eLetters

772 e-Letters

  • Reply to e-letter by Xue et al - Use of preoperative neutrophil gelatinase-associated lipocalin to predicts acute kidney injury and mortality after cardiac surgery

    We thank Xue et al for their interest in our article (1). The KDIGO classification (2) comprises 3 criteria in the diagnosis of acute kidney injury (AKI), namely an increase in serum creatinine (SCr) by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or an increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume <0.5 ml/kg/h for 6 hours. In our study, we had collected serial blood samples for the first 72 hours and the second KDIGO criterion (an increase in SCr to ≥1.5 times baseline) was applied over the 72 hours period to assess for AKI. As for the impact of perioperative fluid balance, this is not currently part of the recommendation, and the available evidence quoted (3) was taken from a retrospective, single-center study using the AKIN classification for AKI. Unfortunately the perioperative fluid balance was not collected in our study and we could not take this into account.
    We did look at the Receiver Operating Characteristic curve analysis using sNGAL as a continuous variable. The area under the curve (AUC) was 0.57 (95%CI 0.54-0.60), very similar to that of sNGAL tertiles reported in our paper.(1) The diagnostic performance of sNGAL alone was quite low and therefore we did not provide cut-off values/sensitivity/specificity and predictive values. Expressing sNGAL as quartiles is more practical from a clinical point of view and we showed that by adding clinical factors, the c-statistic improved...

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  • Targeting beta blocker therapy to individual heart failure with preserved ejection fraction phenotypes

    The letter by Dr Al-Mohammad is welcomed by the study authors and highlights some of the important challenges with using single value cut-offs for diagnosis and in determining treatment options. This is particularly true for heart failure with preserved left ventricular ejection fraction (LVEF) (HFpEF) (and more recently mid-range ejection fraction [HFmrEF], 40-49%) where decisions on starting prognostic medications can be made based on subjective echocardiographic measurements, albeit with evidence of diastolic dysfunction (tissue Doppler, flow Doppler, and volumes). Clearly, additional patient-specific factors should be taken into account, including aetiology, co-morbidities, and underlying rhythm, which are nicely highlighted in the editorial piece accompanying our study[1 2].
    The Study Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With Heart Failure (SENIORS) trial investigated the effects of the beta-blocker nebivolol in the treatment of heart failure in patients aged 70 and over[3]. Patients were required to have a clinical diagnosis of heart failure with either hospitalisation for heart failure in the previous 12 months, or a documented LVEF ≤35%. Baseline LVEF was measured by transthoracic echocardiography in 94% of cases. While van Veldhuisen et al. used an LVEF cut-off of 35% to compare “reduced” with “preserved” ejection fraction, they also examined and reported on the effect of Nebivolol in 643 patients with an LVEF ≥40%....

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  • Is traumatic intracranial hemorrhage a specific risk factor of atrial fibrillation: Reply

    To the Editor:

    We thank Dr. Launey Y et al for their constructive comments regarding our recent report.[1] We also greatly appreciate their shared interests in traumatic intra-cranial hemorrhage (ICH) and the subsequent incidence of atrial fibrillation (AF).

    Dr Launey and colleagues concerned about the acute effects of inflammation on the onset of AF.[2] In our study, the mean follow-up period was 4.36 (standard deviation, SD=3.41) and 5.35 (SD=3.19) years in traumatic ICH group and control group, respectively. Interestingly, the mean follow-up period of the onset of AF was 2.94 years (SD=2.64) in traumatic ICH group, which is significantly less than 3.57 (SD=2.67) years in control group (Table 1) (p<0.001). Although acute inflammation plays a role on the onset of AF,[3, 4] our study along with previous evidence indicate the chronic persistent inflammation, which occurs after traumatic brain injury (TBI), contributes the development of AF.[1, 5] This partly explains the results of AF occurrence on TBI patients in our study.

    We agree that sepsis may contribute to the development of AF. In this study, after adjustment for age, sex, and comorbidities including sepsis and ventilator associated pneumonia, the adjusted HR (aHR) for developing AF was 1.24-fold higher (95% CI = 1.18-1.31) for patients with traumatic ICH compared with the control cohorts in multivariable cox regression models (Table 2). These results further support the association betwee...

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  • REACHing the wrong conclusion: residual confounding by indication

    Dear Professor Otto –

    In a recent edition of Heart, Potier et al reported the results of a large, observational analysis of the REACH registry[1]. The authors sought to retrospectively compare clinical outcomes in angiotensin receptor blocker (ARB), and angiotensin converting enzyme inhibitor (ACEi) treated patients, using propensity score matching to reduce confounding by indication. They conclude that treatment with ARB was more effective than with ACEi, across a wide spectrum of cardiovascular diseases and with regard to a number of different clinical outcomes. However, we believe that their methodology falls short of the standards expected from a well-conducted pharmacoepidemiological analysis[2].

    Although the REACH Registry is a well-powered cohort of patients at risk of adverse cardiovascular outcomes, several characteristics make it disadvantageous in the context of comparative drug efficacy analysis. Firstly, exposure to ACEi or ARB was established at baseline; all participants were prevalent users of these agents. Much evidence exists to suggest that bias is introduced by such an approach; the characteristics of prevalent users may be affected by the drug itself[3]. A new-user design would have eliminated such concerns.

    The indication for ACE inhibition and angiotensin receptor blockade differed greatly in this cohort of patients, recruited in 2003 and 2004. During this time, the evidence base for the use of ARBs was limited; most patients wo...

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  • Author response to Siniorakis et al.

    The authors thank Siniorakis et al. for highlighting the cardioprotective effect of enkephalins (ENK) as well as their potential role as biomarkers in post infarct heart failure (HF).[1] We had restricted our discussion around ENK and other vasoactive peptides to allow for a broader analysis of various concepts and also to comply with article length limitations. We note that the comments of Siniorakis et al. are consistent with the objective of our article, which is to highlight the potential role of other vasoactive pathways beyond that of the natriuretic peptide system when using sacubitril / valsartan in HF.[2] Indeed there is evidence to suggest that proenkephalin may be a prognostic indicator in acute heart failure.[3]

    References:
    1 Siniorakis E, Arapi S, Kaplanis I, et al. Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors. [Letter to Editor], Heart 2017.
    2 Singh JSS, Burrell LM, Cherif M, et al. Sacubitril/valsartan: beyond natriuretic peptides. Heart 2017.
    3 Ng LL, Squire IB, Jones DJ, et al. Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study. J Am Coll Cardiol 2017;69:56-69.

  • Use of preoperative neutrophil gelatinase-associated lipocalin to predicts acute kidney injury and mortality after cardiac surgery

    We read with great interest the recent article by Bulluck and colleagues regarding use of preoperative serum neutrophil gelatinase-associated lipocalin (sNGAL) to predict acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. They showed that preoperative sNGAL was an independent predictor of postoperative AKI and 1-year mortality. Although the valuable study has been actualized, two issues in methodology seem important to avoid any optimistic interpretation or misinterpretation of results.
    First, when using the KDIGO criteria to define and grade AKI, Bulluck et al1 used a time window of 72 h to include patients with different serum creatinine (sCr) increases from baseline, rather than 48 h, as specified by the guideline. Furthermore, it was unclear whether the sCr levels used for diagnosis and staging of AKI had been corrected based on perioperative fluid balance. The available evidence shows that not adjusting sCr levels for fluid balance may underestimate incidence of AKI after cardiac surgery, as a positive perioperative fluid balance may dilute sCr.2
    Second, this study only assessed the associations of preoperative sNGAL levels with the risks of postoperative AKI and 1-year mortality, but did not provide the true predictive performances of preoperative sNGAL. To determine discriminative ability of preoperative sNGAL for adverse postoperative outcomes, the receiver operating charac...

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  • Cardioprotective effects of enkephalins and potential interference from neprilysin inhibitors

    To the Editor, Singh et al¹ refer to cardiocirculatory effects of sacubitril/valsartan beyond those related to the activation of the natriuretic peptide system. Sacubitril, by inhibiting neprilysin (NEP), upregulates various vasoactive peptides, with enkephalins (ENK) performing a major role among them. It is not by chance that PARADIGM-HF trial, which established the novel NEP inhibitor, bestows NEP with the name ‘enkephalinase’, since the latter catalyzes the degradation of ENK. Singh et al¹ concentrate on the sacubitril-related augmentation of substance P, bradykinin and adrenomedullin, while they refrain from referring to ENK. ENK and proenkephalins, their precursors, are endogenous opioids, ligands to delta and kappa opioid receptors (ORs), which are abundant in the neural system as well as in the myocardium. The endogenous opioid system exerts a significant antinociceptive action in the heart, as we deduce by observations in animal and human models². An important field where ENK have already demonstrated their cardioprotective role, is reperfusion-related ischemia, with myocardial infarction, coronary artery by pass and angioplasty constituting the principal clinical equivalents in this setting³. In all the above mentioned conditions, ENK are overexpressed, both in the neural system and locally in the myocardium. ENK action during reperfusion ischaemia is exerted via various pathways. In detail, they increase intracellular Ca²+ levels, while, simultaneously, they ope...

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  • Older Chinese patients will benefit more from treatment for erectile dysfunction

    We read with great interest this paper which demonstrated erectile dysfunction (ED), not only as a preclinical predictor of cardiovascular disease (CVD), treatment for ED. But also has a role in a reduced mortality and heart failure hospitalization1.However, a multi-country and region population-based survey indicated that the majority of Asian men have never sought treatment for ED because of cultural factors or sexual conservatism2.
    Unfortunately, this situation is more serious in China. A multi-center investigation of 3327 subjects showed that although the proportion of severe cases (IIEF<8) among the Chinese elderly is the highest in all age groups, most elderly men are reluctant to visit the hospital just for the loss of erectile function (EF). They consider the loss of libido and EF with increasing age to be a natural process of aging3. Moreover, even the old men who seek help for ED were more concerned about the side effects of Western medicine (e.g., PDE5i); only a few of them (19%) used Western medicine as the first choice4. Furthermore, Chinese physicians seldom ask patients about their sexual health during routine consultations, their neglect of the health education about ED also aggravated this vicious circle2, 4.
    Hence, there is a substantial need for promoting Andersson et al 's 1 findings on health education of elderly ED patients in China. The improved awareness and cultural factors would lead more Chinese elderly to visit the hospi...

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  • Do Beta Blockers really reduce the mortality in patients with HFPEF?

    I do welcome the systemic review and meta-analysis on drug treatment effects on outcomes in heart failure with preserved ejection fraction, by Dr Zheng and co-workers.(1) I do note the authors' definition of HFPEF as having a left ventricular ejection fraction of >40% as per the suggestions of the American Guidelines.(2) They acknowledge the difficulties posed by those with LVEF 40-49% where the evidence base is largely lacking with the exception of the more recent sub-study of CHARM data in those with LVEF in the above mid-range.(3)
    I have however an issue with their inclusion of the SENIORS study data.(4) Although the mean LVEF of those labelled as HF with preserved LVEF was 49%, the patients included as those with preserved left ventricular ejection fraction, were those with LVEF>35%. This calls into question as to whether the positive effect on mortality of beta-blockers in this trial was caused by the impact of including patients with LVEF 35-40% within this group. I am sure that the authors would agree that the positive impact of the beta-blockers on the mortality of patients with LVEF 35-40%, is un-controversial.(4) While another publication from the SENIORS study group found no statistically significant difference between those deemed HFREF and those deemed HFPEF. We do know that the comparison here may be flawed for the above mentioned issue.
    I would therefore, encourage the authors to reconsider their firm conclusion about the effectivenes...

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  • Is traumatic intracranial hemorrhage a specific risk factor of atrial fibrillation ?

    We read the study of Wei-Shiang Lin et al.[1] with a great interest. In their large-scale cohort retrospective study, they found that traumatic intracranial hemorrhage was associated with an increased risk of atrial fibrillation (AF) and hypothesized that inflammation and/or secondary cardiac insult due to the traumatic brain injury (TBI) may cause AF. Nevertheless, several points should be discussed. First, acute inflammation is well-known to be related to AF in trauma patients. The risk of new-onset AF is reasonably expected to occur at the acute phase following the trauma. This point has already been previously demonstrated to occur during the days following cardiac surgery or septic shock onset.[2] In the same way, cardiac insult occurs at the very early phase of TBI and the consecutive cardiac systolic dysfunction was reported to be reversible within the first week after the trauma. [3] In this perspective, how to explain that the risk of AF persists one year after the trauma? It would be very helpful if the authors could provide data on the delay between the day of trauma and the day of new-onset AF. Furthermore, inflammation and cardiac dysfunction are related to the TBI severity and it would be valuable to know whether the more severe TBI patients are more prone to develop AF than mild or moderate TBI. Finally, in their statistical model, the authors have taken into account comorbidities which are also known to favor AF. But others factors, such as sepsis and relat...

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