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We read with interest the excellent and timely article on increasingly detected cases of isolated tricuspid valve regurgitation (1) . The authors rightly note that there is an emerging population of adult patients without left-sided heart disease, pulmonary hypertension or congenital abnormalities who develop symptomatic isolated tricuspid regurgitation. While this is true, we believe that a proportion of these cases of isolated tricuspid regurgitation may well be congenital in origin.
The spectrum of congenital abnormalities of tricuspid valve abnormalities is large (2), and while Ebstein anomaly and tricuspid valve anomalies associated with atrioventricular septal defects and pulmonary atresia are the most commonly discussed, there is a group of patients with tricuspid valve dysplasia or congenitally abnormal tricuspid valves that are under-recognized. Said et al (3) and Dearani et al (4) from the authors’ institution have previously discussed the wide spectrum of congenital tricuspid valve anomalies. The importance of recognizing this group of cases as a separate entity is twofold. One that tricuspid valve dysplasia from failure of delamination of the tricuspid valve, like Ebstein anomaly can be associated with cardiomyopathy and arrhythmia and other congenital anomalies can be missed if focus if just on the valve. Secondly, surgical approach for tricuspid valve surgery, as authors suggest, should focus on the mechanisms of tricuspid regurgitation, which are uni...
We read with interest the excellent and timely article on increasingly detected cases of isolated tricuspid valve regurgitation (1) . The authors rightly note that there is an emerging population of adult patients without left-sided heart disease, pulmonary hypertension or congenital abnormalities who develop symptomatic isolated tricuspid regurgitation. While this is true, we believe that a proportion of these cases of isolated tricuspid regurgitation may well be congenital in origin.
The spectrum of congenital abnormalities of tricuspid valve abnormalities is large (2), and while Ebstein anomaly and tricuspid valve anomalies associated with atrioventricular septal defects and pulmonary atresia are the most commonly discussed, there is a group of patients with tricuspid valve dysplasia or congenitally abnormal tricuspid valves that are under-recognized. Said et al (3) and Dearani et al (4) from the authors’ institution have previously discussed the wide spectrum of congenital tricuspid valve anomalies. The importance of recognizing this group of cases as a separate entity is twofold. One that tricuspid valve dysplasia from failure of delamination of the tricuspid valve, like Ebstein anomaly can be associated with cardiomyopathy and arrhythmia and other congenital anomalies can be missed if focus if just on the valve. Secondly, surgical approach for tricuspid valve surgery, as authors suggest, should focus on the mechanisms of tricuspid regurgitation, which are unique to each given patient. For example, the surgical management of a cleft tricuspid valve (another well-known congenital entity) would be different from a case of tricuspid valve dysplasia when the mechanism of tricuspid regurgitation is a tethered anterior leaflet of tricuspid valve, which is failure of delamination issue.
We recognize this manuscript as an excellent resource for isolated tricuspid valve regurgitation; we would nonetheless underscore that congenital tricuspid valve disease (other than Ebstein anomaly) may be more common than anticipated, and may masquerade as primary idiopathic tricuspid regurgitation. We believe (likely as do the authors) that evaluation of all presumed isolated tricuspid valve disease deserves assessment by cardiologists expert in such distinction and classification.
1. Fender EA, Zack CJ, Nishimura RA. Isolated tricuspid regurgitation: outcomes and therapeutic interventions. Heart 2017.
2. Becker AE, Becker MJ, Edwards JE. Pathologic spectrum of dysplasia of the tricuspid valve. Features in common with Ebstein's malformation. Arch Pathol 1971;91:167-78.
3. Said SM, Burkhart HM, Dearani JA. Surgical management of congenital (non-Ebstein) tricuspid valve regurgitation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2012;15:46-60.
4. Dearani JA, Danielson GK. Congenital Heart Surgery Nomenclature and Database Project: Ebstein's anomaly and tricuspid valve disease. Ann Thorac Surg 2000;69:S106-17.
We have read the interesting article from Bokma and colleagues [1] documenting the outcomes of pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF). In this large multi-centre rTOF cohort, PVR was not associated with a reduced rate of death at mid-term follow-up. Additionally, authors highlighted that there were more events after PVR compared with no PVR in subjects not meeting consensus criteria.
Currently, although the overall hemodynamic benefits of PVR are evident with broad consensus for surgery before clinical deterioration or symptoms develop, uncertainties remain about the optimal timing for PVR.
Haemodynamic assessment surrounding PVR has focused on assessment of the right ventricle (RV) size and function, with the goal of intervening in patient prior to the development of irreversible RV deterioration failure. However, although the concept of using RV volumes for decision-making for PVR is widely used, its evidence regarding its impact on long-term outcomes remains weak.
New information about optimal PVR timing has been continuously addressed. A cardiac magnetic resonance based study suggested that a preoperative RVESVi cutoff of ≤82 mL/m2 was equally sensitive and more specific for normalization of RV volumes compared with our preoperative RVEDVi threshold of ≤158 mL/m2, justifying the use of RVESVi for clinical timing for PVR [2]. In 2015, Bokma concluded that preoperative RVESVi < 80 mL/m2 was the best thr...
We have read the interesting article from Bokma and colleagues [1] documenting the outcomes of pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF). In this large multi-centre rTOF cohort, PVR was not associated with a reduced rate of death at mid-term follow-up. Additionally, authors highlighted that there were more events after PVR compared with no PVR in subjects not meeting consensus criteria.
Currently, although the overall hemodynamic benefits of PVR are evident with broad consensus for surgery before clinical deterioration or symptoms develop, uncertainties remain about the optimal timing for PVR.
Haemodynamic assessment surrounding PVR has focused on assessment of the right ventricle (RV) size and function, with the goal of intervening in patient prior to the development of irreversible RV deterioration failure. However, although the concept of using RV volumes for decision-making for PVR is widely used, its evidence regarding its impact on long-term outcomes remains weak.
New information about optimal PVR timing has been continuously addressed. A cardiac magnetic resonance based study suggested that a preoperative RVESVi cutoff of ≤82 mL/m2 was equally sensitive and more specific for normalization of RV volumes compared with our preoperative RVEDVi threshold of ≤158 mL/m2, justifying the use of RVESVi for clinical timing for PVR [2]. In 2015, Bokma concluded that preoperative RVESVi < 80 mL/m2 was the best threshold to achieve mid-to-late RV normalization [3]. The impact of abnormal RV mechanics on the LV has been appreciated, with the assessment of LV assuming higher priority in decision-making.
Interestingly, another study from INDICATOR cohort [4] found previous implantation of RV-pulmonary artery conduits was associated with adverse outcomes rather than RV volumes. Age at TOF repair was also identified as risk factor for post-PVR arrhythmia. It’s well summarized that TOF anatomical variants, trans-ventricular repair and preoperative cyanosis were also know as determinants for PVR outcomes [2].
Hence more information could be further illustrated, including the baseline anatomical and surgical features of TOF repair, the surgical techniques of PVR and their potential relationship with PVR outcomes. Moreover, additional comments about this issue would be helpful.
[1] Bokma JP, Geva T, Sleeper LA, et al. Heart Published Online First: [1-Nov-2017]. doi:10.1136/ heartjnl-2017-312048.
[2] Heng EL, Gatzoulis MA, Uebing A, et al. Immediate and Midterm Cardiac Remodeling After Surgical Pulmonary Valve Replacement in Adults With Repaired Tetralogy of Fallot: A Prospective Cardiovascular Magnetic Resonance and Clinical Study. Circulation. 2017;136:1703-1713.
[3] Bokma JP, Winter MM, Oosterhof T, et al. Pre-operative thresholds for mid-to-late haemodynamic and clinical outcomes after pulmonary valve replacement in tetralogy of Fallot. Eur Heart J. 2016;37(10):829-35.
[4] Valente AM, Gauvreau K, Assenza GE, et al. Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort. Heart 2014;100:247–253.
Title of E-letter: Intra coronary imaging to detect mal apposition: Are We Seeing Too Much!
Authors Name: Dr Yasir Parviz
Institution: Columbia University Medical Center
Intracoronary Imaging Heart 2017; 0: heartjnl-2015-307888v1
Link to the original paper: http://hwmaint.heart.bmj.com/cgi/content/full/heartjnl-2015-307888v1
Main Text:
We would like to congratulate Giavarini A et al on this comprehensive, educational article on intracoronary imaging. [1] Various modalities can be used to understand the mechanism of stent failure, and there is an ongoing debate on detection of stent mal-apposition, and whether this has any clinical impact. Acute stent mal-apposition on its own is not associated with adverse clinical events unless associated with under expansion or having inflow- outflow issues. Acute mal-apposition and its associated clinical events are possibly reduced due to negative remodelling.[2] The clinically events are non-significant may be due to the fact that newer generation of stents and stronger antiplatelets are performing very well. There is limited literature evidence to support that acute mal-apposition is associated with stent thrombosis. [3] Late acquired malaposition in combination with other contributing factors can be associated with stent failure. Most of the available literature looking into the mechanism of stent failure is from...
Title of E-letter: Intra coronary imaging to detect mal apposition: Are We Seeing Too Much!
Authors Name: Dr Yasir Parviz
Institution: Columbia University Medical Center
Intracoronary Imaging Heart 2017; 0: heartjnl-2015-307888v1
Link to the original paper: http://hwmaint.heart.bmj.com/cgi/content/full/heartjnl-2015-307888v1
Main Text:
We would like to congratulate Giavarini A et al on this comprehensive, educational article on intracoronary imaging. [1] Various modalities can be used to understand the mechanism of stent failure, and there is an ongoing debate on detection of stent mal-apposition, and whether this has any clinical impact. Acute stent mal-apposition on its own is not associated with adverse clinical events unless associated with under expansion or having inflow- outflow issues. Acute mal-apposition and its associated clinical events are possibly reduced due to negative remodelling.[2] The clinically events are non-significant may be due to the fact that newer generation of stents and stronger antiplatelets are performing very well. There is limited literature evidence to support that acute mal-apposition is associated with stent thrombosis. [3] Late acquired malaposition in combination with other contributing factors can be associated with stent failure. Most of the available literature looking into the mechanism of stent failure is from IVUS studies and newer technology, OCT due to superior resolution has the ability to detect a higher percentage of mal appositions.[4] There is on-going research on to the clinical significance of these findings.
We are presenting a summary of some evidence in detection of malapposition by IVUS /OCT and its clinical impact.
1)Im et al. Circ Cardiovasc Interv 2014;7:88-96.
356(n),62%(OCT), no impact.
2)Kubo et al. JACCCardiovasc Imaging 2013;6:1095-104.
100(n), 14%(IVUS), 39%(OCT), no impact
3)Kawamori et al. EHJ Cardiovasc Imaging 2013;14:865-75.
40(n), 65%(OCT), no impact
4)Bezerra et al. JACC Cardiovasc Interv 2013;6:228-36
26(n), 42% (IVUS), 96%(OCT), no impact
5)Ali ZA et al Lancet. 2016 Nov 26;388(10060):2618-2628.
304(n), 39% (IVUS), 41% OCT, no impact
6)Prati et al JACC Cardiovascular Imaging November 2015 2015;8:1297.
832(n), 50%(OCT), no impact
7)Prati F et al Am Heart J. 2015 Feb;169(2):249-56.
63(n), 52%(OCT), no impact
8)Hong et al, Circulation. 2006;113:414-9.
557(n), 12 %(IVUS),no impact
9)Steinberg et al J Am Coll Cardiol Intv 3:486-494.
1580(n), 7-10%(IVUS), no impact
10)Soeda et al Circulation. 2015 Sep 15;132(11):1020-9.
786(n), 39%(OCT), no impact
11)Kimura M Am J Cardiol. 2006;98:436-442.
168(n) 77% (IVUS), no impact
References.
1.Giavarini A, Kilic ID, Redondo Dieguez A, Longo G, Vandormael I, Pareek N, Kanyal R, De Silva R and Di Mario C. Intracoronary Imaging. Heart. 2017.
2. Guo N, Maehara A, Mintz GS, He Y, Xu K, Wu X, Lansky AJ, Witzenbichler B, Guagliumi G, Brodie B, Kellett MA, Jr., Dressler O, Parise H, Mehran R and Stone GW. Incidence, mechanisms, predictors, and clinical impact of acute and late stent malapposition after primary intervention in patients with acute myocardial infarction: an intravascular ultrasound substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. Circulation. 2010;122:1077-84.
3. Alfonso F, Suarez A, Angiolillo DJ, Sabate M, Escaned J, Moreno R, Hernandez R, Banuelos C and Macaya C. Findings of intravascular ultrasound during acute stent thrombosis. Heart. 2004;90:1455-9.
4. Ali ZA, Maehara A, Genereux P, Shlofmitz RA, Fabbiocchi F, Nazif TM, Guagliumi G, Meraj PM, Alfonso F, Samady H, Akasaka T, Carlson EB, Leesar MA, Matsumura M, Ozan MO, Mintz GS, Ben-Yehuda O, Stone GW and Investigators IIOP. Optical coherence tomography compared with intravascular ultrasound and with angiography to guide coronary stent implantation (ILUMIEN III: OPTIMIZE PCI): a randomised controlled trial. Lancet. 2016;388:2618-2628.
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...
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 to 0.69. We are aware that the value of 0.69 is not ideal for clinical application and our work was a post-hoc analysis of a randomized controlled trial (4) consisting of high-risk patients (EuroSCORE≥5). Therefore, further work remains to be done in a larger number of all-comers going for cardiac surgery to improve the identification of patients at risk of AKI.
References
1. Bulluck H, Maiti R, Chakraborty B, et al. Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality. Heart 2017 doi: 10.1136/heartjnl-2017-311760
2. James M, Bouchard J, Ho J, et al. Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. American journal of kidney diseases : the official journal of the National Kidney Foundation 2013;61(5):673-85. doi: 10.1053/j.ajkd.2013.02.350
3. Moore E, Tobin A, Reid D, et al. The Impact of Fluid Balance on the Detection, Classification and Outcome of Acute Kidney Injury After Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia 2015;29(5):1229-35. doi: 10.1053/j.jvca.2015.02.004
4. Hausenloy DJ, Candilio L, Yellon DM. Remote Ischemic Preconditioning and Cardiac Surgery. The New England journal of medicine 2016;374(5):491-2.
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%....
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%. Results for this subgroup were included in our meta-analysis, ensuring that all patients included in our meta-analysis had an ejection fraction greater than this. Of note, inclusion of an additional 109 patients with an LVEF of 35-40% had minimal effect on the primary composite outcome of all-cause mortality or cardiovascular hospitalisation (LVEF ≥35%: HR 0.81, NS; LVEF ≥40%: HR 0.82, NS), or all-cause mortality (LVEF ≥35%: HR 0.91, NS; LVEF ≥40%: HR 0.92, NS). Indeed in SENIORS, the point estimate for reduction in the primary outcome was greater in those with an LVEF ≥40% (HR 0.82, NS) than in those with LVEF ≤35% (HR 0.86, NS).
We have tentatively concluded that beta-blockers may be of benefit in HFpEF, on the basis of pooled analysis from 3 trials, enrolling just 1046 participants. A large propensity-matched study from the Swedish Heart Failure registry (8244 patients) mirrored these findings with a 7% reduction in all-cause mortality at 5 years (P=0.04)[4]. Results from an individual patient data meta-analysis of beta-blockers in heart failure were recently presented at the European Society of Cardiology Congress and suggested reductions in all-cause and cardiovascular mortality in patients with HFmrEF (LVEF 40 to 49%) and sinus rhythm, but not in HFpEF (LVEF ≥50%) with sinus rhythm[5]. This study importantly highlights the importance of additional patient characteristics such as underlying rhythm. There is currently insufficient evidence to recommend widespread use of beta-blockers in HFpEF, and large prospective randomised controlled trial using a beta-blocker of proven benefit in reduced ejection fraction (e.g. bisoprolol, carvedilol, metoprolol[6]) is needed. It will be critically important to untangle and identify which specific patients with HFpEF may benefit from beta-blocker therapy.
1. Zheng SL, Chan FT, Nabeebaccus AA, et al. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart 2017 doi: 10.1136/heartjnl-2017-311652published Online First: Epub Date]|.
2. Schnell F, Donal E. Pharmacological strategies in heart failure with preserved ejection fraction: time for an individualised treatment strategy? Heart 2017 doi: 10.1136/heartjnl-2017-312119published Online First: Epub Date]|.
3. van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-Blockade With Nebivolol in Elderly Heart Failure Patients With Impaired and Preserved Left Ventricular Ejection Fraction. Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). Journal of the American College of Cardiology 2009;53(23):2150-58 doi: http://dx.doi.org/10.1016/j.jacc.2009.02.046published Online First: Epub Date]|.
4. Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. Jama 2014;312(19):2008-18 doi: 10.1001/jama.2014.15241published Online First: Epub Date]|.
5. Kotecha D. Efficacy of beta-blockers in heart failure according to left ventricular ejection fraction: An individual patient level analysis of double-blind randomised trials. Secondary Efficacy of beta-blockers in heart failure according to left ventricular ejection fraction: An individual patient level analysis of double-blind randomised trials 2017. http://congress365.escardio.org/Presentation/162249 - .WbHKsNOGMWo.
6. Chatterjee S, Biondi-Zoccai G, Abbate A, et al. Benefits of beta blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ (Clinical research ed.) 2013;346:f55 doi: 10.1136/bmj.f55published Online First: Epub Date]|.
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...
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 between TBI and AF.
We acknowledge that our study had several limitations including no available data on the severity of TBI and AF occurrence, and the medication use in both traumatic ICH and control groups in the National Health Insurance Research Database. However, with the growing evidence suggesting the mechanisms linking inflammation, TBI, and AF, our studies provide critical clinical evidence supporting the important role of TBI on the development of AF.
References
1 Lin WS, Lin TC, Hung Y, et al. Traumatic intracranial haemorrhage is in association with an increased risk of subsequent atrial fibrillation. Heart 2017;103:1286-91.
2 Launey Y, Seguin, P. Is traumatic intracranial hemorrhage a specific risk factor of atrial fibrillation. Heart 2017;103.
3 Meierhenrich R, Steinhilber E, Eggermann C, et al. Incidence and prognostic impact of new-onset atrial fibrillation in patients with septic shock: a prospective observational study. Crit Care 2010;14:R108.
4 Chaikittisilpa N, Krishnamoorthy V, Lele AV, et al. Characterizing the relationship between systemic inflammatory response syndrome and early cardiac dysfunction in traumatic brain injury. J Neurosci Res 2017.
5 Mitrofanova LB, Orshanskaya V, Ho SY, et al. Histological evidence of inflammatory reaction associated with fibrosis in the atrial and ventricular walls in a case-control study of patients with history of atrial fibrillation. Europace 2016;18:iv156-iv62.
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...
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 would have received an ARB for the treatment of hypertension and heart failure (but not in the post-infarction or high cardiovascular risk settings). The authors match only on propensity score, without restricting or forcing matching by indication. Participants receiving ACEi use had a greater burden of cardiovascular morbidities, such as ischaemic heart disease and heart failure, than those receiving ARBs, who tended to have more hypertension (Supplementary Table 1). Although the burden of these comorbidities was marginally balanced in the propensity-matched ACEi and ARB groups, it is plausible that many patients receiving an ACEi in the early post-infarction setting (at high risk of adverse outcomes) were matched with patients receiving an ARB for hypertension (at relatively lower risk), with similar propensity. Clearly, significant confounding by indication persists.
Given that the conclusions of this analysis are contrary to data from head-to-head randomised controlled trials, and multiple meta-analyses[4], we advise significant caution when interpreting these findings. The analytic methodology is deeply flawed; the conclusions of this study most probably reflect residual confounding by indication.
Yours sincerely,
Jonathan A Batty
Alistair S Hall
1. Potier L, Roussel R, Elbez Y, Marre M, Zeymer U, Reid CM, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk. Heart. 2017.
2. Glynn RJ. Use of Propensity Scores To Design Observational Comparative Effectiveness Studies. Journal of the National Cancer Institute. 2017;109(8).
3. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. American journal of epidemiology. 2003;158(9):915-20.
4. Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. The Cochrane database of systematic reviews. 2014(8):Cd009096.
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.
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...
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 characteristic curve analysis should be performed to provide the optimal cutoff values of preoperative sNGAL for postoperative AKI and mortality as well as its sensitivity, specificity, and positive and negative predictive values. The optimal cutoff value is the one that has the highest sensitivity and specificity combined. By providing the predicted probabilities and observed frequencies for postoperative AKI and mortality based on the cutoff values of preoperative sNGAL, the readers can estimate whether there is a good overall agreement between predicted probabilities and observed frequencies in the development and the validation sets. This study identified preoperative sNGAL as a predictor of AKI, but c-statistic was only improved to 0.69 when controlling perioperative risk factors affecting postoperative myocardial and kidney injuries. Traditionally, a c-statistic of 0.5 means random occurrence, whereas a c-statistic > 0.7 signifies adequate discrimination and > 0.8 indicates strong discrimination.
REFERENCES
1 Bulluck H, Maiti R, Chakraborty B, et al. Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality. Heart 2017 Aug 9. DOI: 10.1136/heartjnl-2017-311760.
2 Moore E, Tobin A, Reid D, et al. The impact of fluid balance on the detection, classification and outcome of acute kidney injury after cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29:1229-35.
3 Merkow RP, Hall BL, Cohen ME, et al. Relevance of the c-statistic when evaluating risk-adjustment models in surgery. J Am Coll Surg 2012; 214:822-30.
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...
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 open mitochondrial K(ATP) channels, thus expressing a marked antiadrenergic and antiarrhythmic effect. Another scenario, where ENK exert their modulating action, is that of heart failure (HF). In HF, acute or chronic, overexpressed ENK and their ORs provoke a cross-talk with catecholamine receptors and calcium homeostasis, depressing arrhythmogenesis and simultaneously enhancing the inotropism. In HF following an acute myocardial infarction, elevated ENK act as a biomarker, signaling the incidence of cardiorenal syndrome, increased in-hospital mortality, and recurrent infarction4. Concluding, beyond the hormonal activation referred by Singh et al¹, NEP-inhibition is expected to establish ENK as promissing cardioprotective markers, especially under conditions of ischaemia and HF.
References
1. Singh JSS, Burell LM, Cherif M, et al. Sacubitril/valsartan: beyond natriuretic peptides. Heart 2017; doi: 10.1136/ heartjnl-2017-311295.
2. Headrick JP, See Hoe LE, Du Toit EF, et al. Opioid receptors and cardioprotection- ‘opioidergic conditioning’ of the heart. Br J Pharmacol 2015; 172:2026-50.
3. Pepe S, van den Brink OW, Lakatta EG, et al. Cross-talk of opioid peptide receptor and beta-adrenergic receptor signalling in the heart. Cardiovasc Res 2004; 63:414-22.
4. Ng LL, Squire IB, Jones DJ, et al. Proenkephalin, renal dysfuntion, and prognosis in patients with acute heart failure: a GREAT network study. J Am Coll Cardiol 2017; 69:56-69.
We read with interest the excellent and timely article on increasingly detected cases of isolated tricuspid valve regurgitation (1) . The authors rightly note that there is an emerging population of adult patients without left-sided heart disease, pulmonary hypertension or congenital abnormalities who develop symptomatic isolated tricuspid regurgitation. While this is true, we believe that a proportion of these cases of isolated tricuspid regurgitation may well be congenital in origin.
Show MoreThe spectrum of congenital abnormalities of tricuspid valve abnormalities is large (2), and while Ebstein anomaly and tricuspid valve anomalies associated with atrioventricular septal defects and pulmonary atresia are the most commonly discussed, there is a group of patients with tricuspid valve dysplasia or congenitally abnormal tricuspid valves that are under-recognized. Said et al (3) and Dearani et al (4) from the authors’ institution have previously discussed the wide spectrum of congenital tricuspid valve anomalies. The importance of recognizing this group of cases as a separate entity is twofold. One that tricuspid valve dysplasia from failure of delamination of the tricuspid valve, like Ebstein anomaly can be associated with cardiomyopathy and arrhythmia and other congenital anomalies can be missed if focus if just on the valve. Secondly, surgical approach for tricuspid valve surgery, as authors suggest, should focus on the mechanisms of tricuspid regurgitation, which are uni...
We have read the interesting article from Bokma and colleagues [1] documenting the outcomes of pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF). In this large multi-centre rTOF cohort, PVR was not associated with a reduced rate of death at mid-term follow-up. Additionally, authors highlighted that there were more events after PVR compared with no PVR in subjects not meeting consensus criteria.
Show MoreCurrently, although the overall hemodynamic benefits of PVR are evident with broad consensus for surgery before clinical deterioration or symptoms develop, uncertainties remain about the optimal timing for PVR.
Haemodynamic assessment surrounding PVR has focused on assessment of the right ventricle (RV) size and function, with the goal of intervening in patient prior to the development of irreversible RV deterioration failure. However, although the concept of using RV volumes for decision-making for PVR is widely used, its evidence regarding its impact on long-term outcomes remains weak.
New information about optimal PVR timing has been continuously addressed. A cardiac magnetic resonance based study suggested that a preoperative RVESVi cutoff of ≤82 mL/m2 was equally sensitive and more specific for normalization of RV volumes compared with our preoperative RVEDVi threshold of ≤158 mL/m2, justifying the use of RVESVi for clinical timing for PVR [2]. In 2015, Bokma concluded that preoperative RVESVi < 80 mL/m2 was the best thr...
Title of E-letter: Intra coronary imaging to detect mal apposition: Are We Seeing Too Much!
Authors Name: Dr Yasir Parviz
Institution: Columbia University Medical Center
Intracoronary Imaging Heart 2017; 0: heartjnl-2015-307888v1
Link to the original paper: http://hwmaint.heart.bmj.com/cgi/content/full/heartjnl-2015-307888v1
Main Text:
We would like to congratulate Giavarini A et al on this comprehensive, educational article on intracoronary imaging. [1] Various modalities can be used to understand the mechanism of stent failure, and there is an ongoing debate on detection of stent mal-apposition, and whether this has any clinical impact. Acute stent mal-apposition on its own is not associated with adverse clinical events unless associated with under expansion or having inflow- outflow issues. Acute mal-apposition and its associated clinical events are possibly reduced due to negative remodelling.[2] The clinically events are non-significant may be due to the fact that newer generation of stents and stronger antiplatelets are performing very well. There is limited literature evidence to support that acute mal-apposition is associated with stent thrombosis. [3] Late acquired malaposition in combination with other contributing factors can be associated with stent failure. Most of the available literature looking into the mechanism of stent failure is from...
Show MoreWe 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.
Show MoreWe 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...
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].
Show MoreThe 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%....
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...
Show MoreDear 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...
Show MoreThe 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.
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.
Show MoreFirst, 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...
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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