Displaying 1-10 letters out of 732 published
Impact of Beta-blocker on The Outcome of Takotsubo Cardiomyopathy
The article by Isogai et al. published in Heart (1) discuss the use of beta-blockers in patients diagnosed and admitted with takotsubo cardiomyopathy (TTC).
Although no effective guidelines have been prescribed for the treatment of TTC, it is suggested that a parable could be drawn by comparing the use of beta-blocker and angiotensin-converting-enzyme inhibitors in these patients with that of control subjects as well as those suffering from coronary artery disease. Beta-blockers were considered more likely to be prescribed to control subjects and patients diagnosed with coronary artery disease than to patients diagnosed with TTC. Interestingly, TTC and coronary artery disease patients received angiotensin-converting-enzyme inhibitors / angiotensin receptor blockers more often than control subjects. The concluding suggestion that the 5 year mortality is similar in both disease groups and higher than control subjects furthers our debate on this topic. The large International Takotsubo Registry reported a 5.6% mortality per-patient year (2) and the use of angiotensin-converting- enzyme inhibitors or angiotensin receptor- blockers was associated with improved survival rates. However, evidence establishing a marked survival benefit with beta-blocker use has yet to be documented. The pathogenesis of TTC is yet to be fully understood. A popular hypothesis suggests the involvement of a catecholamine-mediated mechanism. Although all these trials essentially compared the outcome of TTC with matched cohorts of patients with coronary artery disease, a relevant suggestion elucidates the role of an inflammatory and energetic- metabolic pathway as a possible pathophysiological mechanism (3). We retrospectively described a collective of 114 consecutive patients diagnosed with TTC between January 2003 and September 2015 at our institution. Our data showed that the use of beta-blocker was associated with improved survival rates over mean follow-up of 5 years (4). These novel findings necessitate the need for a standardized treatment regimen in TTC patients. We recommend the urgent need of randomized trials to clearly define treatment approaches and management strategies in takotsubo cardiomyopathy thus enabling the practice of evidence-based medicine within guidelines.
1. Isogai T, Matsui H, Tanaka H, et al. Early beta-blocker use and in -hospital mortality in patients with Takotsubo cardiomyopathy. Heart 2016;102(13):1029-1035. 2 . Templin C, Ghadri JR, Diekmann J, et al. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015;373(10):929-938. 3. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306(3):277-286. 4. Becher T, El-Battrawy I, Baumann S, et al. Characteristics and long- term outcome of right ventricular involvement in Takotsubo cardiomyopathy. Int J Cardiol 2016;220:371-375.
Conflict of Interest: None declared
Conflict of Interest:
It is important to distinguish between HFrEF and HFpEF when interpreting these data
In this interesting article, Lipworth and colleagues report that beta -blockers are underused in patients with heart failure (HF) and COPD, compared to those with HF alone. However, they do not quote the proportion of "HF" patients within their dataset who had HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction (LVEF) <40%) and HF with preserved ejection fraction (HFpEF; LVEF >50%). This distinction is important, as beta-blockers are only recommended in HF guidelines for patients with HFrEF (1), owing to a lack of trial data to support their efficacy in patients with HFpEF.
Furthermore, patients with HFpEF tend to have a higher prevalence of co-morbidities compared to patients with HFrEF, including COPD, hypertension and diabetes (2). Thus, it is possible that "HF and COPD" patients in this dataset may have a higher proportion of HFpEF to HFrEF, in comparison to patients with "HF alone", and the rates of ACE/ARB prescribing may be increased in this group owing to treatment of hypertension and diabetes rather than HF. These considerations may therefore confound the strength of the authors' conclusions regarding underuse of beta-blockers in patients with HF and COPD.
1. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; DOI: 10.1093/eurheartj/ehw128.
2. Ather S, Chan W, Bozkurt B et al. Impact of non-cardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998-1005.
Conflict of Interest:
Hypertrophic cardiomyopathy and the potential influence of etomidate on postoperative outcomes.
We read with interest the paper by Dhillon and colleagues which provided a high quality propensity matched observational study of perioperative outcomes in patients with hypertrophic cardiomyopathy (HCM).1 This study showed no difference in what they defined as 'hard outcomes' such as myocardial infarction, stroke and death. They did however show an increased incidence of composite end points (10%; p= 0.03) such as post-operative congestive heart failure (CHF) (1%) and readmission rates (7%).
One interesting point that we would like to raise is the significantly higher use of etomidate in the HCM cohort (p= 0.002). Understandably, etomidate was chosen in many cases for its rapid onset and stable haemodynamic properties. This was likely reflected in the significantly lower incidence of intra-operative tachycardia and hypotension in HCM patients. However the use of etomidate is not without controversy, with several studies have linked its use as a single dose induction agent to post operative acute adrenal insufficiency.2,3 The use of etomidate may be a significant confounding factor in this study. Previous groups have demonstrated similar types of adverse outcomes with the use of etomidate; Komatsu and colleagues found substantially increased incidence of post-operative adverse events and even mortality when compared to the current paper.2 These differences may be related to a lower rates of etomidate use by Dhillon and colleagues.
Given that there is currently a great deal of controversy surrounding the use of etomidate it would be beneficial to see a breakdown of outcomes in the subgroup that received etomidate. If the increased incidence of adverse outcomes were related to the use of etomidate, then non-cardiac surgery performed on HCM patients in experienced centres may no longer be 'high risk'.
1. Dhillon A, Khanna A, Randhawa M, Cywinski J, Saager L, Thamilarasan M, Lever H & Desai M (2016). Perioperative outcomes of patients with hypertrophic cardiomyopathy undergoing non-cardiac surgery. Heart. 0: 1-6.
2. Komatsu R, You J, Mascha E, Sessler D, Kasuya Y & Turan A (2013). Anaesthetic induction with etomidate, rather than propofol, is associated with increased 30-day mortality and cardiovascular morbidity after noncardiac surgery. Anaesth Analg. 117(6): 1329-37.
3. Chan C, Mitchell A & Shorr A (2012). Etomidate is associated with mortality and adrenal insufficiency in sepsis: A meta-analysis. Crit Care Med. 40(11): 2945-2953.
Conflict of Interest:
Does loneliness and social isolation really increase the risk of CHD and stroke? Pooled results based on quality effect model
Loneliness and social isolation may lead to CHD and stroke? Valtorta et al. answered this question in a recent meta-analysis . After pooling evidence based on 16 cohorts, they found that poor social relationships increase the risk of CHD and stroke. However, do things really like this? Maybe not. The problem is the random-effect (RE) model they used, which may lead to overconfident and biased results [2, 3]. Because under RE model, large studies were given more weight while the study quality was ignored . Moreover, RE model is proved to link with underestimated coverage probability . To solve these limitations, a widely accepted model called quality effect (QE), proposed by Doi et al.  has been gradually valued. In order to see if poor social relationships really increase the risk of CHD and stroke, we might re-pool the evidence by QE model . We use the information of risk of bias summarized in Figure 2 and assume low risk of bias to be 2 score, high risk of bias 0 score, and unclear risk of bias 1 score to quantification estimator of quality. By doing so, the quality of each included study can be measured as total score (also known as Qi in QE model ). Under QE procedure, interestingly, loneliness and social isolation no longer lined with increased risk of CHD (RR=1.24; 95%CI: 0.97, 1.57) and stroke (RR=1.26; 95CI%: 0.95, 1.68). That is to say, when taking quality item into consideration, the pooled results no more statistical significance. Then, can we still claim poor social relationships increase the risk of CHD and stroke? Maybe we should treat the conclusion with caution.
Conflicts: The authors declare no conflicts and interests. Reference 1. Valtorta NK, Kanaan M, Gilbody S, et al. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies. Heart 2016; 102(13):1009-16.
2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials. 1986; 7:177-188.
3. Brockwell SE, Gordon IR. A comparison of statistical methods for meta-analysis. Stat Med. 2001; 20(6): 825-840.
4. Doi SA, Barendregt JJ, Khan S, et al. Advances in the meta- analysis of heterogeneous clinical trials II: The quality effects model. Contemp Clin Trials. 2015; 45(Pt A): 123-129.
Conflict of Interest:
Midregional pro-atrial natriuretic peptide and N-terminal pro-B natriuretic peptide for pediatric heart failure diagnosisMidregional pro-atrial natriuretic peptide and N-terminal pro-B natriuretic peptide for pediatric heart failure diagnosis Running title Natriuretic peptides for pediatric HF diagnosis Guo-Ming Zhang,1 Zhi-De Hu2 1 Department of Laboratory Medicine, Shuyang People's Hospital, Shuyang, China 2 Department of Laboratory Medicine, The General Hospital, Jinan Military Command Region of PLA, Jinan, Shandong, China Correspondence to Dr Zhi-De Hu, Department of Laboratory Medicine, the General Hospital of Jinan Military Command Region, Jinan, Shandong, P.R. China; email@example.com To the Editor, We read with interest the paper from Hauser et al. published recently in Heart . To evaluate the diagnostic values of serum midregional pro-atrial natriuretic peptide (MR-proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), midregional pro-adrenomedullin (MR-proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) for pediatric heart failure (HF), the investigators enrolled 114 pediatric HF patients and 89 controls. Diagnostic values of these biomarkers were evaluated using receiver-operating characteristic (ROC) curve analysis and logistic regression model. They found that both MR-proANP and NT-proBNP were useful for HF diagnosis, while the diagnostic values of GDF-15, MR-proADM and sST2 were limited. Although the diagnostic values of MR-proANP and NT-proBNP have been well documented in adult HF patients [2, 3], their diagnostic values for pediatric HF patients remains largely unknown. Because the causes, signs and symptoms of pediatric HF differs substantially from its adult counterpart, the conclusion derived from adult HF cannot be applied in pediatric patients. Therefore, it is necessary and valuable to investigate the diagnostic values of NT-proBNP and MR-proANP for pediatric HF. The work performed by Hauser et al. is novel and interesting. However, some of the findings in this study need extra attention. In this study, no pre-designed inclusion and exclusion criteria were adopted to enroll entire study cohort consecutively, and controls in this study were patients without heart disease undergoing phlebotomy. Therefore, this is a two-gate design study with alternative diagnosis controls . The major limitation of this type of design is that the specificities of index tests may be biased, depending on the type of alternative diagnosis included. It seems that the controls in this study do not have risk factors, symptoms and signs of HF, and clinicians do not need biomarkers to distinguish between them and patients with HF. It would be better to consecutively enroll all subjects using well defined criteria (one-gate design). Under such a case, the controls are subjects who also have clinical presentations of HF, and the entire cohort represent a target population in whom MR-proANP and NT-proBNP should be tested. Taken together, the work performed by Hauser et al. provides us new insight into the diagnostic values of MR-proANP and NT-proBNP for pediatric HF. However, due to the design weakness, further well designed studies are needed to rigorously evaluate the diagnostic values of MR-proANP and NT-proBNP for pediatric HF Conflicts of interest The authors stated that there are no conflicts of interest regarding the publication of this article. Acknowledgements None References 1 Hauser JA, Demyanets S, Rusai K, et al. Diagnostic performance and reference values of novel biomarkers of paediatric heart failure. Heart 2016. 2 Hu Z, Han Z, Huang Y, et al. Diagnostic power of the mid-regional pro-atrial natriuretic peptide for heart failure patients with dyspnea: a meta-analysis. Clin Biochem 2012;45:1634-9. 3 Roberts E, Ludman AJ, Dworzynski K, et al. The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting. BMJ 2015;350:h910. 4 Rutjes AW, Reitsma JB, Vandenbroucke JP, et al. Case-control and two-gate designs in diagnostic accuracy studies. Clin Chem 2005;51:1335-41.
Conflict of Interest:
Fontan conversion is a dated approach to the Failing Fontan
We read with great interest the report by van Melle et al. who conducted a retrospective multi-centre European study to assess surgical options for the failing Fontan . Firstly, we would like to acknowledge the effort made to bring together the results of these infrequently performed, difficult interventions. However, we would also like to highlight concerns with the conclusions reached from this historical mixed registry data. The authors state that a late failing Fontan patient with poor ventricular function is better off with a heart transplant, while preserved ventricular function can be treated with conversion. It should be noted, however, that heart transplantation here was performed mainly in children, whilst conversion was predominantly indicated for right atrial dilatation and intractable arrhythmia in young adults with atrio-pulmonary Fontans. The atrio-pulmonary Fontan operation has not been performed for more than a decade and patient numbers with this repair are diminishing . As more energy efficient circulations are developed, the substrate for arrhythmia is evolving. It is improbable that these results can therefore be generalised to make a case for future conversions. Furthermore, as the authors acknowledge, the Fontan population is aging; it is our experience that increasingly patients present in their thirties and forties with failure of the circulation due to extra-cardiac disease, most notably the liver [3,4]. Failure to identify, assess and address this in patients with preserved ventricular function may increase the risk and sometimes preclude the option of transplantation. The role of Fontan takedown, as stated, has not been elucidated for the late failing Fontan; we should question too whether there may be an alternative way to balance the circulation, avoiding the Fontan in the first place . In the meantime, addressing listing criteria for late failing Fontan and exploring utility of ventricular assist devices must be the priority for the current population. Fontan conversion may have a role in highly selected cases but should not be regarded as a definitive option to timely transplantation for the growing adult patient group. Extrapolating past results in a changing surgical arena to current and future populations must be treated with caution.
References  van Melle JP, Wolff D, H?rer J et al. Surgical options after Fontan failure. Heart. 2016 Apr 13.  d'Udekem Y, Iyengar AJ, Galati JC et al. Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow -up from the entire population of Australia and New Zealand. Circulation. 2014;130(11 Suppl 1):S32-8.  Coats L, O'Connor S, Wren C et al. The single-ventricle patient population: a current and future concern a population-based study in the North of England. Heart. 2014;100(17):1348-53.  Greenway SC, Crossland DS, Hudson M et al. Fontan-associated liver disease: Implications for heart transplantation. J Heart Lung Transplant. 2016;35(1):26-33.  D'Souza TF, Samuel BP, Hillman ND, Vettukattil JJ, Haw MP. Biventricular Repair of Pulmonary Atresia After Fontan Palliation. Ann Thorac Surg. 2016;101(4):1574-6.
Conflict of Interest:
Loneliness and social isolation and increased risk of of coronary heart disease and stroke: clinical implications
The recent meta-analysis published in Heart by Valtorta et al. (1) showed that loneliness and social isolation are associated with increased coronary heart disease and stroke incidence in 16 large longitudinal studies conducted in high income countries. This finding is not surprising given the extensive literature documenting such harmful consequences of social isolation, including a study my research group published in 1992 (2) showing in a large sample of CHD patients that those who were not married and did not have a confident -- and hence likely to be lonely and socially isolated -- had a 5-year mortality (50%) that was nearly three times larger than that observed (18%) in patients with a spouse and/or partner.
The most important implication of this finding is that interventions that reduce loneliness and social isolation have the potential to prevent disease development and improve prognosis once disease is present. There is encouraging preliminary evidence that such interventions have been developed and shown to reduce social isolation in CHD patients and other groups and improve prognosis in CHD patients. Bishop et al. (3) showed in a randomized controlled trial of Singaporean male coronary artery bypass graft surgery patients that psychosocial skills training delivered in small groups produced a significant increase in satisfaction with social support and satisfaction with life, as well as decreases in depression, anger and blood pressure at rest and in response to anger recall stress. Chun et al. (4) showed in a controlled clinical trial of Chinese medical students that this same psychosocial skills training produced a significant increase in social support as well as improvements in other psychosocial risk factors. Direct support for the clinical efficacy of such training delivered in small groups comes from two randomized controlled trials in Sweden (5, 6) showing that similar interventions produced significant reductions in mortality and recurrent cardiovascular events in CHD patients.
The evidence from the Valtorta et al. study combines with the encouraging evidence that psychosocial skills training has been shown to reduce loneliness and social isolation in both CHD and healthy groups and improve prognosis in CHD patients to make a strong case that it is now appropriate to undertake large simple trials of such interventions in CHD patient groups. If such trials document that such training produces reduced morbidity and mortality, it would then be appropriate to undertake primary prevention trials in healthy groups.
1. Valtorta NK, Kanaan M, Gilbody S, et al. Loneliness and social isolation as risk factors for coronary heart disease and stroke: systematic review and meta-analysis of longitudinal observational studies. Heart Published Online First 2016 (heartjnl-2015-308970).
2. Williams, R.B., Barefoot, J.C., Califf, R.M., Haney, T.L., Saunders, W.B., Pryor, D.B., Hlatky, M.A., Siegler, I.C., Mark, D.B. Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease. JAMA. 1992;267:520-4.
3. Bishop GD, Kaur D, Tan VLM, et al. Effects of a psychosocial skills training workshop on psychophysiological and psychosocial risk in patients undergoing coronary artery bypass grafting. Am Heart J 2005;150:602-609.
4. Chun, L, Chu F, Wang H, Wang XP. Efficacy of Williams LifeSkills training for improving psychological health: a pilot comparison study of Chinese medical students. Asia Pac Psychiatry. 2014;6:161-9.
5. Gulliksson M, Burell G, Vessby B, Lundin L, Toss H, Sverdsudd K. Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). Arch Intern Med. 2011;171:134-40.
6. Orth-Gomer K, Schneiderman N, Wang HX, Walldin C, Blom M, Jernberg T. Stress reduction prolongs life in women with coronary disease: the Stockholm Women's Intervention Trial for Coronary Heart Disease (SWITCHD). Circ Cardiovasc Qual Outcomes. 2009;2:25-32.
Redford B. Williams, M.D. Professor of Psychiatry and Behavioral Sciences, Professor of Medicine, Professor of Psychology and Neuroscience, Director, Behavioral Medicine Research Center
Conflict of Interest:
I am a founder and major stockholder in Williams LifeSkills,Inc., the company that developed the psychosocial skills training program used in the Bishop et al. (3) and Chun et al. (4) papers cited in my letter.
Response: A novel troponin I rule-out value below the upper reference limit for acute myocardial infarction
To the Editor,
Goorden et al aim to establish the optimal threshold to rule out myocardial infarction using a high-sensitivity cardiac troponin I assay. They report that a cardiac troponin I concentration <10 ng/L or a change of <20 ng/L on serial testing had a negative predictive value for the diagnosis of myocardial infarction of 99.8% and 98.7% respectively . Whilst we agree there are better approaches to rule out myocardial infarction than using the 99th centile upper reference limit [2,3], we have several concerns about the generalisability and application of these thresholds in clinical practice.
First, the authors compared diagnostic sensitivity and specificity to identify thresholds for cardiac troponin I with similar diagnostic performance to the reference standard. When used in conjunction with a separate rule in threshold, we believe the optimal threshold to rule out myocardial infarction should prioritise sensitivity alone to ensure a high negative predictive value.
Second, the prevalence of myocardial infarction was low (8%; 114/1490) and included a significant proportion of patients with ST- segment elevation myocardial infarction (2%; 23/1490) where rule-out strategies based on cardiac biomarkers are inappropriate. Inclusion of these patients will overestimate the negative predictive value of the proposed rule out threshold. Furthermore, the negative predictive value will be lower in hospitals with a higher prevalence of myocardial infarction.
Third, this analysis was restricted to patients where symptoms were present for at least 3 hours, limiting the clinical applicability of the derived rule out thresholds as patients presenting early are at increased risk of misdiagnosis and are precisely the population in whom rule out thresholds must be validated.
Fourth, the analysis assumes the thresholds used for the reference standard are optimal. The recommended rule in threshold for cardiac troponin T is 14 ng/L (99th centile upper reference limit ) and the limit of detection (5 ng/L) has been proposed to rule out myocardial infarction. Goorden et al did not apply these thresholds in their analysis, and as such the thresholds derived for cardiac troponin I are challenging to interpret and may not be relevant to current clinical practice.
In the absence of external validation and whilst these uncertainties remain we would caution against the use of these thresholds in clinical practice.
 Goorden SMI, van Engelen, RA, Wong LSM et al. A novel troponin I rule-out value below the upper reference limit for acute myocardial infarction. Heart Published Online First: 11th April 2016. doi:10.1136/heartjnl-2015-308667
 Shah AS, Anand A, Sandoval Y, Lee KK, Smith SW, Adamson PD, Chapman AR et al. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study. Lancet. 2015 Dec 19;386(10012):2481-8.
 Pickering JW, Greenslade JH, Cullen L et al. Validation of presentation and 3 h high-sensitivity troponin to rule-in and rule-out acute myocardial infarction. Heart. Published online first: 8th March 2016. doi:10.1136/ heartjnl-2015-308505
 Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universal definition of myocardial infarction. Circulation. 2012 Oct 16;126(16):2020-35.
Conflict of Interest:
AA has received speaker fees from Abbott Laboratories. ASVS has acted as a consultant for Abbott Laboratories. NLM has acted as a consultant for Abbott Laboratories, Beckman-Coulter, Roche, and Singulex. The other authors declare no competing interests.
Regarding sex differences in cardiovascular ageing: let's not forget iron
The interesting paper of Merz and Cheng did not mention iron as a plausible non-hormonal factor, which might in part explain the sex differences in cardiovascular aging .
Mounting evidence suggests that the metabolic derangements and detrimental cardiovascular effects usually attributed to menopause represent only a mere consequence of the older age of menopausal women, rather than related to the loss of ovarian function. In fact, heart protection by premenopausal levels of female hormones, that is the oestrogen hypothesis, is not consistent with epidemiological findings that premenopausal hysterectomy essentially cancels the protection even in patients with preservation of functioning ovaries . On the contrary, these data  suggest that an intact uterus has an important role in the protection of premenopausal women, and this is likely related to the beneficial effect of iron depletion in menstruating women (i.e. the iron hypothesis suggested since 1981 by Sullivan ).
A protective effect of iron depletion may be related to the decreased availability of redox-active iron within atherosclerotic lesions. Serum ferritin concentrations, commonly used as a surrogate for iron stores, are significantly lower in premenopausal menstruating women (25-50 ng/mL) compared to men (140-150 ng/mL) of similar age, but slowly increase after menopause. Interestingly, average menstrual blood loss each year (780 mL) approximates blood loss from donating approximately two 500 mL units of whole blood . It is noteworthy that phlebotomy of one unit of whole blood twice a year among predominantly white middle-aged and elderly men with peripheral arterial disease, resulted in a significant decrease in overall mortality, myocardial infarction and stroke over a several year period, compared to the control group not phlebotomized . Not surprisingly, during the trial, the average serum ferritin concentration in the iron reduction group was approximately 60 ng/mL compared to 110 ng/mL in the control group . On the contrary, it has become evident that supplemental iron use among elderly woman may be significantly and dose dependently associated with increased total mortality .
In conclusion, higher vascular wall iron, contained in macrophages, might in part explain the sex difference in cardiovascular ageing. Moreover, donating blood twice a year by men and possibly postmenopausal women might decrease CVD morbidity and mortality. Furthermore, unnecessary iron supplements should be avoided and iron fortification of our food supply should be questioned. Finally, randomized trials of iron depletion for the primary and secondary prevention of vascular disease need to be done.
1. Merz AA, Cheng S. Sex differences in cardiovascular ageing. Heart 2016 Feb [Epub ahead of print]. 2. Kannel WB, Levy D. Menopause, hormones, and cardiovascular vulnerability in women. Arch Intern Med 2004;164:479-81. 3. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-4. 4. Zacharski LR, Shamayeva G, Chow BK. Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease. Am Heart J 2011;162:949-957.e1. 5. Mursu J, Robien K, Harnack LJ. Dietary supplements and mortality rate in older women: the Iowa Woman's Health Study. Arch Intern Med 2011;171:1625-1633.
Conflict of Interest:
Author Reply: Sex Differences in Cardiovascular Ageing
We thank Dr. Goldstein for bringing to our attention the iron hypothesis as a potential non-hormonal factor contributing to sex differences in cardiovascular aging. We also find intriguing the possibility that iron depletion in menstruating women may be cardio- protective. We had previously been aware of the potential role of iron as a byproduct of heme-oxygenase activity in mediating cardiometabolic risk, with a number of community studies having reported equivocal findings when examining the relation between either iron or ferritin with respect to outcomes.[2-5] It is our impression that heterogeneity in prior study results may be related to differences in participant sampling methods, the iron measures used (ferritin, total iron binding capacity, transferrin saturation, serum iron, and dietary iron intake), and presence of potential confounding variables that could influence both iron levels and a given outcome of interest (e.g. inflammation, genetic variants). Given that iron accumulation patterns have been observed to vary by age and race as well as sex, we agree that further studies investigating the role of iron as a potential contributor to cardiovascular risk are warranted. In particular, interventional studies could evaluate sex-based differences and also account for variables that could influence both iron levels and a given outcome of interest (e.g. blood donation and/or phlebotomy patterns, supplemental intake of iron, dietary patterns including heme vs. non-heme iron intake, and factors that might elevate ferritin as part of the acute phase response). We look forward to learning more about the potential contribution of iron depletion to sex differences in cardiovascular disease, in particular, as additional evidence emerges from this understudied field.
1. Fredenburgh LE, Merz AA, Cheng S. Haeme oxygenase signalling pathway: implications for cardiovascular disease. Eur Heart J. 2015 Jun 21;36(24):1512-8. doi: 10.1093/eurheartj/ehv114. Epub 2015 Mar 31. Review. PubMed PMID: 25827602; PubMed Central PMCID: PMC4475572.
2. Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Sepp?nen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992 Sep;86(3):803-11. PubMed PMID: 1516192.
3. Baer DM, Tekawa IS, Hurley LB. Iron stores are not associated with acute myocardial infarction. Circulation. 1994 Jun;89(6):2915-8. PubMed PMID: 8205708.
4. Mu?oz-Bravo C, Guti?rrez-Bedmar M, G?mez-Aracena J, Garc?a- Rodr?guez A, Navajas JF. Iron: protector or risk factor for cardiovascular disease? Still controversial. Nutrients. 2013 Jul 1;5(7):2384-404. doi: 10.3390/nu5072384. Review. PubMed PMID: 23857219; PubMed Central PMCID: PMC3738979.
5. Basuli D, Stevens RG, Torti FM, Torti SV. Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol. 2014 May 20;5:117. doi: 10.3389/fphar.2014.00117. eCollection 2014. Review. PubMed PMID: 24904420; PubMed Central PMCID: PMC4033158.
6. Zacharski LR, Ornstein DL, Woloshin S, Schwartz LM. Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data. Am Heart J. 2000 Jul;140(1):98-104. PubMed PMID: 10874269.
Conflict of Interest:
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