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Force–interval relationship predicts mortality in survivors of myocardial infarction with atrial fibrillation

Open AccessPublished:January 06, 2015DOI:https://doi.org/10.1016/j.ijcard.2015.01.018

      Highlights

      • In atrial fibrillation, the myocardial force-interval relationship (FIR) results in beat-to-beat blood pressure fluctuations.
      • FIR can be quantified as PESPAfib based on simultaneous ECG and blood pressure recordings.
      • In 32 survivors of myocardial infarction, high PESPAfib was associated with increased mortality (hazard ratio 4.88).
      • The association of PESPAfib and mortality was independent of LVEF, age, diabetes mellitus or mean heart rate.

      Abstract

      Background

      : RR interval variations lead to beat-to-beat blood pressure differences through the myocardial force–interval relationship (FIR). In sinus rhythm, an altered FIR leads to post-extrasystolic potentiation (PESP) of systolic blood pressure, which has been shown to predict adverse outcome in survivors of acute myocardial infarction (MI). The purpose of this study was (1) to develop a parameter to assess the FIR in patients with atrial fibrillation (AF) and (2) to investigate its association with mortality in MI survivors suffering from AF.

      Methods and results

      : Thirty-two patients with acute MI and AF underwent 30-min recordings of ECG and continuous blood pressure. Episodes of a short RR interval (<80% of mean interval, RRi) preceding a long interval (>140%, RRi+1) were identified. The systolic pressures of the pulse waves following RRi and RRi+1 were labeled Pi and Pi+1. PESPAfib was calculated as (Pi+1 − Pi) / (RRi+1 − RRi).
      During 5 years of follow-up, 13 patients died. When PESPAfib was dichotomized at the median, mortality rates were 63% and 19% in patients with high and low PESPAfib. Hazard ratio for mortality was 4.88 for patients with high PESPAfib (1.33–17.84, p = 0.004). The association of PESPAfib and mortality was independent from LVEF, age, diabetes mellitus or mean heart rate.

      Conclusions

      : PESPAfib, a measure for the FIR in patients with AF, can be derived from simultaneous ECG and blood pressure recordings. The results of this pilot study indicate that PESPAfib may be useful to predict adverse outcome in survivors of myocardial infarction suffering from AF.

      Keywords

      1. Introduction

      It has been known for more than a century that the contractile force of the first heartbeat after a premature ventricular contraction (PVC) is augmented [
      • Langendorff O.
      Ueber elektrische Reizung des Herzens.
      ,
      • Langendorff O.
      Untersuchungen am überlebenden Säugetierherzen III. Abhandlung: Unregelmäßigkeiten des Herzschlages und ihre Ausgleichung.
      ]. This phenomenon is termed post-extrasystolic potentiation (PESP) [
      • Bornstein A.
      Die Postextrasystole.
      ,
      • Hoffman B.F.
      • Bindler E.
      • Suckling E.E.
      Postextrasystolic potentiation of contraction in cardiac muscle.
      ]. Recently, we reported that PESP, measured at the blood pressure level, is a powerful and independent predictor of mortality in survivors of myocardial infarction (MI) [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ].
      Substantial beat-to-beat variations of RR interval durations, similar in their extent to PVC coupling intervals and compensatory pauses, occur also during atrial fibrillation (AF). This allows one to modify the concept of PESP for evaluating beat-to-beat blood pressure changes during AF (PESPAfib). RR sequences of a short interval followed by a long interval can elicit more or less pronounced augmentations of contractility [
      • Varian K.D.
      • Xu Y.
      • Torres C.A.A.
      • Monasky M.M.
      • Janssen P.M.L.
      A random cycle length approach for assessment of myocardial contraction in isolated rabbit myocardium.
      ]. We hypothesized that PESPAfib bears prognostic information in MI survivors presenting with AF.

      2. Methods

      2.1 Study cohort

      During the screening period of the Autonomic Regulation Trial (ART) [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ], we identified 32 patients suffering from acute myocardial infarction (MI) who were excluded from the ART study analyses because of AF [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ]. These patients comprised the study cohort of the present analysis.
      MI was diagnosed based on the presence of at least two of the following findings: (1) typical chest pain for at least 20 min, (2) creatine kinase above twice the upper normal limit, and (3) ST-segment elevation ≥ 0.1 mV or ≥0.2 mV in at least two contiguous limb or precordial leads, respectively. AF was diagnosed in the resting ECGs based on tracings with no P waves, with fibrillatory waves of different amplitudes and duration, and with irregular ventricular response. Patients with the indication for secondary-prophylactic cardioverter-defibrillator (ICD) implantation before hospital discharge were excluded. Written informed consent was obtained from all participants. The study protocol conforms to the ethical principles of the 1975 Declaration of Helsinki and was approved by the local ethics committee.
      The predefined primary study endpoint was all-cause mortality at five years after the index MI. Clinical follow-up appointments were scheduled every 6 months. If a patient did not attend a planned appointment, contact was made via telephone, mail or through the attending general practitioner. If none of these channels were successful, the local population registry was contacted to either receive the patient's new address or confirm that the patient had deceased.

      2.2 Measurements

      Patients underwent simultaneous 30-min recordings of high resolution ECG (sampled at 1.6 kHz in orthogonal XYZ leads, TMS International, Enschede, the Netherlands) and finger photoplethysmographic non-invasive continuous arterial blood pressure monitoring (sampled at 200 Hz with a resolution of 1 mm Hg, FMS, Amsterdam, the Netherlands). The recordings were made in supine resting position after routine administration of morning medication. The raw signals were verified by an experienced technician, and artifacts were eliminated where necessary. Left ventricular ejection fraction (LVEF) was assessed by either left ventricular angiography or by biplane echocardiography (Sonos 5500, Hewlett Packard, Palo Alto, CA, USA), based on endsystolic and enddiastolic images from a representative heartbeat.

      2.3 Quantification of PESPAfib

      All QRS complexes that were not marked as artifacts (i.e. also broad QRS complexes resulting from either ventricular premature beats or aberrantly conducted beats) were considered in the following analysis. For each heartbeat, the average RR interval (RR¯) of 17 surrounding heartbeats (RRi−8, RRi, RRi+8) was calculated. Each RR interval was expressed as percentage of RR¯. Successive heartbeats qualified for PESPAfib assessment if RRi was <80% of RR¯ and RRi+1 was ≥140% of RR¯ (Fig. 1A–C ), in analogy of short–long sequences elicited by PVCs that are used to calculate PESP in patients with sinus rhythm [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ].
      Figure thumbnail gr1
      Fig. 1Quantification of PESPAfib from simultaneous ECG and blood pressure recordings. A representative ECG recording (A), RR interval plot calculated from the ECG (B) and blood pressure recording (C). In the selected segment of the recording, one sequence of RR intervals (denoted RRi and RRi+1) fulfills the criterion that RRi is shorter than 80% and RRi+1 is longer than 140% of the average RR interval of the 17 surrounding heartbeats (RR¯). The line defined by RRi and RRi+1 and the corresponding systolic blood pressure values Pi and Pi+1 are shown in panel (D), together with the formula of PESPAfib calculation.
      The systolic pressures of the pulse waves following RRi and RRi+1 were labeled as Pi and Pi+1. PESPAfib was calculated as (Pi+1 − Pi) / (RRi+1 − RRi), i.e. by relating the systolic pressure change to the RR interval change (Fig. 1D). If more than one RR interval sequence qualified for PESPAfib evaluation, PESPAfib values were averaged.

      2.4 Clinical data

      Complete revascularization at the time of the PESPAfib measurement was assessed from the cardiac catheterization reports and defined as no remaining stenosis of 75% or more in any main coronary artery. Repeat revascularization was defined as any percutaneous coronary intervention or coronary artery bypass surgery within 1 year of the index infarction.

      2.5 Statistics

      Continuous variables are presented as median and inter-quartile range (IQR) and were compared using Mann–Whitney's U test. Categorical data are expressed as absolute frequencies and percentages. Cox proportional hazards models and receiver operating characteristic (ROC) curves were used to assess the prognostic value of mortality predictors. Survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test. Differences were considered statistically significant if p < 0.05. All statistical analyses were done using IBM SPSS Statistics 20.0 and R 3.0.1 (R Foundation for Statistical Computing, Vienna, Austria).

      3. Results

      Median follow-up was 5 years. The clinical characteristics of the study cohort are presented in Table 1. During 5 years of follow-up, 13 patients (41%) died. Of these deaths, six were classified as cardiac deaths (two due to heart failure, two due to re-infarction, one ruptured myocardial aneurysm, one sudden cardiac death). Two deaths were classified as non-cardiac deaths (both due to pneumonia with secondary complications). The precise cause of death of the remaining five deceased patients is unknown.
      Table 1Baseline characteristics.
      VariableStudy cohort

      (n = 32)
      Survivors

      (n = 19)
      Non-survivors

      (n = 13)
      Clinical data
      Age (years), median (IQR)76 (73–82)75 (70–81)80 (73–85)
      Females, n (%)10 (31.3)6 (31.6)4 (30.8)
      Diabetes mellitus, n (%)13 (40.6)7 (36.8)6 (46.2)
      History of previous MI, n (%)4 (12.5)3 (15.8)1 (7.7)
      CK max (U/l), median (IQR)1193 (574–2398)1336 (539–2878)1193 (572–1415)
      LVEF (%), median (IQR)42 (31–51)43 (32–58)36 (27–49)
      Creatinine (mg/dl), median (IQR)1.2 (1.0–1.4)1.1 (0.9–1.4)1.3 (1.1–1.9)
      NYHA I, n (%)17 (51.5)10 (52.6)7 (53.8)
      NYHA II, n (%)9 (27.3)5 (26.3)4 (30.8)
      NYHA III, n (%)3 (9.1)2 (10.5)1 (7.7)
      NYHA IV, n (%)3 (9.1)2 (10.5)1 (7.7)
      Mean heart rate (bpm), median (IQR)74 (66–87)72 (67–84)81 (64–91)
      Anterior infarction, n (%)9 (28.1)8 (42.1)1 (7.7)
      Inferior infarction, n (%)17 (53.1)8 (42.1)9 (69.2)
      Lateral infarction, n (%)4 (12.5)1 (5.3)3 (23.1)
      Paroxysmal atrial fibrillation, n (%)10 (31.1)5 (26.3)5 (38.5)
      Persistent/permanent atrial fibrillation, n (%)2 (68.8)14 (73.7)8 (61.5)
      Peripheral artery disease, n (%)2 (6.3)1 (5.3)1 (7.7)
      Therapy data
      PCI, n (%)25 (78.1)15 (78.9)10 (76.9)
      Thrombolysis, n (%)1 (3.1)1 (5.3)0 (0)
      CABG, n (%)0 (0)0 (0)0 (0)
      No intervention possible/necessary, n (%)6 (18.8)3 (15.8)3 (23.1)
      Complete revascularization, n (%)11 (34.4)7 (36.8)4 (30.8)
      Repeat revascularization, n (%)11 (34.4)7 (36.8)4 (30.8)
      Aspirin, n (%)30 (93.8)17 (89.5)13 (100)
      Beta-blockers, n (%)29 (90.6)17 (89.5)12 (92.3)
      ACE Inhibitors, n (%)29 (90.6)16 (84.2)13 (100)
      Statins, n (%)28 (87.5)15 (78.9)13 (100)
      Diuretics, n (%)23 (71.9)12 (63.2)11 (84.6)
      Digitalis, n (%)2 (6.3)2 (10.5)0 (0)
      Class I/III antiarrhythmics, n (%)0 (0)0 (0)0 (0)
      ACE denotes angiotensin-converting enzyme; CABG, coronary artery bypass grafting; CK, creatine kinase; IQR, inter-quartile range; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association functional class; PCI, percutaneous coronary intervention.
      On average, 14 (median, interquartile range 5–32) successive heartbeat pairs met the requirements for PESPAfib calculation. In survivors and non-survivors, the number was 14 (4–33) and 18 (6–32), respectively. Fig. 2 shows the PESPAfib values of all survivors and non-survivors. The five patients with the largest values died, while the seven patients with the lowest values survived. The difference between PESPAfib values of survivors (median 1.7, IQR −1.8–7.4) and non-survivors (median 15.6, IQR 2.2–32.0) was statistically significant (p = 0.007). The area under the ROC curve (AUC) was 0.78 (95% confidence interval 0.61–0.94), indicating a good discrimination between survivors and non-survivors.
      Figure thumbnail gr2
      Fig. 2PESPAfib in survivors and non-survivors. PESPAfib values from individual patients are shown as black circles. Average PESPAfib values and standard deviations are shown as solid and dashed gray lines, respectively.
      In univariable Cox proportional hazards analysis, PESPAfib was significantly associated with mortality, while LVEF, age, the presence of diabetes mellitus and the mean heart rate were not (Table 2). The hazard ratio for a 1 mm Hg/s increase in PESPAfib was 1.05 (1.06–1.09, p = 0.004, see Table 2). The increase in mortality with increasing PESPAfib cutoff values was almost linear over the range of observed PESPAfib values (Fig. 3).
      Table 2Univariable Cox regression analysis.
      VariableHazard ratioχ2p
      PESPAfibPer 1 mm Hg/s1.06 (1.02–1.09)8.370.004
      4.5 mm Hg/s4.88 (1.33–17.84)5.730.017
      LVEFPer %0.96 (0.92–1.00)2.620.106
      35%1.48 (0.48–4.53)0.470.495
      Presence of diabetes mellitus1.22 (0.41–3.62)0.120.725
      AgePer year1.06 (0.98–1.15)2.080.149
      65 years1.25 (0.16–9.59)0.040.833
      Mean heart ratePer bpm1.04 (0.98–1.09)1.560.212
      >75 bpm2.73 (0.91–8.18)3.230.072
      Afib denotes atrial fibrillation; bpm, beats per minute; LVEF, left ventricular ejection fraction; PESP, post-extrasystolic potentiation.
      Figure thumbnail gr3
      Fig. 3Continuous association of PESPAfib and mortality risk. The mortality risk (black line) together with the 95% confidence interval (gray area) is shown as a function of PESPAfib cutoff value.
      When PESPAfib was dichotomized at its median (4.5 mm Hg/s), patients with larger PESPAfib had a mortality rate of 63% (10/16), compared to a rate of 19% (3/16) in patients with smaller PESPAfib. Kaplan–Meier curves for all-cause mortality in these patient groups are depicted in Fig. 4. The difference between groups was statistically significant (p = 0.008). The hazard ratio for PESPAfib ≥ 4.5 mm Hg/s was 4.88 (1.33–17.84, p = 0.004, see Table 2).
      Figure thumbnail gr4
      Fig. 4Mortality risk over five years of patients stratified by PESPAfib dichotomized at the median (4.5 mm Hg/s) is depicted. The number of patients at risk is indicated below the graph using the same color coding.
      The association of PESPAfib with mortality was independent from established risk factors. The low number of events precluded us from performing a factual multivariable Cox analysis including all candidate prognostic parameters. However, when PESPAfib was entered together with either LVEF, age, presence of diabetes mellitus or mean heart rate in a pairwise fashion into multivariable Cox models, PESPAfib consistently remained significantly associated with mortality (Fig. 5).
      Figure thumbnail gr5
      Fig. 5Analysis for possible confounding factors. The hazard ratio and 95% confidence interval for PESPAfib obtained from univariable Cox analysis as well as those obtained from multivariable analyses including one of several other risk predictors (LVEF, diabetes, age, mean heart rate) are shown. The gray dashed line indicates a hazard ratio of one. PESPAfib remained a significant predictor of mortality in all multivariable models.
      To investigate the reproducibility of PESPAfib, we divided the 30-minute recording period of each patient into two consecutive 15-minute segments that were separately analyzed. Twenty-nine patients had short–long sequences suitable for PESPAfib calculation in both segments. In each segment, the patient risk was classified as high or low by applying the PESPAfib dichotomy of 4.5 mm Hg/s. The risk classification was concordant in 23 of these patients (79%), indicating reasonable short-term reproducibility.
      For the calculation of PESPAfib, we did not eliminate broad QRS complexes resulting from PVCs. The average number of PVCs in the 30-minute recordings was 16. Of the short–long sequences used for the calculation of PESPAfib, 8.5% were initiated by PVCs. If we excluded PVCs from the analysis, the AUC decreased from 0.78 to 0.73. If PESPAfib was calculated only based on short–long sequences initiated by PVCs, there was no significant association with mortality.

      4. Discussion

      The main finding of our study is that PESPAfib predicts the outcome of post-MI patients suffering from AF. This observation is in line with the results of our recent report [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ] demonstrating that PESP is a strong predictor of mortality in two independent patient cohorts with sinus rhythm, one of MI survivors and one of heart failure patients. Together with previous observations, our data support the concept that evaluating PESP in a clinical setting based on non-invasive continuous blood pressure recordings is suitable to assess the functional status of myocardium for signs of heart failure.
      Our observation is potentially clinically important, since in AF patients, the usual non-invasive procedures of risk stratification are of little if any predictive value: Heart rate variability [
      • Huikuri H.
      • Stein P.K.
      Clinical application of heart rate variability after acute myocardial infarction.
      ], heart rate turbulence [
      • Schmidt G.
      • Malik M.
      • Barthel P.
      • Schneider R.
      • Ulm K.
      • Rolnitzky L.
      • Camm A.J.
      • Bigger Jr., J.T.
      • Schömig A.
      Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction.
      ,
      • Bauer A.
      • Malik M.
      • Schmidt G.
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      • Cygankiewicz I.
      • Guzik P.
      • Lombardi F.
      • Müller A.
      • Oto A.
      • Schneider R.
      • Watanabe M.
      • Wichterle D.
      • Zareba W.
      Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use.
      ], deceleration capacity of heart rate [
      • Bauer A.
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      • Barthel P.
      • Schneider R.
      • Mäkikallio T.
      • Ulm K.
      • Hnatkova K.
      • Schömig A.
      • Huikuri H.
      • Bunde A.
      • Malik M.
      • Schmidt G.
      Deceleration capacity of heart rate as a predictor of mortality after myocardial infarction: cohort study.
      ] and T-wave alternans [
      • Verrier R.L.
      • Klingenheben T.
      • Malik M.
      • El-Sherif N.
      • Exner D.V.
      • Hohnloser S.H.
      • Ikeda T.
      • Martínez J.P.
      • Narayan S.M.
      • Nieminen T.
      • Rosenbaum D.S.
      Microvolt T-wave alternans. Physiological basis, methods of measurement, and clinical utility — consensus guideline by international society for Holter and noninvasive electrocardiology.
      ] can only be measured during sinus rhythm. Even the assessment of LVEF during atrial fibrillation lacks precision. Other risk predictors such as respiratory rate [
      • Barthel P.
      • Wensel R.
      • Bauer A.
      • Müller A.
      • Wolf P.
      • Ulm K.
      • Huster K.M.
      • Francis D.P.
      • Malik M.
      Respiratory rate predicts outcome after acute myocardial infarction: a prospective cohort study.
      ,
      • Dommasch M.
      • Sinnecker D.
      • Barthel P.
      • Müller A.
      • Dirschinger R.J.
      • Hapfelmeier A.
      • Huster K.M.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Nocturnal respiratory rate predicts non-sudden cardiac death in survivors of acute myocardial infarction.
      ,
      • Sinnecker D.
      • Dommasch M.
      • Barthel P.
      • Müller A.
      • Dirschinger R.J.
      • Hapfelmeier A.
      • Huster K.M.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Assessment of mean respiratory rate from ECG recordings for risk stratification after myocardial infarction.
      ] or periodic repolarization dynamics [
      • Rizas K.D.
      • Nieminen T.
      • Barthel P.
      • Zürn C.S.
      • Kähönen M.
      • Viik J.
      • Lehtimäki T.
      • Nikus K.
      • Eick C.
      • Greiner T.O.
      • Wendel H.P.
      • Seizer P.
      • Schreieck J.
      • Gawaz M.
      • Schmidt G.
      • Bauer A.
      Sympathetic activity-associated periodic repolarization dynamics predict mortality following myocardial infarction.
      ] are theoretically applicable in AF patients. However, their prognostic value in AF has not been investigated yet and is thus unknown. A novel non-invasive method to predict mortality risk of MI patients with AF thus covers an important unmet clinical need.
      PESP and its derivative PESPAfib are manifestations of the myocardial force–interval relationship (FIR). It has been shown that the FIR is a major determinant of the beat-to-beat blood pressure variability during atrial fibrillation [
      • Hardman S.M.C.
      • Noble M.I.M.
      • Seed W.A.
      Postextrasystolic potentiation and its contribution to the beat-to-beat variation of the pulse during atrial fibrillation.
      ,
      • Hardman S.M.C.
      • Pfeiffer K.P.
      • Kenner T.
      • Noble M.I.M.
      • Seed W.A.
      Analysis of left ventricular contractile behaviour during atrial fibrillation.
      ,
      • Hardman S.M.C.
      • Noble M.I.M.
      • Biggs T.
      • Seed A.
      Evidence for an influence of mechanical restitution on beat-to-beat variations in haemodynamics during chronic atrial fibrillation in patients.
      ,
      • Suzuki S.
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      • Yamaguchi H.
      • Sano S.
      • Ohe T.
      • Hirakawa M.
      • Suga H.
      Ventricular contractility in atrial fibrillation is predictable by mechanical restitution and potentiation.
      ].
      The FIR is determined to a large extent by the magnitude of intracellular calcium transients in the cardiomyocytes [
      • Endoh M.
      Force–frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance.
      ]. Most experimental studies have determined FIR (typically expressed as its inverse, the force–frequency relation, FFR) under steady-state conditions by pacing the myocardium at different frequencies. In the normal heart beating within the physiological range of heart rates, this steady-state contractility increases with higher heart rates (i.e., with shorter beat-to-beat intervals). A blunted or even inverse FFR is a hallmark of failing myocardium [
      • Hasenfuss G.
      • Pieske B.
      Calcium cycling in congestive heart failure.
      ]. The FIR, however, also manifests at disequilibrium when the steady state of a constant heart rate is disturbed, e.g. by an ectopic beat [
      • Hardman S.M.C.
      Clinical implications of the interval–force relationship of the heart.
      ] or, as investigated in the present study, by the highly-variable beat-to-beat cycle lengths during AF [
      • Hardman S.M.C.
      • Noble M.I.M.
      • Seed W.A.
      Postextrasystolic potentiation and its contribution to the beat-to-beat variation of the pulse during atrial fibrillation.
      ].
      The increased contractility of a post-extrasystolic heartbeat can be understood on the basis of the underlying calcium signaling processes [
      • Wier W.G.
      • Yue D.T.
      Intracellular calcium transients underlying the short-term force–interval relationship in ferret ventricular myocardium.
      ,
      • Rice J.J.
      • Jafri M.S.
      • Winslow R.L.
      Modeling short-term interval–force relations in cardiac muscle.
      ]. A premature heartbeat results in calcium influx via the plasma membrane at a time point when a relevant fraction of the ryanodine receptor calcium channels in the membrane of the sarcoplasmic reticulum (SR) is still refractory. Consequently, calcium release through the ryanodine receptors is reduced compared to normal heartbeats. In the post-extrasystolic pause, the SR calcium content is further increased due to re-sequestration by the sarco-endoplasmatic reticulum calcium ATPase (SERCA). The increased SR calcium content available for release at the post-extrasystolic heartbeat results in an augmented post-extrasystolic contraction.
      In the failing myocardium, the SR calcium content is reduced, as several integral compounds of the calcium cycling system are dysregulated (e.g. leakiness of ryanodine receptors and reduced SERCA activity) [
      • Hasenfuss G.
      • Pieske B.
      Calcium cycling in congestive heart failure.
      ]. Starting from this lower steady state, the relative increase of SR calcium content during the post-extrasystolic pause and, consequently, the relative potentiation of post-extrasystolic calcium release are augmented as compared to normal hearts. This is supported by both modeling studies and experimental data. For example, in a computational model of myocardial calcium handling, an attenuation of SERCA activity resulted in increased PESP [
      • Iribe G.
      • Kohl P.
      • Noble D.
      Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval–force relations: a modeling study.
      ]. In a mouse model, overexpression of the SERCA inhibitor phospholamban was associated with a reduced SR calcium content and increased PESP [
      • Hoit B.D.
      • Tramuta D.A.
      • Kadambi V.J.
      • Dash R.
      • Ball N.
      • Kranias E.G.
      • Walsh R.A.
      Influence of transgenic overexpression of phospholamban on postextrasystolic potentiation.
      ].
      In the present study, as in our previous study [
      • Sinnecker D.
      • Dirschinger R.
      • Barthel P.
      • Müller A.
      • Morley-Davies A.
      • Hapfelmeier A.
      • Dommasch M.
      • Huster K.M.
      • Hasenfuss G.
      • Laugwitz K.L.
      • Malik M.
      • Schmidt G.
      Post-extrasystolic blood pressure potentiation predicts poor outcome of cardiac patients.
      ], a steeper-than-normal FIR (indicated by larger-than-normal PESP or PESPAfib) was associated with an increased mortality. Although at first sight counterintuitive, it is well established that in the failing heart, PESP is typically enhanced as compared to normal ventricles [
      • Beck W.
      • Chesler E.
      • Schrire V.
      Postextrasystolic ventricular pressure responses.
      ,
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      • Liander B.
      • Broman H.
      • Varnauskas E.
      Quantitative evaluation of postectopic beats in the normal and failing human heart using indices derived from catheter-tip manometer readings.
      ,
      • Merillon J.P.
      • Motte G.
      • Aumont M.C.
      • Masquet C.
      • Lecarpentier Y.
      • Gourgon R.
      Post-extrasystolic left ventricular peak pressure with and without left ventricular failure.
      ,
      • Seed W.A.
      • Noble M.I.
      • Walker J.M.
      • Miller G.A.
      • Pidgeon J.
      • Redwood D.
      • Wanless R.
      • Franz M.R.
      • Schoettler M.
      • Schaefer J.
      Relationships between beat-to-beat interval and the strength of contraction in the healthy and diseased human heart.
      ,
      • Voss A.
      • Baier V.
      • Schumann A.
      • Hasart A.
      • Reinsperger F.
      • Schirdewan A.
      • Osterziel K.J.
      • Leder U.
      Postextrasystolic regulation patterns of blood pressure and heart rate in patients with idiopathic dilated cardiomyopathy.
      ].
      Further investigation of PESPAfib in various clinical conditions is needed. In particular, it would be appropriate to know whether treatment of acutely decompensated heart failure is accompanied by regression of PESPAfib values. Moreover, since the pathophysiological concept of PESPAfib is closely related to that of PESP, a comparison of these two parameters in patients who have both sinus rhythm and atrial fibrillation (e.g. before and after cardioversion of persistent AF or in patients with paroxysmal AF) might help for improving our understanding of the correlation of these two phenomena.

      5. Limitations

      The main limitations of our study are the small sample size and the retrospective nature of the analysis, which call for a prospective validation of the approach in a larger patient cohort.
      PESPAfib was assessed on the basis of systolic blood pressure changes. Systolic blood pressure is not solely determined by the contractile state of the heart, but also affected by the compliance of the vascular system. Therefore, increased peripheral arterial resistance might contribute to the steep PESPAfib found in high-risk patients. The maximum systolic rise of left ventricular pressure (dP/dtmax) would be more closely correlated with myocardial contractility than systolic blood pressure; however, determining this parameter would require invasive catheterization of the left ventricle. If PESPAfib was calculated based on dP/dtmax taken from the non-invasive peripheral blood pressure recordings, however, we still observed a significant association with mortality, although reaching slightly lower statistical significance levels (data not shown).
      Regional analysis of post-extrasystolic myocardial contractility has been used as a tool to identify “stunned” or “hibernating” myocardial regions, that are hypocontractile at rest due to ischemia and might benefit from revascularization [
      • Cooper M.W.
      Postextrasystolic potentiation: do we really know what it means and how to use it?.
      ]. The presence of such regions might also influence PESPAfib measured at the blood pressure level. A substantial fraction of the included patients were not completely revascularized at the time of the PESPAfib assessment, or underwent repeat revascularizations within one year (see Table 1). However, when either complete revascularization status or repeat revascularization was included in the Cox model together with PESPAfib, only PESPAfib remained in the model as a significant predictor of mortality (data not shown). We conclude that regional ischemia is not a relevant confounder in our data.
      We assessed PESPAfib during the acute hospitalization, on median 8 days (interquartile range 4–11) after the index MI. It is possible that a different timing (e.g. in the stable phase > 30 days after the MI) might influence the predictive value of the test.
      The criteria for the identification of suitable heartbeat pairs qualified for PESPAfib assessment (RRi as <80% and RRi+1 as ≥140% of RR¯, where RR¯ is calculated as mean of 17 surrounding RR intervals) were developed in our data set to optimize the signal-to-noise ratio. These criteria might not be universally optimum.

      6. Conclusions

      PESPAfib, a measure for the force–interval relationship in patients with AF, can be derived from simultaneous ECG and blood pressure recordings. The results of this pilot study indicate that PESPAfib may be useful to predict adverse outcome in survivors of myocardial infarction suffering from AF.

      Conflict of interest

      None of the authors have any conflict of interest.

      Acknowledgments

      This work was supported by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie ( 13N/7073/7 ) and by the Deutsche Forschungsgemeinschaft ( Si 1747/1-1 ). The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

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