 2013) showing frequent monomorphic ventricular ectopic beats with left bundle-branch block morphology and an inferior axis, as well as frequent R-on-T phenomenon triggering ventricular fibrillation. The type 1 Brugada pattern can …

BACKGROUND:Transvenous lead extraction (TLE) is a complex invasive procedure and the experience of the operator and the team is a major determinant of procedural outcomes. AIM:Because of very limited data available on minimum procedural volumes to enable training and ongoing competency for TLEs, we performed a meta-analysis aimed at assessing the outcomes of TLE in the centres with low, medium, and high volume of procedures. METHODS:Of the 280 papers initially retrieved until February 2013, 66 observational studies met inclusion criteria and were included in at least one stratified meta-analysis: 17 were prospective studies; 47 had a retrospective design; and 2 were defined 'experience studies'. We included only articles published after the introduction of laser technique (year 1999). We divided the studies in low, medium, and high volume centres utilizing either the European Heart Rhythm Association (EHRA) or Lexicon classification criteria. RESULTS:When meta-analyses were carried out separately for the studies with larger and smaller sample sizes, either using EHRA or Lexicon classification criteria, no clear differences emerged in the combined rate of major complications or intraoperative deaths. In contrast, both minor complications and mortality at 30 days decreased as centre volume increased. CONCLUSIONS:In our meta-analysis of observational studies, patients who have been treated in higher volume centres have a lower probability of minor complications and death at 30 days regardless of the infection rate, length of lead duration, type of device, and type of extraction.

ICD Interventions and MortalityBackgroundPatients with severe structural heart disease have increased mortality after implantable cardioverter‐defibrillator (ICD) shocks. Whether this is limited to ICD shock therapy only or extends also to no‐shock therapies, such as antitachycardia pacing (ATP), is unclear. We investigated the impact of different ICD therapies on long‐term mortality.MethodsWe enrolled 573 patients who underwent ICD implantation at our institution from 2004 to 2011. The population was divided into 3 groups: no device interventions (group 1), ATP interventions (group 2), and shock interventions (group 3). The endpoint was the all‐cause mortality.ResultsOver a follow‐up period of 48 months (range 1–110), 447 (78%) had no device interventions, 71 (12%) had ATP therapy only, and 55 (10%) had at least one shock intervention. All‐cause mortality occurred in 94 patients in group 1 (21%), 23 patients (43%) in group 2, and 21 patients (38%) in group 3. At multivariable Cox regression analysis, ATP intervention (HR: 1.8; 95% CI 1.1–3; P < 0.001), shock intervention (HR: 1.39; 95% CI 1.09–1.77; P = 0.008), age (HR: 1.05; 95% CI 1.02–1.07; P < 0.001), and LVEF (HR: 0.95; 95% CI 0.93–0.98; P = 0.001) were predictors of all‐cause mortality. No significant difference in mortality was found between group 2 and 3.ConclusionPatients with ICDs who receive appropriate interventions are at increased risk of mortality. Such risk is not dependent on different types of ICD therapy, such as shocks or ATP. Our data suggest that sustained ventricular arrhythmias per se have a negative impact on prognosis rather than modality of ICD therapy.

In patients with myocarditis, early diagnosis and appropriate therapy are mandatory, as well as close clinical follow-up with particular regard to progression of disease and ventricular arrhythmia recurrences. The management of ventricular arrhythmias should follow current guidelines for ICD implantation, but new therapeutic options could be evaluated in these patients, such as combined epicardial/endocardial ablation and external wearable defibrillator. Particularly, depressed left ventricular ejection fraction (LVEF) represents the only risk marker for sudden cardiac death currently used in myocarditis, although the use of a single risk factor has limited utility. On this regard, combined analysis of myocardial tissue structure by cardiac magnetic resonance (CMR) and endomyocardial biopsy, in association with resting cardiac systolic function, could improve predictive accuracy for SCD in patients with myocarditis.

OBJECTIVE:To evaluate the preoperative presence of C-reactive protein (CRP) and troponin T(hs-TnT) in patients with coronary artery disease (CAD) undergoing cardiopulmonary bypass (CPB) in order to better clarify the role of atrial inflammation and/or myocardial ischemia in the development of postoperative atrial fibrillation (POAF).DESIGN:Prospective, nonrandomized study.SETTING:University hospital.PARTICIPANTS:Thirty-eight consecutive ischemic patients admitted to the authors' hospital for CAD undergoing elective on-pump coronary artery bypass grafting (CABG).INTERVENTION:Elective on-pump CABG.MEASUREMENTS AND MAIN RESULTS:Peripheral blood samples were collected from all patients before and 24 hours after CABG to assess high sensitive (hs)-CRP and troponin T (hs-TnT) levels. The patients' heart rhythm was monitored by continuous ECG telemetry. Biopsies from the right atrial appendage were obtained at the beginning of the CABG procedure in order to perform immunohistochemistry for CRP and reverse transcription polymerase chain reaction for CRP mRNA expression. Fourteen patients out of 38 (36%) developed POAF. Atrial CRP was found in 31 patients (82%), 10 with POAF and 21 with sinus rhythm (71% v 87% respectively, p = ns). None of the atrial samples was positive for CRP mRNA. Atrial CRP did not correlate with serum hs-CRP levels and with occurrence of POAF, but with the incidence of diabetes (p = 0.010). Postoperative hs-TnT levels, but not hs-CRP levels, were identified as the only predictor of POAF occurrence (p = 0.016).CONCLUSIONS:In patients undergoing CABG, neither peripheral nor tissue preoperative CRP levels, but only postoperative hs-TnT levels, correlated with POAF, suggesting the primary role of an ischemic trigger of atrial fibrillation.

Ischemic heart disease (IHD) is the leading cause of death in women as in men. Several disease mechanisms, however, differ between genders. Women with IHD more frequently than men have normal or non-obstructive epicardial arteries, plaque erosion, spontaneous coronary dissection, microvascular dysfunction, stress cardiomyopathy, and heart rupture after acute infarction. Compared to men, IHD presents 7-10 years later with a heavier burden of cardiovascular risk factors, even after correction for age. The typical woman with IHD is old and frail, with comorbidities such as renal failure. Another vulnerable group comprises those with acute coronary syndromes before the age of 60 in whom hospital mortality is reported to be almost twice that of age-matched men. Such vulnerabilities in women, in apparent contrast with the delayed onset and lesser extent of epicardial atherosclerosis, may be attributable to biases in prevention, presentation, diagnosis and treatment of female IHD, but also to gender-related differences in disease mechanisms.

La cardiopatia ischemica è la principale causa di morte nella donna come nell’uomo. La malattia presenta tuttavia aspetti fisiopatologici diversi nei due sessi. Nella donna l’ischemia miocardica si associa più spesso ad arterie epicardiche normali o prive di stenosi significative, erosione piuttosto che rottura di placca, dissezione coronarica spontanea, disfunzione del microcircolo, cardiomiopatia da stress, e rottura di cuore dopo infarto acuto. Rispetto all’uomo, la cardiopatia ischemica nella donna si presenta 7-10 anni più tardi e si associa a un numero maggiore di fattori di rischio anche dopo normalizzazione per età. Tipicamente la donna coronaropatica è fragile perché anziana e gravata da comorbilità quali l’insufficienza renale. Un altro gruppo vulnerabile è costituito da donne con sindromi coronariche acute prima dei 60 anni la cui mortalità intraospedaliera risulta quasi doppia rispetto agli uomini di pari età. Tali vulnerabilità, in apparente contrasto con l’insorgenza ritardata e con la minor estensione di aterosclerosi epicardica, sono riferibili in parte a bias di prevenzione, presentazione, diagnosi e cura della coronaropatia nella donna, in parte a meccanismi fisiopatologici diversi nei due sessi.

Tra i soggetti apparentemente sani l’eccesso ponderale aumenta la probabilità di un successivo evento cardiovascolare. Il sovrappeso si associa alla presenza di tessuto adiposo bianco, viscero-addominale, infiltrato da macrofagi, promotore di insulino-resistenza e meno differenziato rispetto al grasso bruno o sottocutaneo. Tra i pazienti con malattia cardiovascolare, per contro, i soggetti magri hanno una maggiore ricorrenza di eventi aterotrombotici rispetto a quelli più grassi (il cosiddeto «paradosso dell’obesità»). Rispetto ai pazienti cardiovasculopatici più grassi, quelli magri hanno, in media, un maggior carico di comorbilità; sviluppano più spesso complicanze emorragiche; infine, probabilmente, celano fattori patogenetici ancora sconosciuti»). e quindi difficilmente trattabili.

Erythropoietin (Epo) is a hematopoietic hormone produced mainly by the kidneys in response to hypoxia. Recent acquisitions in the fields of hematology, neurology, cardiology, and experimental medicine show cytoprotective, angiogenetic and antinflammatory effects of Epo. Exogenous erythroPoietin in Acute Myocardial Infarction: New Outlook aNd Dose Association Study (EPAMINONDAS, EudraCTno. 200500485386) is one of four ongoing randomized controlled trials, each testing the effects of Epo in ≥100 patients with STEMI. EPAMINONDAS is a multicenter, prospective, double-blind, placebo-controlled, dose-finding study assessing intravenous moderate doses of human recombinant Epo (epoietin-α, 100 or 200 IU/kg/die) versus placebo, given on the first 3 days, in 102 patients with first ST-segment elevation myocardial infarction. Initial dosing is within 12 h of primary percutaneous coronary revascularization. The primary endpoint is infarct size, quantified by CK-MB time–concentration curve, left ventricular wall motion score index, and pattern of contrast-enhanced magnetic resonance imaging. Secondary endpoints are ischemic recurrences, ventricular remodelling, and safety events, assessed in-hospital and at 12 months’ follow-up. The results of current phase II studies will help define the safety/efficacy profile of Epo for patients with STEMI.

Excessive body mass among healthy subjects carries an increased risk of subsequent cardiovascular events. Excess weight implies the presence of white, viscero-abdominal fat, that promotes insulin-resistance, is infiltrated by macrophages, and is less differentiated compared to subcutaneous or brown fat. Conversely, among patients with cardiovascular disease, slim patients have a greater risk of recurrent atherothrombotic events than fatter patients ("obesity paradox"). Lean patients with cardiovascular disease, on average, have more comorbidities and haemorrhagic complications than their heavier counteparts, and probably they conceal predisposing factors that are still unknown and therefore difficult to treat.

Pregnancy-associated plasma protein-A (PAPP-A), first characterised in pregnancy in the 1970s, is a potentially useful prognostic and diagnostic marker for patients with coronary artery disease [ [1] Bayes-Genis A. Conover C.A. Overgaard M.T. et al. Pregnancy-associated plasma protein-A as a marker of acute coronary syndromes. N Engl J Med. 2001; 345: 1022-1029 Crossref PubMed Scopus (524) Google Scholar ]. Even among stable and troponin-negative patients, plasma PAPP-A concentrations are directly associated with the risk of an acute coronary syndrome (ACS) [ [2] Lund J. Qin Q.P. Ilva T. et al. Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation. Circulation. 2003; 108: 1924-1926 Crossref PubMed Scopus (213) Google Scholar ] and with the number of unstable (and total) coronary plaques [ [3] Cosin-Sales J. Christiansen Kaminski P. et al. Pregnancy-associated plasma protein-A and its endogenous inhibitor, the proform eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris. Circulation. 2004; 109: 1724-1728 Crossref PubMed Scopus (91) Google Scholar ]. In ACS, raised PAPP-A levels are more sensitive for early diagnosis than CK-MB or troponin T [ 2 Lund J. Qin Q.P. Ilva T. et al. Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation. Circulation. 2003; 108: 1924-1926 Crossref PubMed Scopus (213) Google Scholar , 4 Iversen K.K. Teisner A.S. Teisner B. et al. Pregnancy associated plasma protein A, a novel, quick, and sensitive marker in ST elevation myocardial infarction. Am J Cardiol. 2008; 101: 1389-1394 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ] and a stronger predictor of adverse events than C-reactive protein [ [5] Heeschen C. Dimmeler S. Hamm C.W. Fichtlscherer S. Simoons M.L. Zeiher A.M. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes. J Am Coll Cardiol. 2005; 45: 229-237 Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar ].

Large studies of initially healthy men and women consistently link adiposity with an increased risk of cardiovascular events.1,2 Compared with a reference body mass index (BMI) <25 kg/m2, the relative risk of dying during the next decade ranges from 1.2 for overweight (25–29.9 kg/m2) to 3.8 for severely obese (≥40 kg/m2) subjects, after adjustment for age, smoking, alcohol, and physical activity.1 Abdominal fat, measured as the waist–hip ratio, more reliably predicts the risk of ischaemic heart disease and death than BMI, even within normal body weights and after additional adjustment for blood pressure and cholesterol.2,3 In striking contrast, among patients with known atherothrombotic diseases4,5 or multiple risk factors,6 just the opposite is seen (‘obesity paradox’): the leanest fare worse4 and the heavier fare better than the normal weight reference groups.4–6 Among stable hypertensive ischaemic heart disease patients, thin (<20 kg/m2) compared with normal weight patients had a 3-year hazard of death, non-fatal myocardial infarction, and non-fatal stroke of 1.5, similar to that conferred by a 10-year increment in age.4 At the other extreme, obese and very obese patients with non-ST-elevation acute coronary syndromes had a 3-year hazard of dying of 0.3 compared with normal BMI patients.5 … *Corresponding author. Tel. +39 06 30154187, Fax +39 06 3055535, Email: felicita.andreotti{at}iol.it

Erythropoietin (Epo) is synthesized mainly under hypoxic conditions by renal and extrarenal tissues, including liver, spleen, brain, lung, bone marrow, and reproductive organs. Hypoxia abrogates the degradation of hypoxia-inducible factors (HIF)-1 and -2, that can then bind to the hypoxia response element within the Epo gene, activating its transcription. Receptors for Epo are expressed on cells known to synthesize Epo, but also on cardiomyocytes, cardiac fibroblasts, and endothelial, retinal, gastric, prostate and vascular smooth muscle cells. Epo-receptor binding triggers at least three intracellular signalling cascades: (1) janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5); (2) phosphatidylinositol-3 kinase (PI3K)/Akt, and (3) RAS/mitogen-activated protein kinase (MAPK). Epo also enhances nitric oxide (NO) bioavailability through endothelial NO synthase transcription and activation, and exerts antiapoptotic actions through Bcl-2 and Bcl-XL. NO is a powerful vasodilator, insulin-sensitizer, inhibitor of atherothrombosis and apoptosis, and essential for progenitor mobilization. This article is a concise review of recent advances regarding the molecular and cardiovascular effects of Epo.