Van Veldhuisen Research Articles

Response to Letter Regarding Article, “Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy”

HomeCirculationVol. 123, No. 2Response to Letter Regarding Article, “Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy” Free AccessReplyPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReplyPDF/EPUBResponse to Letter Regarding Article, “Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy” Karin Y. van Spaendonck-Zwarts, J. Peter van Tintelen and Jan D.H. Jongbloed Dirk J. van Veldhuisen, Rik van der Werf and Maarten P. van den Berg Walter J. Paulus Dennis Dooijes Karin Y. van Spaendonck-ZwartsKarin Y. van Spaendonck-Zwarts Department of GeneticsUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Spaendonck-Zwarts, van Tintelen, Jongbloed) Search for more papers by this author , J. Peter van TintelenJ. Peter van Tintelen Department of GeneticsUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Spaendonck-Zwarts, van Tintelen, Jongbloed) Search for more papers by this author and Jan D.H. JongbloedJan D.H. Jongbloed Department of GeneticsUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Spaendonck-Zwarts, van Tintelen, Jongbloed) Search for more papers by this author Dirk J. van VeldhuisenDirk J. van Veldhuisen Department of CardiologyUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Veldhuisen, van der Werf, van den Berg) Search for more papers by this author , Rik van der WerfRik van der Werf Department of CardiologyUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Veldhuisen, van der Werf, van den Berg) Search for more papers by this author and Maarten P. van den BergMaarten P. van den Berg Department of CardiologyUniversity Medical Centre GroningenUniversity of GroningenGroningen, the Netherlands (van Veldhuisen, van der Werf, van den Berg) Search for more papers by this author Walter J. PaulusWalter J. Paulus Department of PhysiologyFree University Medical CentreAmsterdam, the Netherlands (Paulus) Search for more papers by this author Dennis DooijesDennis Dooijes Department of GeneticsErasmus Medical CentreRotterdam, the Netherlands (Dooijes) Search for more papers by this author Originally published18 Jan 2011https://doi.org/10.1161/CIRCULATIONAHA.110.984971Circulation. 2011;123:e9We thank Dr Baruteau et al for their comments. They raise an important issue, and recommend cardiological screening in all first-degree relatives of patients with peripartum cardiomyopathy (PPCM), not only when it concerns PPCM without recovery.Our findings strongly suggested that a subset of PPCM is part of the spectrum of familial dilated cardiomyopathy.1 The article by Morales et al2 in the same issue of Circulation underscores this. Taking these new data into account, we consider the genetic susceptibility of PPCM properly addressed in the recent statement from the Heart Failure Association of the European Society of Cardiology Working Group on PPCM.3In our article, we discussed a major limitation of our study: that we had not performed cardiological screening of family members of those PPCM patients who had recovered left ventricular function. We emphasized the importance of studying these cases in the future because they also can be part of familial cardiomyopathy. This is corroborated by the case report by Baruteau et al on the occurrence of PPCM in two sisters with full recovery.4 Besides, apparent recovery is not always true recovery, because it has been reported that patients have died during extended follow-up despite recovery of left ventricular function at 6 months' assessment.5 Thus, we fully agree with Baruteau et al that it is justifiable to offer cardiological screening to first-degree relatives of recovered PPCM patients.Karin Y. van Spaendonck-Zwarts, MDJ. Peter van Tintelen, MD, PhDJan D.H. Jongbloed, PhD Department of Genetics University Medical Centre Groningen University of Groningen Groningen, the NetherlandsDirk J. van Veldhuisen, MD, PhDRik van der Werf, MDMaarten P. van den Berg, MD, PhD Department of Cardiology University Medical Centre Groningen University of Groningen Groningen, the NetherlandsWalter J. Paulus, MD, PhD Department of Physiology Free University Medical Centre Amsterdam, the NetherlandsDennis Dooijes, PhD Department of Genetics Erasmus Medical Centre Rotterdam, the NetherlandsDisclosuresNone.

Response to Letter Regarding Article, “Endogenous Erythropoietin and Outcome in Heart Failure”

HomeCirculationVol. 122, No. 10Response to Letter Regarding Article, “Endogenous Erythropoietin and Outcome in Heart Failure” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Endogenous Erythropoietin and Outcome in Heart Failure” Anne M.S. Belonje, MD, Adriaan A. Voors, MD, PhD, Peter van der Meer, MD, PhD, Tiny Jaarsma, PhD and Dirk J. van Veldhuisen, MD, PhD Wiek H. van Gilst, PhD Anne M.S. BelonjeAnne M.S. Belonje Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author , Adriaan A. VoorsAdriaan A. Voors Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author , Peter van der MeerPeter van der Meer Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author , Tiny JaarsmaTiny Jaarsma Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author and Dirk J. van VeldhuisenDirk J. van Veldhuisen Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author Wiek H. van GilstWiek H. van Gilst Department of Experimental Cardiology, University Medical Center Groningen, Groningen, the Netherlands Search for more papers by this author Originally published7 Sep 2010https://doi.org/10.1161/CIRCULATIONAHA.110.960831Circulation. 2010;122:e450We thank Dr Incalzi and coauthors for their thorough reading of our article.1 They raise an important issue on chronic obstructive pulmonary disease (COPD)–related arterial hypoxemia and its influence on erythropoietin production. We agree that besides the presence of heart failure (and its known comorbidities), other factors can influence the level of erythropoietin.However, in several clinical studies, no increase in erythropoietin was found in nonanemic patients with COPD compared with healthy control subjects.2,3 In our heart failure study population, 28% (167 of 605) were diagnosed with COPD, which is consistent with data from other heart failure studies.4 The presence of COPD did not influence erythropoietin levels in our study as assessed by univariable linear regression analysis (β=0.026; P=0.53). To evaluate whether COPD influenced mortality of all causes in this heart failure cohort, we adjusted our multivariable Cox regression model for the presence of COPD. The addition of COPD did not strengthen our model, and more important, COPD was not an independent predictor of prognosis (hazard ratio, 1.18; 95% confidence interval, 0.90 to 1.56; P=0.24). Finally, the presence of COPD in patients with higher-than-expected erythropoietin levels based on their hemoglobin value was not significantly higher compared with patients with low or normal levels of erythropoietin. From these results, we conclude that the presence of COPD had no significant influence on the data that we presented.DisclosuresDr Voors has received unrestricted research grants from Amgen and Ortho Biotech. Dr van Veldhuisen has received lecture fees from Amgen and is a member of the Executive Committee of the Darbepoetin Morbidity/Mortality Heart Failure Trial (RED-HF). The other authors report no conflicts. References 1 Belonje AM, Voors AA, van der Meer P, van Gilst WH, Jaarsma T, van Veldhuisen DJ. Endogenous erythropoietin and outcome in heart failure. Circulation. 2010; 121: 245–251.LinkGoogle Scholar2 John M, Hoernig S, Doehner W, Okonko DD, Witt C, Anker SD. Anemia and inflammation in COPD. Chest. 2005; 127: 825–829.CrossrefMedlineGoogle Scholar3 Sala E, Balaguer C, Villena C, Rios A, Noguera A, Nunez B, Agusti A. Low erythropoietin plasma levels during exacerbations of COPD. Respiration. 2010; 80: 190–197.CrossrefMedlineGoogle Scholar4 Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail. 2009; 11: 130–139.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 7, 2010Vol 122, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.110.960831 Originally publishedSeptember 7, 2010 PDF download Advertisement SubjectsCongenital Heart Disease

Heart rate in acute heart failure, lower is not always better

Mounting evidence shows that elevated heart rate (HeartR) might be a risk factor for mortality in patients admitted with acute heart failure (AHF). However, this association with mortality has not been universally reproduced [ [1] Rienstra M. Van Gelder I.C. Van den Berg M.P. Boomsma F. Hillege H.L. Van Veldhuisen D.J. A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: effects on clinical profile, neurohormones and survival. Int J Cardiol. 2006; 109: 95-100 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar ]. We hypothesized that the prognostic value of HeartR might differ according to patient's heart rhythm. In order to challenge this hypothesis, we sought to determine whether the patient's heart rhythm present during an episode of AHF modifies the relationship between HeartR and the risk of long-term mortality.

MicroRNAs and Heart Failure Diagnosis

See related article, pages 1035–1039 Heart disease is the greatest noninfectious health hazard ever to confront the human race. It is the leading cause of death in industrialized nations, and, accordingly, it is responsible for a huge economic burden to society. It is estimated that 5 million Americans have heart failure (HF), a syndrome with mortality of approximately 50% at 5 years.1 Now, evidence indicates that the epidemic of HF is extending to the developing world. The road to advances in the treatment of HF is littered with failures, and many new means of diagnosing and tracking disease progression have disappointed. Therefore, there is an urgent need to identify novel mechanisms, markers, and therapeutic targets in HF pathogenesis. MicroRNAs (miRNAs or miRs) are among the most exciting areas in medicine and science today. MicroRNAs are endogenous, highly conserved, ≈22-nucleotide-long noncoding RNAs that regulate the stability and subsequent translation of nascent mRNA transcripts. Generally, miRs inhibit protein translation and/or promote mRNA degradation by base-pairing with 3′ untranslated regions within a transcript. MicroRNAs were first discovered in 1993 in Caenorhabditis elegans and are known to be critical to early vertebrate development and in an increasing number of basic molecular processes. Over the last few years, miRs have emerged as important mechanisms in human disease, including cardiovascular disease, diabetes, and cancer.2–6 Now, there is burgeoning interest in testing whether miRs could serve as markers for disease progression or prognostication. Indeed, in the cancer literature, strategies are emerging to use miR profiles for diagnosis and risk stratification. Currently, miR profiling is being evaluated in prostate cancer, head and neck squamous cell carcinomas, breast cancer, acute lymphoblastic leukemia, malignant mesothelioma, and other tumors.2,7–10 Most clinical studies to date on miRs have relied on tissue-based measurement of miR abundances, but miRs are …

Higher levels of education may be a marker of higher disease-specific knowledge in patients with chronic heart failure

the EU Working Group on Socioeconomic Inequalities in Health. Socioeconomic inequalities in morbidity and mortality in Western Europe. Lancet 1997;349:1655–9. [3] Dalstra JAA, Kunst AE, Mackenbach JP, The EU Working Group on Socioeconomic Inequalities in Health. A comparative appraisal of the relationship of education, income and housing tenure with less than good health among the elderly in Europe. Soc Sci Med 2006;62:2046–60. [4] Tibazarwa K, Ntyintyane L, Sliwa K, et al. A time bomb of cardiovascular risk factors in South Africa: results from the Heart of Soweto Study “Heart Awareness Days”. Int J Cardiol 2009;132:233–9. [5] Webel AR, Frazier SK, Moser DK, Lennie TA. Daily variability in dyspnea, edema, and body weight in heart failure patients. Eur J Cardiovasc Nurs 2007;6:60–5. [6] Pattenden JF, Roberts H, Lewin RJP. Living with heart failure: patient and carer perspective. Eur J Cardiovasc Nurs 2007;6:273–9. [7] van der Wal MH, Jaarsma T, Moser DK, Veeger NJ, van Gilst WH, van Veldhuisen DJ. Compliance in heart failure patients: the importance of knowledge and beliefs. Eur Heart J 2006;27:434–40. [8] Lainscak M, Cleland JGF, Lenzen MJ, et al. Patient recall of lifestyle advice in patients recently hospitalized with heart failure: a EuroHeart Failure survey analysis. Eur J Heart Fail 2007;9:1095–103. [9] Lainscak M, Keber I. Patients knowledge and beta blocker treatment improve prognosis of patients from heart failure clinic. Eur J Heart Fail 2006;8:187–90. [10] Jaarsma T, Van der Wal MHL, Lesman-Leegte I, et al. Effect of moderate or intensive disease management program on outcome in patients with heart failure. The Coordinating study evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Arch Intern Med 2008;168:316–24. [11] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.

The Cornucopia of “Pleiotropic” Actions of Statins

See related article, pages 255–264 Initially described in patients with coronary artery disease undergoing coronary artery bypass graft (CABG) surgery, myocardial “hibernation” denotes a state of adaptive reduction in myocardial contractile function in response to limited energy supply caused by reduced blood flow.1,2 In this precarious equilibrium, the myocardium can remain viable for sustained periods of time (although not indefinitely) and slowly resumes contractile activity on restoration of perfusion.2,3 Hibernating myocardium resulting from a flow-limiting coronary artery stenosis is a common clinical entity that contributes to myocardial dysfunction in many patients with ischemic heart disease1,2; its clinical importance stems from the fact that is it is potentially reversible. The pathophysiological basis of this syndrome was proposed as a conceptual framework in 19924 and subsequently tested in various animal models5–8: it is likely to involve recurrent brief episodes of ischemia, which initially result in repetitive “stunning” with normal resting flow and eventually cause a persistent decrease in resting function and flow.2,4–6,8 Over time, these changes lead to myocyte loss resulting from degenerative changes and apoptosis.2,8 Because mechanical dysfunction is caused by a restriction in blood flow, revascularization has traditionally been the cornerstone of therapy for myocardial hibernation. Indeed, restoration of blood flow via CABG or percutaneous coronary interventions often improves the mechanical performance of hibernating myocardium.1–3,8,9 In those cases in which these procedures are not feasible, however, there is a need for alternative approaches. Direct transmyocardial laser revascularization10 and intramyocardial gene transfer of phVEGF16511 or fibroblast growth factor-57 have been reported to enhance perfusion and contractile reserve and improve regional function in experimental models of hibernation. Transplantation of circulating progenitor cells following revascularization has also been reported to attenuate hibernation (ie, to increase coronary flow reserve …

Low-dose digoxin and reduction in mortality and morbidity in heart failure

We thank Drs. van Veldhuisen and de Boer for their insightful comments regarding our recent report based on the Digitalis Investigation Group (DIG) trial [1]. We agree that digoxin should continue to play an important role in the management of heart failure [2, 3]. However, unfortunately digoxin continues to be underutilized in clinical practice [4]. This may be due to a lack of scientific discussion at national meetings, a lack of industry promotion, and an overemphasis on mortality over hospitalization as outcomes [5]. This latter reason is particularly ironic as hospitalization due to worsening heart failure, common in heart failure, is reduced by digoxin regardless of serum concentrations or daily dosages [6]. The introduction of beta-blockers since the DIG trial may also have contributed to the underuse of digoxin [5]. Most heart failure patients are older adults and we agree that beta-blockers are safe and well tolerated in elderly systolic heart failure patients [7–10]. In the SENIORS trials, nebivolol significantly reduced the primary combined end point of all-cause mortality or cardiovascular hospitalization in elderly heart failure patients, but had no significant effect on individual components of that composite end point [7]. In the MERIT-HF trial, metoprolol extended release was as effective in the elderly as in the younger heart failure patients [9]. However, heart failure patients enrolled in major beta-blocker trials were over a decade younger than typical heart failure patients seen in clinical practice [4, 10]. Mortality and morbidity in contemporary heart failure patients receiving beta-blockers and other neurohormonal antagonists remain high and many subsequent clinical trials using other interventions have failed to further improve outcomes. Yet, the role of digoxin in these patients is often questioned as the DIG trial was conducted before the beta-blocker era of heart failure therapy. Although this issue can only be definitively resolved with a large randomized clinical trial of digoxin in contemporary heart failure patients receiving beta-blockers, data from post-hoc analysis of beta-blocker trials suggest that digoxin and carvedilol may be equally effective in the presence or absence of each other. Digoxin reduced the combined endpoint of all-cause death or all-cause hospitalization in patients receiving carvedilol (relative risk {RR}, 0.64; 95% confidence interval {CI}, 0.52 to 0.79) and placebo (RR, 0.82; 95% CI, 0.71 to 0.99) [11]. Carvedilol, on the other hand, had similar effect on combined endpoint in patients receiving (RR, 0.63; 95% CI, 0.52 to 0.75) and not receiving (RR, 0.80; 95% CI, 0.64 to 1.00) digoxin [11]. A plausible explanation of this synergy may be that by reducing digoxin-induced serious arrhythmias, beta-blockers enhance the effectiveness of digoxin, and by providing inotropic support, digoxin improves the tolerability for beta-blockers. All major beta-blocker trials in heart failure excluded patients with diastolic heart failure, who constitute nearly half of all elderly heart failure patients. Data from the DIG ancillary trial suggest that digoxin may play a role in the management of diastolic heart failure [12]. The effects of digoxin in these patients were very similar to those of candesartan, the only other drug tested in diastolic heart failure in a large randomized clinical trial [5, 12]. Digoxin was better tolerated and patients receiving digoxin had fewer adverse effects than those receiving candesartan [5]. Digoxin is also inexpensive, an important consideration for millions of heart failure patients in the developing world, whose left ventricular ejection fraction often cannot be known. The safety and effectiveness of digoxin in elderly heart failure patients has been documented in a post-hoc analysis of the DIG trial [13]. Findings from that analysis suggest that the use of digoxin in low doses (≤0.125 mg/day) was a strong predictor of low serum concentrations, which was significantly associated with reduced mortality and hospitalization in these patients [13]. However, in frail elderly heart failure patients with impaired kidney function, even a lower daily dose (0.125 mg every other day) may be preferable [13]. For a definite resolution of the role of digoxin in contemporary heart failure patients, a second multicenter randomized clinical trial of digoxin is warranted. This trial should be designed to include equal representations of men and women, whites and non-whites, and systolic and diastolic heart failure patients. However, there may not be enthusiasm in the industry to fund such a trial. We therefore hope that public international funding would be made available to support a definitive trial of digoxin in contemporary heart failure in the greater public health interest.

Low-dose digoxin in heart failure

With interest we read the study by Ahmed et al [ [1] Ahmed A. Pitt B. Rahimtoola S. et al. Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: a propensity-matched study of the DIG-trial. Int J Cardiol. 2008; 123: 138-146 Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar ] in which the authors showed that morbidity and mortality in patients with chronic heart failure (CHF) was significantly reduced by digoxin at low serum digoxin concentrations (SDC) in the DIG study, and that these low SDCs were strongly related to low-dose use of the drug. Clearly, digoxin still has an important place in the management of patients with CHF [ [2] Gheorghiade M. Van Veldhuisen D.J. Colucci W. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006; 113: 2556-2564 Crossref PubMed Scopus (164) Google Scholar ] as the authors point out, but its role has been declining in recent years. In a large CHF trial that was conducted between 1992 and 1995 (PRIME-II) [ [3] Hampton J.R. Van Veldhuisen D.J. Kleber F.X. et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet. 1997; 349: 971-977 Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar ], as many as 64% of the population was using digoxin at the time, although there were large differences between European countries, with digoxin use ranging from 39% in the UK to 87% in Germany [ [4] Van Veldhuisen D.J. Charlesworth A. Crijns H.J.G.M. Lie K.I. Hampton J.R. Differences in drug treatment of chronic heart failure between European countries. Eur Heart J. 1999; 20: 666-672 Crossref PubMed Scopus (54) Google Scholar ]. In a recent large CHF survival study (CORONA), which enrolled patients between 2003 and 2005, only 33% was still using digoxin [ [5] Kjekshus J. Apetrei E. Barrios V. et al. Rosuvastatin in older patients with heart failure. N Engl J Med. 2007; 357: 2248-2261 Crossref PubMed Scopus (1244) Google Scholar ]. Although the populations were largely comparable in terms of baseline demographics, there was a significant difference in age (mean age in PRIME-II vs CORONA, 65±9 years vs 73±9 years). Furthermore, in contrast to the decrease in digoxin use was the increase in the use of beta-blockers, going from only 6% in 1992–1995 [ 3 Hampton J.R. Van Veldhuisen D.J. Kleber F.X. et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Lancet. 1997; 349: 971-977 Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar , 4 Van Veldhuisen D.J. Charlesworth A. Crijns H.J.G.M. Lie K.I. Hampton J.R. Differences in drug treatment of chronic heart failure between European countries. Eur Heart J. 1999; 20: 666-672 Crossref PubMed Scopus (54) Google Scholar ] to 75% in 2003–2005 [ [5] Kjekshus J. Apetrei E. Barrios V. et al. Rosuvastatin in older patients with heart failure. N Engl J Med. 2007; 357: 2248-2261 Crossref PubMed Scopus (1244) Google Scholar ].

Letter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)”

HomeCirculationVol. 117, No. 1Letter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by de Boer and van Veldhuisen Regarding Article, “Risk of Thromboembolism in Heart Failure: An Analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)” Rudolf A. de Boer and Dirk J. van Veldhuisen Rudolf A. de BoerRudolf A. de Boer University Medical Center Groningen, Thoraxcenter, Department of Cardiology, Groningen, The Netherlands Search for more papers by this author and Dirk J. van VeldhuisenDirk J. van Veldhuisen University Medical Center Groningen, Thoraxcenter, Department of Cardiology, Groningen, The Netherlands Search for more papers by this author Originally published1 Jan 2008https://doi.org/10.1161/CIRCULATIONAHA.107.725440Circulation. 2008;117:e7To the Editor:We read with interest the recent article from Freudenberger et al.1 The major observation in this article is the incidence of thromboembolism in patients receiving contemporary heart failure management. The increased risk for thromboembolism in heart failure has been appreciated for quite some time, but whether preventive treatment with antiplatelet or anticoagulant agents is indicated in heart failure remains a controversial issue. Current American Heart Association/American College of Cardiology guidelines for the treatment of heart failure do not recommend standard treatment with antiplatelet or anticoagulant agents, except in patients with additional diseases such as coronary artery disease, atrial fibrillation, or ventricular thrombus, or with prosthetic valves.Much to our surprise, treatment with anticoagulant agents (warfarin) was not associated with a lower rate of thromboembolic events in the analysis of Freudenberger et al.1 From the data presented, it remains somewhat unclear which patients are struck by thromboembolism, as the authors do not present data on what percentage of the patients using either antiplatelet or anticoagulant or no antithrombotic therapy developed a thromboembolic event. The authors speculate that the number of embolic events, mainly consisting of ischemic stroke, may have primarily been driven by hypertension and atherosclerosis rather than by cardiogenic embolism. Such a mechanism may have been predominant, because the current analysis excluded patients with prior atrial fibrillation or atrial flutter. Nevertheless, from a pathophysiological perspective, oral anticoagulants should theoretically reduce the occurrence of thromboembolism.These data are important because they add to the currently scarce database on anticoagulant therapy in heart failure. Several (retrospective) analyses from heart failure cohorts2–4 have suggested that anticoagulant agents may reduce heart failure–associated mortality. Thus, next to amiodarone and an implantable cardioverter-defibrillator, available observational evidence suggests that treatment with anticoagulants may reduce morbidity and mortality in heart failure. A large prospective randomized trial testing the efficacy of antiplatelet and anticoagulant therapy in heart failure5 is eagerly awaited.DisclosuresNone. References 1 Freudenberger RS, Hellkamp AS, Halperin JL, Poole J, Anderson J, Johnson G, Mark DB, Lee KL, Bardy GH; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation. 2007; 115: 2637–2641.LinkGoogle Scholar2 Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, Lamas GA, Moyé LA, Goldhaber SZ, Pfeffer MA. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997; 336: 251–257.CrossrefMedlineGoogle Scholar3 Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Warfarin anticoagulation and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 1998; 31: 749–753.CrossrefMedlineGoogle Scholar4 de Boer RA, Hillege HL, Tjeerdsma G, Verheugt FW, van Veldhuisen DJ. Both antiplatelet and anticoagulant therapy may favorably affect outcome in patients with advanced heart failure. A retrospective analysis of the PRIME-II trial. Thromb Res. 2005; 116: 279–285.CrossrefMedlineGoogle Scholar5 Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS; on behalf of the WARCEF Investigators. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail. 2006; 12: 39–46.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 1, 2008Vol 117, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.725440PMID: 18172042 Originally publishedJanuary 1, 2008 PDF download Advertisement SubjectsAnticoagulantsCerebrovascular Disease/StrokeCongenital Heart Disease

The Transforming Growth Factor-β/Smad3 Pathway

Myocardial infarction (MI) is followed by a well-described sequence of events known as postinfarction ventricular remodeling, a process that involves both the infarct scar itself and the residual surviving myocardium.1 The net results of infarct remodeling are changes in chamber size, function, and geometry. Furthermore, the remodeled ventricle becomes a substrate for both heart failure and sudden cardiac death. The elements of post-MI remodeling include infarct expansion, neurohormonal activation, myocardial hypertrophy, myocardial fibrosis, and cellular apoptosis. Article p 2127 These are linked physiological responses that attempt to compensate for the sudden decrease in contractility resulting from acute myocardial cell death.2 Infarct expansion is the thinning of the infarcted segment from slippage and stretching of myocytes and cell rupture. It is highly influenced by hemodynamic loading conditions.3 The prototypic pathways that participate in post-MI remodeling include the autonomic nervous system and renin-angiotensin-aldosterone system, which may be an attempt to maintain blood pressure and cardiac output.4 Over time, however, elevated adrenergic activity may lead to further myocardial cell loss from apoptosis,5 and both adrenergic and renin-angiotensin-aldosterone system upregulation have an adverse impact on cardiac hemodynamics. Myocardial hypertrophy, fibrosis, and apoptosis are primarily seen in the noninfarcted regions of the heart, particularly within the peri-infarct zones.2,6–8 Hypertrophy occurs in response to the increased workload for the surviving myocardiocytes, especially under suboptimal hemodynamic conditions. Myocardial hypertrophy, fibrosis, and apoptosis in the noninfarcted regions are believed to result, in part, from the neurohormonal activation of the sympathetic nervous system, renin-angiotensin-aldosterone system and cytokine cascades. The effect of these processes is to further compound the myocardial damage sustained during the initial acute injury. The end result of these remodeling responses is global ventricular dilatation, which is a significant predictor of dysfunction and future mortality.9 Understanding the components of remodeling …

Vasculoprotective Effects of Anti-Tumor Necrosis Factor-α Treatment in Aging

Vascular aging is associated with dysregulation of tumor necrosis factor (TNF)-alpha expression. TNF-alpha is a master regulator of vascular proatherogenic phenotypic changes, and it has been linked to endothelial dysfunction and apoptosis. To test the hypothesis that anti-TNF-alpha treatment exerts vasculoprotective effects in aging, aged (29 months old) F344 rats were treated with etanercept (1 mg/kg/week for 4 weeks), which binds and inactivates TNF-alpha. In aged carotid arteries, relaxations to acetylcholine were decreased, and endothelial O2* production was increased (as shown by dihydroethidine fluorescence measurements). Etanercept treatment significantly improved responses to acetylcholine and decreased vascular NAD(P)H oxidase activity and expression. In aged carotid and coronary arteries, there were increases in DNA fragmentation rate and caspase 3/7 activity (indicating an increased rate of apoptotic cell death), which were attenuated by etanercept treatment. In aged vessels, there was an up-regulation of inflammatory markers, including inducible nitric-oxide synthase and intercellular adhesion molecule-1, which was decreased by etanercept treatment. In carotid arteries of young animals, recombinant TNF-alpha elicited endothelial dysfunction, oxidative stress, and increased apoptosis and proinflammatory gene expression, mimicking many of the symptoms of vascular aging. Thus, we propose that anti-TNF-alpha treatment exerts anti-aging vasculoprotective effects.

N-Terminal Pro-B-Type Natriuretic Peptide as an Indicator of Disease Severity in a Heterogeneous Group of Patients With Chronic Precapillary Pulmonary Hypertension

N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) is well established as a predictor of prognosis in patients with left ventricular dysfunction. Although a similar prognostic significance has been suggested in 1 study of right ventricular failure and idiopathic pulmonary arterial hypertension, NT-pro-BNP has not been assessed as a marker of disease severity in a more heterogenous group of patients with chronic precapillary pulmonary hypertension (PH). Hence, this study assessed plasma NT-pro-BNP and other clinical variables in 61 consecutively recruited patients with various forms of chronic precapillary PH. Right-sided cardiac catheterization and cardiopulmonary exercise testing were performed at baseline, and the prognostic significance of NT-pro-BNP was investigated with a mean follow-up of 25 months. Compared with age-matched controls (n = 10), plasma NT-pro-BNP was significantly greater in those with idiopathic pulmonary arterial hypertension (n = 16), chronic precapillary PH associated with other diseases (n = 26), and chronic thromboembolic disease (n = 19) and was correlated with hemodynamic variables and functional capacity. In 17 medically treated patients, the significant decrease in NT-pro-BNP levels correlated with improved hemodynamics. During follow-up, 15 patients died from cardiopulmonary causes. Baseline NT-pro-BNP was an independent predictor of mortality. Kaplan-Meier survival analysis according to the median value of NT-pro-BNP (168 pmol/L) demonstrated a significantly higher mortality rate in those with supramedian values than in those with low plasma levels (p = 0.010). In conclusion, these findings suggest that in a heterogenous group of patients with chronic precapillary PH, plasma NT-pro-BNP can be used to determine the clinical severity of disease and is independently associated with long-term mortality.

Contemporary Use of Digoxin in the Management of Cardiovascular Disorders

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

First line treatment with beta-blockers followed by adjuvant ACE inhibitors after six months may be safe in older people with heart failure

ee front matter & 2006 Elsevier Ltd. All rights reserv bcm.2006.01.037 from Willenheimer R, van Veldhuisen DJ, Silke B on survival and hospitalization of initiating hronic heart failure with bisoprolol followed by mpared with the opposite sequence: results of Cardiac Insufficiency Bisoprolol Study (CIBIS) III. 5; 112(16): 2426–35. ventricular ejection fraction less than or equal to 35%, who had not received ACE inhibitors, betablockers, or angiotensin receptor blockers for more than seven days within three months. Mean age 72 years; 32% were women.

Comment on “Clinical trials update from the European Society of Cardiology meeting 2005: CIBIS‐III, by JGF Cleland and others”

Citation for the published paper: Willenheimer, Ronnie and Krum, Henry and van Veldhuisen, Dirk J and FunckBrentano, Christian and Erdmann, Erland and Meyer, Wilfried R. Comment on Clinical trials update from the European Society of Cardiology meeting 2005: CIBIS-III, by JGF Cleland and others. European Journal of Heart Failure, 2006, Vol: 8, Issue: 2, pp. 219-20. http://dx.doi.org/10.1016/j.ejheart.2006.01.006

Section 15: Management of Heart Failure in Special Populations

Section 15: Management of Heart Failure in Special Populations

Digitalis therapy for patients in clinical heart failure.

The most commonly used preparation of digitalis is digoxin, which is obtained from the leaves of Digitalis lanata , a common flowering plant called “foxglove.” The words digitalis and digoxin in this article are used interchangeably. An exhaustive review published in 19961 cited a large number of references and had detailed data and descriptions of a large number of studies and all early trials. The present article summarizes those data but focuses on and emphasizes data collected since that time. These have been described in detail previously1 and are briefly summarized. ### Inotropic Effects The inotropic effects have been documented in the isolated papillary muscles and in the normal hearts of animals and humans. The inotropic action occurs in both ventricles and in both atria. In the normal heart and in those with coronary artery disease and normal left ventricular (LV) systolic function, with digitalis the LV function curve is moved upward and to the left.1 As a result, LV end-diastolic pressure and LV end-diastolic and end-systolic volumes are reduced, and there is an increase of LV ejection fraction (LVEF).1 ### Patients With Heart Failure In patients with heart failure (HF), digoxin slows the ventricular rate (1) in sinus rhythm because of an improvement in HF and withdrawal of sympathetic stimulation and (2) in atrial fibrillation by increasing parasympathetic tone. The combination of digoxin and carvedilol is superior to digoxin or carvedilol alone.2 ### Peripheral Vessels In normal subjects given intravenous ouabain, there is arterial and venous vasocontriction.3 The vasoconstriction is obviated by administering digoxin slowly over a period of 15 to 20 minutes1; moreover, the vasoconstriction lasts up to 30 minutes. The seminal study of Mason and Braunwald3 showed that in HF, the effects are different. Digitalis produces an increase of blood flow, a decrease of vascular resistance, venodilation, and a …

1363: Quality of Life and Depression are Related in Heart Failure Patients

Restricted accessAbstractFirst published April 20041363: Quality of Life and Depression are Related in Heart Failure PatientsI. Lesman-Leegte [email protected], T. Jaarsma, […], M. van der Wal, and D.J. van Veld-huisen+1-1View all authors and affiliationsVolume 3, Issue 1https://doi.org/10.1017/147451510400300164

Reducing radiotherapy dose in early breast cancer: the concept of conformal intraoperative brachytherapy.

MD, FRCS, FRCRMeyerstein Institute of Oncology and Academic Department of Surgery, University College London Hospitals NHS Trust,London, UKIn Time magazine’s extensively researched breast cancerissue (June 10, 2002), one particular quote had a specialresonance for us. In the introduction to a remarkablycomprehensive article, Dr Julie Gralow, an Oncologist atthe Fred Hutchinson Cancer Research Centre in Seattle,stated ‘‘We may be far overtreating our patients… We’venow got women being diagnosed with tumours that wouldprobably never have been treated if we didn’t havemammography. They probably would have lived long,natural, healthy lives never knowing they had breastcancer’’ (J Gralow, quoted in [1]).For some years it has been apparent that, for manypatients, powerful treatment by surgery (even when limitedto tumour excision with breast preservation) together witha 6 week programme of radiation therapy may be morethan sufficient. We already know a good deal (althoughnot of course enough) about the profile of a typical breastcancer patient with low risk of local and distant recur-rence: a small, low or moderate grade tumour, surgicallycompletely excised, positive for oestrogen and/or proges-terone receptors, negative for HER2 and with negativeaxillary nodes. Post-menopausal patients clearly have alower incidence of local recurrence; for example, in thelarge study by Bartelink et al [2], patients over the age of60 years had a rate of local recurrence following 50 Gywhole breast radiation of only 4% (without an additionalboost), the rate reducing still further to 2.5% with anadditional 16 Gy given by electron beam therapy. Forpatients aged 41 to 50 years, the rates were 9.5% and 5.8%,respectively (median follow-up 5.1 years). What’s more, anever increasing number of patients now present with smalltumours (,1 cm) identified on mammographic screening,of whom approximately three-quarters will have oestrogenreceptor (ER)/progesterone receptor (PR) positive tumours,for which targeted hormone therapy with tamoxifen offerssustained long-term benefit for both local and distantrelapse [3, 4]. Using a well tolerated oral aromataseinhibitor such as Anastrazole reduces the risk still further(for both local and distant relapse), also, incidentally,reducing by three-quarters the risk of development of acontralateral primary breast cancer [5].For all these reasons, we strongly support Gralow’sview. Even in younger women known to be at higher riskof relapse, including those with axillary node-positivedisease, the use of systemic adjuvant cytotoxics sharplyreduces the risk of recurrence [3, 4, 6]. For hormonereceptor-positive patients, i.e. the large majority, adjuvanthormone therapy as well as surgical or medical oophor-ectomy all add further benefit [2–4, 6].What is the consequence of Gralow’s observation? Inthe past, it has been regarded as mere flight of fancy toimagine that we can identify patients at such low risk ofrecurrence that a less intensive form of treatment thanlocal surgical excision followed by whole breast irradiationcould be regarded as ‘‘adequate’’. In this sense, thisgeneral policy remains little different in principle from theequally compelling (in its day) policy of radical, then lessdamaging forms of mastectomy – although admittedly,using local excision, breast preservation and post-operativeradiotherapy is generally regarded as more ‘‘humane’’ eventhough attempts at demonstrating an improved quality oflife have been largely elusive [7]. None the less, theevolving history of local treatment for early breast cancerhas centred on an ever increasing recognition of theimportance of breast conservation for body image andcosmesis, an essential requirement for most women. Thishas largely been achieved by the increasing acceptance ofbreast-conserving surgery with post-operative radiotherapy[8]. Yet despite this ready acceptance, recent data from theworld’s largest ever randomized breast cancer study, withexcellent quality control and a high level of expertise,confirm a mastectomy rate approaching 50% [ATACTrialists Group, unpublished data].We believe that the time has come to move on further.For many patients, particularly those presenting over theage of 50 years with small, low grade, ER positive, axillarynode negative tumours, it is surely right to question thenecessity of a lengthy and sometimes damaging course ofradiation therapy. Radiation oncologists who are totallysatisfied with their often excellent cosmetic results and lowrelapse rates following standard treatment should bearin mind the work of the Oxford-based Early BreastCancer Trialists’ Collaborative Group, namely that despitea lower breast cancer cause-specific death rate in irradiatedpatients, the increased mortality for other non-cancercauses wipes out this advantage [9]. The assumption thatthe excess non-cancer-related deaths in this large meta-analysis were due essentially to reliance on older outmodedradiation techniques may be correct – but it remains anassumption only, and considerable additional data attestto the cardiac, pulmonary and neurological dangers ofwhole breast irradiation [10–12]. Moreover, the use ofanthracycline-based chemotherapy regimens apparentlyincreases some of these risks still further [13].

Progression of Heart Failure

The cardiac ryanodine receptor (RyR2)/Ca2+ release channel on the sarcoplasmic reticulum (SR) is regulated by evolutionarily highly conserved signaling pathways that control excitation-contraction (EC) coupling in the heart. Phosphorylation of RyR2 by cAMP-dependent protein kinase (PKA) plays a key role in regulating the channel in response to stress via activation of the sympathetic nervous system (the “fight-or-flight response”).1 Maladaptive PKA hyperphosphorylation of RyR2 in failing hearts alters channel function, which may cause depletion of SR Ca2+ and diastolic release of SR Ca2+. This can initiate delayed afterdepolarizations that trigger ventricular arrhythmias.1 Mutations in RyR2 recently have been identified in patients with catecholaminergic induced sudden cardiac death (SCD).2–4⇓⇓ There may be a direct link between the PKA hyperphosphorylation of RyR2 that occurs during the progression of heart failure and fatal cardiac arrhythmias. Regulation of cardiac EC coupling by the release of Ca2+ from the SR via RyR2 in cardiomyocytes, known as Ca2+-induced Ca2+ release (CICR), has been appreciated for more than a decade.5,6⇓ Furthermore, it is well known that the amplitude of the Ca2+ transient generated by SR Ca2+ release determines contractile force in cardiomyocytes. The systems that regulate SR Ca2+ release include: (1) the triggers (predominantly Ca2+ influx through the voltage-gated Ca2+ channel on the plasma membrane); (2) the SR Ca2+ release channel or type 2 RyR2; and (3) the SR Ca2+ reuptake pump (SERCA2a) and its regulator phospholamban. These systems (trigger, release, and reuptake) are modulated by signaling pathways, including the β-adrenergic receptor (β-AR) signaling pathway (ie, phosphorylation by PKA). Activation of the sympathetic nervous system in response to stress results in elevation of cAMP levels and activation of PKA. Phosphorylation of RyR2 may not correlate directly …