Short-Period Temporal Dispersion Repolarization Markers Predict 30-Days Mortality in Decompensated Heart Failure

Gianfranco Piccirillo, Federica Moscucci, Gaetano Bertani, Ilaria Lospinuso, Fabiola Mastropietri, Marcella Fabietti, Teresa Sabatino, Giulia Zaccagnini, Davide Crapanzano, Ilaria Di Diego, Andrea Corrao, Pietro Rossi, Damiano Magrì, Gianfranco Piccirillo, Federica Moscucci, Gaetano Bertani, Ilaria Lospinuso, Fabiola Mastropietri, Marcella Fabietti, Teresa Sabatino, Giulia Zaccagnini, Davide Crapanzano, Ilaria Di Diego, Andrea Corrao, Pietro Rossi, Damiano Magrì

Abstract

Background and objectives: Electrocardiographic (ECG) markers of the temporal dispersion of the myocardial repolarization phase have been shown able to identify chronic heart failure (CHF) patients at high mortality risk. The present prospective single-center study sought to investigate in a well-characterized cohort of decompensated heart failure (HF) patients the ability of short-term myocardial temporal dispersion ECG variables in predicting the 30-day mortality, as well as their relationship with N-terminal Pro Brain Natriuretic Peptide (NT-proBNP) plasmatic values.

Method: One hundred and thirteen subjects (male: 59, 67.8%) with decompensated CHF underwent 5 min of ECG recording, via a mobile phone. We obtained QT end (QTe), QT peak (QTp) and T peak to T end (Te) and calculated the mean, standard deviation (SD), and normalized index (VN).

Results: Death occurred for 27 subjects (24%) within 30 days after admission. Most of the repolarization indexes (QTe mean (p < 0.05), QTeSD (p < 0.01), QTpSD (p < 0.05), mean Te (p < 0.05), TeSD (p < 0.001) QTeVN (p < 0.05) and TeVN (p < 0.01)) were significantly higher in those CHF patients with the highest NT-proBNP (>75th percentile). In all the ECG data, only TeSD was significantly and positively related to the NT-proBNP levels (r: 0.471; p < 0.001). In the receiver operating characteristic (ROC) analysis, the highest accuracy for 30-day mortality was found for QTeSD (area under curve, AUC: 0.705, p < 0.01) and mean Te (AUC: 0.680, p < 0.01), whereas for the NT-proBNP values higher than the 75th percentile, the highest accuracy was found for TeSD (AUC: 0.736, p < 0.001) and QTeSD (AUC: 0.696, p < 0.01).

Conclusion: Both mean Te and TeSD could be considered as reliable markers of worsening HF and of 30-day mortality. Although larger and possibly interventional studies are needed to confirm our preliminary finding, these non-invasive and transmissible ECG parameters could be helpful in the remote monitoring of advanced HF patients and, possibly, in their clinical management. (ClinicalTrials.gov number, NCT04127162).

Keywords: QT; QTVI, QT variability index; T peak–T end; chronic heart failure; mortality; temporal dispersion of repolarization phase..

Conflict of interest statement

The Authors deny personal or financial conflicts of interest regarding this paper.

Figures

Figure 1
Figure 1
Linear regression between log TeSD and NT-proBNP. NT-proBNP: N-terminal Pro Brain Natriuretic Peptide; SD: standard deviation.
Figure 2
Figure 2
(A) QTe, QTp and Te means in the cardiovascular and non-cardiovascular deceased subjects. In the box plots, the central line represents the median distribution. Each box spans from the 25th to 75th percentile points, and error bars extend from the 10th to 90th percentile points. (B) QTe, QTp and Te standard deviations (SD) in the cardiovascular and non-cardiovascular deceased subjects. In the box plots, the central line represents the median distribution. Each box spans from the 25th to 75th percentile points, and error bars extend from the 10th to 90th percentile points.In the ROC analysis, the highest accuracy for 30-day mortality was found for the following variables: QTeSD (AUC: 0.705, p < 0.01), mean Te (AUC: 0.680, p < 0.01), QTeVN (AUC: 0.686, p < 0.01) and TeSD (AUC: 0.648, p < 0.05) (Figure 3A). ROC, receiver operating characteristic; AUC, area under curve; NS, not significant. QTe, QTp, Te, QTeVN (explained in the text).
Figure 3
Figure 3
(A,B) ROC curve of statistically significant examined variables. Sensitivity–specificity of different variables for mortality (A) and higher NT-proBNP levels (≥75th percentile) (B). Univariable Cox regression analysis reported a significant relationship between 30-day mortality and QTeSD (hazard ratio: 1.10, 95% confidence limit: 1.03–1.18, p < 0.05), mean Te (hazard ratio 1.02, 95% confidence limit: 1.01–1.04, p < 0.001) and TeSD (hazard ratio 1.12, 95% confidence limit: 1.01–1.23, p < 0.001) (Table 3). All number value in the table of the figure should be intended as follow: .526 means 0.526.
Figure 4
Figure 4
(A) Kaplan–Meier survival curve for total mortality by subdividing the study subjects with a cutoff at the 75th percentile of mean Te. (B) Kaplan–Meier survival curve for cardiovascular mortality by subdividing the study subjects with a cutoff at the 75th percentile of mean Te.

References

    1. Tereshchenko L.G., Cygankiewicz I., McNitt S., Bayes-Genis A., Han L., Sur S., Couderc J.P., Berger R.D., de Luna A.B., Zareba W. Predictive value of beat-to-beat QT variability index across the continuum of left ventricular dysfunction: Competing risks of noncardiac or cardiovascular death and sudden or nonsudden cardiac death. Circ. Arrhythmia Electrophysiol. 2012;5:719–727. doi: 10.1161/CIRCEP.112.970541.
    1. Piccirillo G., Magrì D., Matera S., Magnanti M., Torrini A., Pasquazzi E., Schifano E., Velitti S., Marigliano V., Quaglione R., et al. QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: A prospective study. Eur. Heart J. 2007;28:1344–1350. doi: 10.1093/eurheartj/ehl367.
    1. Haigney M.C., Zareba W., Gentlesk P.J., Goldstein R.E., Illovsky M., McNitt S., Andrews M.L., Moss A.J., Multicenter Automatic Defibrillator Implantation Trial II investigators QT interval variability and spontaneous ventricular tachycardia or fibrillation in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients. J. Am. Coll. Cardiol. 2004;44:1481–1487. doi: 10.1016/j.jacc.2004.06.063.
    1. Baumert M., Porta A., Vos M.A., Malik M., Couderc J.P., Laguna P., Piccirillo G., Smith G.L., Tereshchenko L.G., Volders P.G. QT interval variability in body surface ECG: Measurement, physiological basis, and clinical value: Position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology. Europace. 2016;18:925–944.
    1. Tyack P.L., Calambokidis J., Friedlaender A., Goldbogen J., Southall B. First Long-Term Behavioral Records from Cuvier’s Beaked Whales (Ziphiuscavirostris) Reveal Record-Breaking Dives. PLoS ONE. 2014;9:e92633.
    1. Disertori M., Rigoni M., Pace N., Casolo G., Masè M., Gonzini L., Lucci D., Nollo G., Ravelli F. Myocardial Fibrosis Assessment by LGE Is a Powerful Predictor of Ventricular Tachyarrhythmias in Ischemic and Nonischemic LV Dysfunction: A Meta-Analysis. JACC Cardiovasc. Imaging. 2016;9:1046–1055. doi: 10.1016/j.jcmg.2016.01.033.
    1. Antzelevitch C. Drug-induced spatial dispersion of repolarization. Cardiol. J. 2008;15:100–121.
    1. Li M., Ramos L.G. Drug-Induced QT Prolongation and Torsades de Pointes. Pharm. Ther. 2017;42:473–477.
    1. Piccirillo G., Moscucci F., Fabietti M., Di Iorio C., Mastropietri F., Sabatino T., Crapanzano D., Bertani G., Zaccagnini G., Lospinuso I., et al. Age, gender and drug therapy influences on Tpeak-tendinterval and on electrical risk score. J. Electrocardiol. 2020;59:88–92. doi: 10.1016/j.jelectrocard.2020.01.009.
    1. Piccirillo G., Magnanti M., Matera S., Di Carlo S., De Laurentis T., Torrini A., Marchitto N., Ricci R., Magrí D. Age and QT variability index during free breathing, controlled breathing and tilt in patients with chronic heart failure and healthy control subjects. Transl. Res. 2006;148:72–78. doi: 10.1016/j.trsl.2006.02.001.
    1. Piccirillo G., Cacciafesta M., Lionetti M., Nocco M., Di Giuseppe V., Moisè A., Naso C., Marigliano V. Influence of age, the autonomic nervous system and anxiety on QT-interval variability. Clin. Sci. (Lond.) 2001;101:429–438. doi: 10.1042/cs1010429.
    1. Piccirillo G., Moscucci F., Pascucci M., Pappadà M.A., D’Alessandro G., Rossi P., Quaglione R., Di Barba D., Barillà F., Magrì D. Influence of aging and chronic heart failure on temporal dispersion of myocardial repolarization. Clin. Interv. Aging. 2013;8:293–300. doi: 10.2147/CIA.S41879.
    1. Piccirillo G., Moscucci F., Fabietti M., Parrotta I., Mastropietri F., Di Iorio C., Sabatino T., Crapanzano D., Vespignani G., Mariani M.V., et al. Arrhythmic Risk in Elderly Patients Candidates to Transcatheter Aortic Valve Replacement: Predictive Role of Repolarization Temporal Dispersion. Front. Physiol. 2019;10:991. doi: 10.3389/fphys.2019.00991.
    1. Child N., Hanson B., Bishop M., Rinaldi C.A., Bostock J., Western D., Cooklin M., O’Neil M., Wright M., Razavi R., et al. Effect of mental challenge induced by movie clips on action potential duration in normal human subjects independent of heart rate. Circ. Arrhythmia Electrophysiol. 2014;7:518–523. doi: 10.1161/CIRCEP.113.000909.
    1. Taggart P., Critchley H., van Duijvendoden S., Lambiase P.D. Significance of neuro-cardiac control mechanisms governed by higher regions of the brain. Auton. Neurosci. 2016;199:54–65. doi: 10.1016/j.autneu.2016.08.013.
    1. Piccirillo G., Magrì D., Ogawa M., Song J., Chong V.J., Han S., Joung B., Choi E.K., Hwang S., Chen L.S., et al. Autonomic nervous system activity measured directly and QT interval variability in normal and pacing-induced tachycardia heart failure dogs. J. Am. Coll. Cardiol. 2009;54:840–850. doi: 10.1016/j.jacc.2009.06.008.
    1. Piccirillo G., Rossi P., Mitra M., Quaglione R., Dell’Armi A., Di Barba D., Maisto D., Lizio A., Barillà F., Magrì D. Indexes of temporal myocardial repolarization dispersion and sudden cardiac death in heart failure: Any difference? Ann. Noninvasive Electrocardiol. 2013;18:130–139. doi: 10.1111/anec.12005.
    1. Piccirillo G., Magrì D., Pappadà M.A., Maruotti A., Ogawa M., Han S., Joung B., Rossi P., Nguyen B.L., Lin S.F., et al. Autonomic nerve activity and the short-term variability of the Tpeak-Tend interval in dogs with pacing-induced heart failure. Heart Rhythm. 2012;9:2044–2050. doi: 10.1016/j.hrthm.2012.08.030.
    1. Piccirillo G., Moscucci F., D’Alessandro G., Pascucci M., Rossi P., Han S., Chen L.S., Lin S.F., Chen P.S., Magrì D. Myocardial repolarization dispersion and autonomic nerve activity in a canine experimental acute myocardial infarction model. Heart Rhythm. 2014;11:110–118. doi: 10.1016/j.hrthm.2013.10.022.
    1. Yehya Y.M., Hussein A.M., Ezam K., Eid E.A., Ibrahim E.M., Sarhan M.A.F.E., Elsayed A., Sarhan M.E. Blockade of Renin Angiotensin System Ameliorates the Cardiac Arrhythmias and Sympathetic Neural Remodeling in Hearts of Type 2 DM Rat Model. Endocr. Metab. Immune Disord. Drug Targets. 2020;20:464–478. doi: 10.2174/1871530319666190809150921.
    1. Tamargo J., Caballero R., Gómez R., Delpón E. Cardiac electrophysiological effects of nitric oxide. Cardiovasc. Res. 2010;87:593–600. doi: 10.1093/cvr/cvq214.
    1. Sordillo P.P., Sordillo D.C., Helson L. Review: The Prolonged QT Interval: Role of Pro-inflammatory Cytokines, Reactive Oxygen Species and the Ceramide and Sphingosine-1 Phosphate Pathways. In Vivo. 2015;29:619–636.
    1. Lazzerini P.E., Capecchi P.L., Laghi-Pasini F. Long QT Syndrome: An Emerging Role for Inflammation and Immunity. Front. Cardiovasc. Med. 2015;2:26. doi: 10.3389/fcvm.2015.00026.
    1. Ramírez J., Orini M., Mincholé A., Monasterio V., Cygankiewicz I., Bayés de Luna A., Martínez J.P., Laguna P., Pueyo E. Sudden cardiac death and pump failure death prediction in chronic heart failure by combining ECG and clinical markers in an integrated risk model. PLoS ONE. 2017;12:e0186152. doi: 10.1371/journal.pone.0186152.
    1. Elitok A., Emet S., Karaayvaz E.B., Erdogan O., Aydogan M., Engin B., Cevik E., Orta H., Okumus G., Bilge A.K. The relationship between t-wave peak-to-end interval and hemodynamic parameters in patients with pulmonary arterial hypertension. Ann. Noninvasive Electrocardiol. 2020;18:e12764. doi: 10.1111/anec.12764.
    1. Ponikowski P., Voors A.A., Anker S.D., Bueno H., Cleland J.G., Coats A.J., Falk V., González-Juanatey J.R., Harjola V.P., Jankowska E.A., et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2016;18:891–975.
    1. Berger R.D., Kasper E.K., Baughman K.L., Marban E., Calkins H., Tomaselli G.F. Beat-to-beat QT interval variability: Novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation. 1997;96:1557–1565. doi: 10.1161/01.CIR.96.5.1557.
    1. Piccirillo G., Moscucci F., Persi A., Di Barba D., Pappadà M.A., Rossi P., Quaglione R., Nguyen B.L., Barillà F., Casenghi M., et al. Intra-QT spectral coherence as a possible noninvasive marker of sustained ventricular tachycardia. Biomed. Res. Int. 2014;2014:583035. doi: 10.1155/2014/583035.
    1. Piccirillo G., Ottaviani C., Fiorucci C., Petrocchi N., Moscucci F., Di Iorio C., Mastropietri F., Parrotta I., Pascucci M., Magrì D. Transcranial direct current stimulation improves the QT variability index and autonomic cardiac control in healthy subjects older than 60 years. Clin. Interv. Aging. 2016;11:1687–1695. doi: 10.2147/CIA.S116194.
    1. Piccirillo G., Moscucci F., Pofi R., D’Alessandro G., Minnetti M., Isidori A.M., Francomano D., Lenzi A., Puddu P.E., Alexandre J., et al. Changes in left ventricular repolarization after short-term testosterone replacement therapy in hypogonadal males. J. Endocrinol. Investig. 2019;42:1051–1065. doi: 10.1007/s40618-019-01026-5.
    1. La Rovere M.T., Pinna G.D., Maestri R., Mortara A., Capomolla S., Febo O., Ferrari R., Franchini M., Gnemmi M., Opasich C., et al. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation. 2003;107:565–570. doi: 10.1161/01.CIR.0000047275.25795.17.
    1. Adams K.F., Jr., Uddin N., Patterson J.H. Clinical predictors of in-hospital mortality in acutely decompensated heart failure-piecing together the outcome puzzle. Congest. Heart Fail. 2008;14:127–134. doi: 10.1111/j.1751-7133.2008.04641.x.
    1. Rahm A.K., Lugenbiel P., Schweizer P.A., Katus H.A., Thomas D. Role of ion channels in heart failure and channelopathies. Biophys. Rev. 2018;10:1097–1106. doi: 10.1007/s12551-018-0442-3.
    1. Tse G., Gong M., Wong W.T., Georgopoulos S., Letsas K.P., Vassiliou V.S., Chan Y.S., Yan B.P., Wong S.H., Wu W.K.K., et al. The Tpeak-Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: A systematic review and meta-analysis. Heart Rhythm. 2017;14:1131–1137. doi: 10.1016/j.hrthm.2017.05.031.
    1. Gronda E., Vanoli E., Sacchi S., Grassi G., Ambrosio G., Napoli C. Risk of heart failure progression in patients with reduced ejection fraction: Mechanisms and therapeutic options. Heart Fail. Rev. 2020;25:295–303. doi: 10.1007/s10741-019-09823-z.
    1. Kurokawa J., Abriel H. Neurohormonal regulation of cardiac ion channels in chronic heart failure. J. Cardiovasc. Pharmacol. 2009;54:98–105. doi: 10.1097/FJC.0b013e3181b2b6d4.
    1. Chan T.O., Zhang X.Q., Gao E., Song J., Koch W.J., Feldman A.M., Cheung J.Y. Induced overexpression of Na+/Ca2+ exchanger transgene: Altered myocyte contractility, [Ca2+]i transients, SR Ca2+ contents, and action potential duration. Am. J. Physiol. Heart Circ. Physiol. 2009;297:590–601.
    1. Rossow C.F., Dilly K.W., Yuan C., Nieves-Cintrón M., Cabarrus J.L., Santana L.F. NFATc3-dependent loss of I(to) gradient across the left ventricular wall during chronic beta adrenergic stimulation. J. Mol. Cell. Cardiol. 2009;46:249–256. doi: 10.1016/j.yjmcc.2008.10.016.
    1. Domenighetti A.A., Boixel C., Cefai D., Abriel H., Pedrazzini T. Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. J. Mol. Cell. Cardiol. 2007;42:63–70. doi: 10.1016/j.yjmcc.2006.09.019.
    1. Rivard K., Paradis P., Nemer M., Fiset C. Cardiac-specific overexpression of the human type 1 angiotensin II receptor causes delayed repolarization. Cardiovasc. Res. 2008;78:53–62. doi: 10.1093/cvr/cvn020.
    1. Rougier J.S., Muller O., Berger S., Centeno G., Schütz G., Firsov D., Abriel H. Mineralocorticoid receptor is essential for corticosteroid-induced up-regulation of L-type calcium currents in cultured neonatal cardiomyocytes. Pflugers Arch. 2008;456:407–412. doi: 10.1007/s00424-007-0387-z.
    1. Boixel C., Gavillet B., Rougier J.S., Abriel H. Aldosterone increases voltage-gated sodium current in ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 2006;290:2257–2266. doi: 10.1152/ajpheart.01060.2005.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe