Divergence Between Refractoriness of His-Purkinje System and Ventricular Muscle With Abrupt Changes in Cycle Length

Authors, Journal, Affiliations, Type, DOI

• Authors: Stephen Denker, MD; Michael H. Lehmann, MD; Rehan Mahmud, MD; Carol Gilbert, RN; Masood Akhtar, MD
• Journal: Circulation 1983;68(6):1212–1221. © 1983 American Heart Association. Published under the section headings PATHOPHYSIOLOGY AND NATURAL HISTORY / ELECTROPHYSIOLOGY. Received 8 March 1983; revision accepted 1 September 1983
• Affiliation: The Natalie and Norman Soref and Family Electrophysiology Laboratory, University of Wisconsin–Mount Sinai Medical Center, Milwaukee, Wisconsin
• Type: Prospective human electrophysiological study, n=30, with a within-patient controlled design — every patient served as their own control by having refractoriness measured under both a constant and an abruptly-altered cycle length at an identical reference cycle length
• DOI: no DOI is printed in the 1983 article (it predates publisher DOI assignment). The value above is the AHA retrospective identifier reconstructed from the journal's numbering convention; it is not verified from the source and should be treated as unconfirmed
• Why this source matters here: this is the primary source for the cycle-length-dependent dissociation between conduction-system and myocardial refractoriness that the wiki's LBBAP pages use to explain programmed-stimulation capture diagnosis (sources/denker-pes-lbbap-jce-2020, sources/programmed-septal-stim-lbbp-jce-2020). It was previously cited only second-hand, via a 2020 gloss of it

Overview

The textbook model of cardiac refractoriness held that the His-Purkinje system and ventricular muscle behave in parallel — both shortening as the basic cycle length shortens. This study tested what happens when cycle length changes abruptly rather than in steady state, and found that the two tissues diverge. In 30 patients with normal intraventricular conduction, refractoriness was measured with the ventricular extrastimulus (V2) technique under a constant drive (method I) and then under an abrupt change in the cycle length immediately preceding the last drive beat (method II), with the cycle length immediately before V2 held identical between methods (the reference cycle length, CLR). When cycle length was abruptly shortened (CLp > CLR), His-Purkinje refractoriness shortened while ventricular-muscle refractoriness lengthened; when abruptly lengthened (CLp < CLR), both moved the opposite way. Most strikingly, His-Purkinje refractoriness was 50 ms longer in the lengthening protocol despite the preceding cycle length being 600 ms shorter — an inverse relationship, where ventricular muscle varied directly with the preceding cycle length and never once deviated. The authors conclude that ventricular muscle reflects the cumulative effect of preceding cycle lengths, whereas the His-Purkinje system responds to the direction and rate of change. Two qualifications bound the finding, and both are load-bearing for how the wiki uses it: the authors state explicitly that an exact mechanism for the divergence cannot be derived from their study, and they contradict an earlier canine study that found parallel behaviour in both tissues. The clinical relevance is left openly unevaluated.

Keywords

(No keyword list is printed. The article is indexed under Pathophysiology and Natural History / Electrophysiology.)

Key Takeaways

Abstract — the finding in the authors' own numbers

• The received model, and why it was incomplete: that HPS and ventricular-muscle refractoriness both vary directly with cycle length was based on observations during constant cycle length. During abrupt changes, ventricular-muscle refractoriness was known to reflect the cumulative durations of preceding cycle lengths; the effect of such changes on retrograde refractoriness of the HPS was not known
• Design: refractoriness of ventricular muscle and of the HPS was evaluated in 30 patients with normal intraventricular conduction by the ventricular extrastimulus (V2) technique during constant cycle length (method I) and during abrupt cycle length changes (method II)
• The reference cycle length (CLR): in method II the cycle length immediately before V2 was identical to the constant cycle length of method I. The cycle length preceding CLR (CLp) was either longer than CLR (method IIA, by 100–300 ms, in 11 patients) or shorter than CLR (method IIB, by 100–300 ms, in 30 patients)
• The two results that constitute the divergence:

• ERP of the HPS was prolonged with short CLp (method IIB) compared with long CLp (method IIA) — i.e. it moved inversely with the preceding cycle length, while ventricular muscle moved directly
• The authors' summary of the mechanism as they construe it: "Whereas ventricular muscle responded to cumulative effects of preceding cycle lengths and varied directly with CLp, the HPS appeared to respond to directional and/or dynamic changes in cycle length and varied inversely with CLp"
• A further asymmetry: the HPS "appeared to be responsive to rate of change in cycle length whereby short-to-long change in cycle length had a greater effect than long-to-short change"

Introduction — the reasoning that motivated the study

• Refractoriness of the HPS and ventricular muscle had been extensively studied, but generally during steady-state conditions, i.e. constant basic cycle length, where both behave in parallel fashion, shortening as basic cycle length abbreviates
• Han and Moe (canine) had again demonstrated parallel behaviour of the HPS and ventricular muscle, and showed a so-called cumulative effect on refractoriness of preceding cycle lengths
• The authors' own contrary observation: during abrupt alteration in atrial cycle length, their observations on HPS refractoriness "were markedly different" — rather than responding to the cumulative effect of preceding cycle lengths, the HPS response "was opposite of that anticipated from studies on ventricular muscle", suggesting it responds to directional and/or dynamic changes. This implied "a dissociation of functional behavior between the HPS and ventricular muscle that has not been previously demonstrated in man"
• The present study was designed to further define that dissociation by evaluating retrograde refractoriness of the HPS and ventricular muscle during constant and abruptly-changed cycle lengths

Methods

• 30 patients with symptomatic or suspected cardiac arrhythmias, studied in the postabsorptive unsedated state after signed informed consent
• Multipolar electrode catheters positioned in the high right atrium, atrioventricular junction, and right ventricle; satisfactory right bundle branch recordings obtained in 16 of the patients
• Intracardiac electrograms (filter 30–500 Hz), three surface ECG leads (I, II, V1), and time lines displayed on a multichannel oscilloscope and recorded on magnetic tape
• Programmed electrical stimulation with a digital stimulator delivering rectangular impulses of adjustable amplitude and duration; in no patient was the magnitude or duration of the electrical pulse altered during the study; stimulation via an isolation unit

The two protocols

• Method I (constant cycle length) — the conventional ventricular premature stimulation technique (S2 or V2). V2 was introduced after a series of 6 ventricular beats of predetermined cycle length (S1S1 or V1V1); the ventricular coupling interval (S1S2 or V1V2) was progressively decreased by 10 ms until the ERP of ventricular muscle was reached
• Method II (abrupt change) — the cycle length preceding (CLp) the last beat of the ventricular drive was altered. Because the cycle length immediately before V2 was identical in both methods, it was termed the reference cycle length (CLR)
  • Method IIA: abrupt shortening of cycle length, i.e. CLp greater than CLR
  • Method IIB: abrupt lengthening of cycle length, i.e. CLp less than CLR
• In patients with atrioventricular dissociation during ventricular pacing, simultaneous atrial and ventricular pacing was performed during the basic drive, to avoid interruption of the drive by intermittent ventricular capture from sinus beats
• Programmed atrial extrastimuli were introduced after V2 when V2 demonstrated retrograde block, in order to document the site of block (AV node vs HPS)

A methodological strength worth noting

• "All determinations of refractory period were performed two or three times in quick succession, and values were only used if they were identical on two occasions." Refractory-period measurement is operator-dependent and single determinations are unreliable; requiring agreement on repeat measurement is a genuine internal-validity safeguard, and it is unusual for the era
• Statistical analysis: Student's t test

Definitions of terms (as defined in this paper)

• Antegrade HPS conduction: the HV and RB-V intervals, measured from onset of the respective deflections to the earliest detectable ventricular activation on the surface ECG or local electrogram

• Retrograde HPS conduction: retrograde His bundle and right bundle branch potentials for the basic drive beats (H1 and RB1) could not be identified; when the two deflections emerged from the local V2 electrogram, the S2H2 (V2H2) and S2RB2 (V2RB2) intervals were measured from the stimulus artifact (and local ventricular electrogram) to the onset of the respective potentials

• Retrograde relative refractory period (RRP) of the HPS: the longest S1S2 (V1V2) interval where either H2 or RB2 was clearly identified after emerging from the local ventricular electrogram

• Retrograde ERP of the HPS: the longest S1S2 (V1V2) interval where S2 (V2) was retrogradely blocked below the recording site of the His bundle

• ERP of the ventricular muscle: the longest S1S2 interval where S2 did not produce a ventricular response

  These definitions matter for interpreting the result: the HPS measures here are retrograde (assessed during ventricular stimulation), and HPS "ERP" is defined as conduction block below the His recording site — not as tissue inexcitability. The authors later identify this choice as the probable reason they diverge from Han and Moe, who measured excitability (see Discussion and Limitations).

Results

• The 30 consecutive patients — 18 men and 12 women — had a mean age of 52 ± 17 years
• Exclusions: patients with acute myocardial infarction, electrolyte imbalance, or preexisting patterns of bundle branch block were excluded
• All patients were in sinus rhythm, had normal HV intervals (30 to 55 ms), and were taking no cardioactive medication at the time of study
• In all patients the expected abbreviation of refractoriness of the HPS and of ventricular muscle consistently occurred with shortening of constant cycle length (i.e. method I) — establishing that the conventional parallel behaviour was present in this cohort before the abrupt-change protocols were applied

Effect of abrupt decrease in cycle length (method IIA, CLp > CLR)

• Evaluated in 11 patients (Nos. 1–11) and compared with method I
• At the same CLR, RRP of the HPS was shorter in 7 patients (Nos. 2, 3, 5, 6, 7, 9, 10) by 13 ± 5 ms, unchanged in 2 (Nos. 8, 11), and longer in 2 (Nos. 1, 4) by 10 ± 0 ms
• For all 11 patients, RRP of the HPS decreased from 350 ± 29 to 344 ± 29 ms (p < .04) — despite a longer CLp with method IIA by 164 ± 67 ms. That is the surprising direction: a longer preceding cycle length produced a shorter HPS refractory period
• S2H2 delays at the longest comparable V1V2 intervals were essentially the same (difference < 5 ms) between methods. At the shortest comparable V1V2 intervals, S2H2 was shorter (by 5–15 ms) in 9 of 11 patients and the same in the remaining 2 (Nos. 7, 11)
• ERP of the HPS was encountered less frequently with method IIA than method I — in 1 patient (No. 1) vs 3 patients (Nos. 1, 3, 10) — but mean values did not differ significantly
• ERP of ventricular muscle was longer in 10 patients by 10 ± 0 ms and unchanged in 1 (No. 4). A decrease in ventricular-muscle ERP during method IIA was NEVER observed
• For all 11 patients, ventricular-muscle ERP increased from 225 ± 21 to 233 ± 20 ms (p < .0001)
• The summary contrast: when cycle length was abruptly shortened, HPS refractoriness was shorter than at constant cycle length with identical CLR, "whereas refractoriness of ventricular muscle never shortened and usually was longer"

Effect of abrupt increase in cycle length (method IIB, CLp < CLR)

• Compared with method I in all 30 patients
• At the same CLR, RRP of the HPS was longer in 23 patients by 24 ± 9 ms, unchanged in 3 (Nos. 8, 17, 26), and shorter in 4 (Nos. 16, 19, 20, 24) by 10 ± 0 ms
• For all 30 patients, RRP of the HPS increased from 335 ± 30 to 351 ± 35 ms (p < .0001) — despite a shorter CLp with method IIB by 200 ± 26 ms. Again the inverse direction: a shorter preceding cycle length produced a longer HPS refractory period
• At the longest comparable V1V2 intervals, S2H2 delays were 5–10 ms longer in 10 patients, unchanged in 11, and shorter in the remaining 9. At the shortest comparable coupling intervals, S2H2 was longer in 26, unchanged in 2 (Nos. 18, 22), and shorter in 2 (Nos. 24, 30)
• ERP of the HPS increased from 253 ± 65 to 309 ± 65 ms (p < .04) in the 7 patients (Nos. 1–3, 10, 14, 17, 22) in whom this parameter was manifest with either method
• ERP of ventricular muscle was shorter in 27 patients by 11 ± 4 ms and unchanged in 3. An increase in ventricular-muscle ERP during method IIB was NEVER observed
• For all 30 patients, ventricular-muscle ERP decreased from 223 ± 23 to 213 ± 22 ms (p < .0001)
• The summary contrast: an abrupt increase in cycle length produced longer HPS refractoriness than at constant cycle length with identical CLR, "whereas refractoriness of ventricular muscle never increased and usually was shorter"

The direct long-CLp vs short-CLp comparison — the sharpest statement of the inverse relationship

• To compare a broader range of CLp, short CLp vs long CLp was evaluated at a given identical CLR in the same 11 patients (Nos. 1–11)
• Mean CLR 600 ± 45 ms; mean CLp 400 ± 0 ms where CLp < CLR (method IIB), but mean CLp 764 ± 103 ms where CLp > CLR (method IIA)
• "Remarkably, despite a mean CLp shorter by more than 350 msec, RRP of the HPS was longer in 10 patients by 29 ± 7 ms" with method IIB compared with method IIA, and unchanged in one (No. 8)
• Figure 2 gives the single clearest illustration (patient 9): RRP of the HPS was 50 ms longer with method IIB than method IIA, while CLp was 600 ms shorter — the inverse relationship in one patient, in one figure
• ERP of the HPS was longer with method IIB in the one patient (No. 1) in whom it was manifest with both methods, and in 3 further patients (Nos. 2, 3, 10) it was manifest only with method IIB
• Conversely, ERP of ventricular muscle was shorter by 18 ± 6 ms in ALL 11 patients with method IIB compared with method IIA — the direct/cumulative relationship holding without exception
• The overall statistical result for the divergence itself: p < .005
• In the 16 patients with right bundle branch recordings, no change in the sequence of activation of the His bundle and right bundle branch occurred between any method at V1V2 intervals where H2 and RB2 emerged from the local ventricular electrogram — an important negative control, ruling out a shift in retrograde route as the explanation

Discussion

• The classic concept was a description of steady-state properties only. The present findings revealed that "when cycle lengths were abruptly altered, a disparity between behavior of the HPS and ventricular muscle became apparent"
• Three components of the divergence, as the authors enumerate them:
  1. Refractoriness of the HPS varied inversely with CLp, whereas refractoriness of ventricular muscle varied directly with CLp
  2. HPS refractoriness departed from its own steady-state value for the altered cycle length — where CLp > CLR, HPS refractoriness was less than during CLR at steady state; where CLp < CLR, it was greater. Ventricular muscle, by contrast, "reflected the cumulative values obtained for CLp and CLR during their steady state" under either direction of change
  3. HPS change was direction-dependent — of greater magnitude where CLp < CLR than where CLp > CLR — whereas ventricular-muscle change was of similar magnitude in both directions
• Novelty: "Divergence between refractoriness of the HPS and ventricular muscle has not been previously demonstrated in man"
• The contrast with animal data, and the authors' explanation for it: several investigators had reported nonparallel behaviour between action potential duration of HPS and ventricular muscle in response to premature stimulation in canine and porcine preparations — but an increase in HPS refractoriness after abrupt short-to-long cycle length change was NOT suggested by animal studies. Han and Moe, studying canine hearts, found the HPS and ventricular muscle to behave in parallel fashion with both tissues showing a cumulative effect
  • The proposed methodological explanation: in Han and Moe, direct stimulation of the His bundle was performed and His refractory period was defined as the minimal interval between stimuli (SS2) at which a propagated response could be evoked — i.e. excitability. In this study, right ventricular stimulation was used and HPS refractoriness was defined as onset of conduction delay (RRP) and conduction block (ERP) in the HPS
  • Therefore: "the variance in results between these reports... may be due to the fact that different properties of the HPS were being investigated, i.e. excitability in the study of Han and Moe vs conduction delay and/or block of propagated impulse in the present study"
  • A second candidate: species differences in the electrophysiologic behaviour of the HPS with sudden changes in basic cycle length — "another unknown but potentially important factor"
• Alternative explanations considered and argued against:
  • Fatigue from the shorter paced cycle lengths preceding the long cycle — argued unlikely, because scanning of identical constant short cycle lengths consistently produced SHORTENING of RRP, the opposite of a fatigue effect
  • A shift in the route of retrograde impulse propagation producing apparent RRP prolongation — argued unlikely, because no shift in the retrograde activation sequence was noted in any patient with both His and right bundle recordings, and because the S2H2 delays at close coupling intervals and bilateral retrograde block followed the same pattern as the RRP
• The unexplained residual, stated frankly: the discrepancy in S2H2 behaviour "may have a complex electrophysiologic basis, and the mechanism is not readily obvious." It may relate to tissues between the stimulation site and the HPS — ventricular muscle and the Purkinje-muscle junction (PMJ):
  • Ventricular-muscle refractoriness as detected by latency in the stimulus-to-response interval was not encountered at longer V1V2 intervals but "could have played a role at very short coupling intervals"
  • "Refractoriness of the PMJ, which cannot be directly assessed, could have significantly contributed to these results." If PMJ refractoriness behaves like ventricular muscle, its shortening with short-to-long change could have "partially or completely nullified the prolongation of refractoriness of the HPS in some patients." The S2H2 interval is a composite of transseptal, intramuscle, PMJ and HPS conduction, and "may therefore not necessarily parallel the RRP of the HPS as defined here"
• The rate-of-change hypothesis (offered as an explanation, explicitly not established): differences in magnitude with long vs short CLp suggest that in addition to the direction of change, the rate of change may be an important determinant:
  • CLR 600 ms with CLp 800 ms → rate of change 200/800 = 25%
  • CLR 600 ms with CLp 400 ms → rate of change 200/400 = 50%
  • "A similar response does not appear to be operative in ventricular muscle." The authors note these theoretical responses are "quantitively comparable" to the observed findings — a consistency argument, not a demonstration
• The authors' own hedge on the whole explanatory edifice: "While such explanations may be an oversimplification of complex phenomena, the demonstration of dissociation between the behavior of the HPS and ventricular muscle suggests the need to reassess accepted concepts"
• Clinical framing, and its limits: because the response of the HPS was similar in most patients, such changes are "probably functional in nature", and awareness of these properties "may be helpful in determining disease states of the HPS or drug effects". Since dispersion of refractoriness is a substrate for reentry, "the role, if any, that abrupt cycle length changes play in the initiation of clinical arrhythmias needs to be evaluated" — an explicit statement that no clinical consequence was demonstrated

Figures

• Figure 1 — the stimulation protocols; the essential difference between methods I and II is that in method II the cycle length just before S2 (V2) is abruptly altered relative to the preceding cycle lengths, while CLR is identical across methods
• Figure 2 — effect of abrupt cycle length change on HPS refractoriness (patient 9): RRP shortens to 390 ms with CLp 1000→700 ms (IIA) and lengthens to 440 ms with CLp 400→700 ms (IIB); HPS RRP is 50 ms longer in IIB while CLp is 600 ms shorter
• Figure 3 — effect on ventricular-muscle ERP: 270 ms at constant cycle length; lengthens to 280 ms with CLp 1000→700 ms and shortens to 260 ms with CLp 400→700 ms; "ERP of the ventricular muscle varies directly with CLp"
• Figure 4 — long vs short CLp on ERP of the HPS (patient 1); ERP of the HPS occurs at a coupling interval of 360 ms in IIA vs 380 ms in IIB, i.e. 20 ms longer in IIB although CLp is 400 ms shorter
• Figure 5 — plots of RRP-HPS and ERP-VM during constant vs abrupt cycle length change, showing the parallel behaviour under constant cycle length giving way to inverse (HPS) vs direct (VM) behaviour under abrupt change

Limitations of the document

Authors' own stated limitations

• The mechanism is explicitly NOT derived. "Although an exact mechanism for this divergence in behavior cannot be derived from our study, it appears that the HPS responded to directional and/or dynamic changes in cycle lengths." The rate-of-change formulation is a consistency argument ("quantitively comparable"), not a demonstrated mechanism, and the authors concede their explanations "may be an oversimplification of complex phenomena"
• The Purkinje-muscle junction (PMJ) confound "cannot be directly assessed" and "could have significantly contributed to these results." Because S2H2 is a composite of transseptal, intramuscle, PMJ and HPS conduction, it "may therefore not necessarily parallel the RRP of the HPS as defined here" — so the measured quantity may not be a pure HPS property
• The clinical relevance is openly unevaluated: "The role, if any, that abrupt cycle length changes play in the initiation of clinical arrhythmias needs to be evaluated"

Additional limitations evident in the study

• A prior study by the same group is contradicted by — or at least in tension with — this one. The authors' own earlier report (reference 20: Denker, Shenasa, Gilbert, Akhtar, Circulation 1983;67:60) found effects of abrupt cycle length change on HPS refractoriness in man; reference 18 (Wiener et al., Circulation 1981;64:245) reported effects of sudden cycle-length change on human atrial, AV nodal and ventricular refractory periods. The paper does not reconcile these with the present result
• The divergence is contradicted by the canine literature, and the authors' reconciliation is untested. Han and Moe found parallel behaviour in both tissues. The authors attribute the discrepancy to methodology (excitability vs conduction delay/block) and possibly species. This is a plausible but untested explanation — and it cuts both ways: if the divergence arises from how HPS refractoriness is defined rather than from a fundamental tissue difference, then the "dissociation" may be partly a measurement construct. The paper does not attempt to measure both properties in the same preparation to settle it
• n=30, single centre, no independent replication cohort, and no blinding (blinding is largely inapplicable to a within-patient physiology protocol, but it means the 10 ms-step endpoint determinations rest on unblinded operator judgement — the two-or-three-repeat rule mitigates but does not eliminate this)
• The population is unrepresentative of the clinical setting where this physiology is now invoked. Patients had normal intraventricular conduction, normal HV intervals (30–55 ms), and preexisting bundle branch block was an exclusion criterion. The wiki's LBBAP sources that rely on this dissociation apply it in patients with conduction disease — including LBBB and RBBB — which is precisely the substrate this study excluded. The divergence has not been demonstrated in the population where capture-confirmation protocols are used
• The effect sizes are small in absolute terms at the level of RRP — 350 ± 29 → 344 ± 29 ms (a 6 ms change) and 335 ± 30 → 351 ± 35 ms (16 ms) — with standard deviations several times the mean change in the first case. The direction is consistent across patients and the p values are significant in this within-patient design, but individual-level discrimination is poor, and the 11-patient IIA comparison is small
• Not all patients showed the direction claimed. In method IIA, HPS RRP was longer in 2 of 11 patients (by 10 ± 0 ms) and unchanged in 2; in method IIB it was shorter in 4 of 30 and unchanged in 3. The authors report these honestly, but "divergence" is a majority phenomenon in this cohort, not a universal one — relevant when the LBBAP protocols assume a predictable directional response
• Rating rationale: rated high rather than very high. In its favour: a prospective human study with an unusually strong within-patient controlled design, deterministic measurement (repeat determinations required to agree before use), explicit exclusions, clear effect sizes with p values, an important negative control (no shift in retrograde activation sequence in the 16 patients with bundle recordings), and a finding that has stood as the reference for 40+ years and is now the physiological basis of a clinical protocol. Against: n=30, the mechanism is explicitly not derived, the finding contradicts prior canine work by the authors' own admission with an untested reconciliation, a confound they cannot measure (PMJ) may underlie the measurement, and the clinical relevance is unevaluated by their own statement. 'High' reflects that the phenomenon is well and carefully demonstrated while the explanation is not

Key Concepts Mentioned

• concepts/Cardiac-Refractoriness — the concept this paper is the primary source for
• concepts/Left-Bundle-Branch-Area-Pacing — the clinical application that now depends on this dissociation (programmed-stimulation capture diagnosis)
• concepts/Conduction-System-Pacing — the umbrella category for that application
• Effective refractory period (ERP) and relative refractory period (RRP) — the two measured quantities; note the HPS values here are retrograde measures, with "ERP of the HPS" defined as conduction block below the His recording site rather than tissue inexcitability
• Reference cycle length (CLR) and preceding cycle length (CLp) — the design's key terms; CLR held constant across methods is what isolates the effect of CLp
• Method I / method IIA / method IIB — constant, abruptly shortened, and abruptly lengthened drive, respectively
• Cumulative vs directional/dynamic dependence — the paper's central contrast: ventricular muscle integrates preceding cycle lengths, the HPS responds to the direction and rate of their change
• Purkinje-muscle junction (PMJ) — the unmeasurable confound the authors identify; part of the composite S2H2 interval
• Dispersion of refractoriness as a substrate for reentry — the paper's stated clinical implication

Key Entities Mentioned

• concepts/Cardiac-Refractoriness — concept page created by this ingest
• Han and Moe — the canine study (Am J Physiol 1969;217:106) finding parallel behaviour and cumulative effects in both tissues; the principal contradicting evidence, which this paper attributes to a methodological difference
• Wiener et al. (Circulation 1981;64:245) and Denker et al. (Circulation 1983;67:60) — prior human studies of abrupt cycle-length change; the latter by the same group
• University of Wisconsin–Mount Sinai Medical Center, Milwaukee — the single investigating centre; the Natalie and Norman Soref and Family Electrophysiology Laboratory
• American Heart Association / Circulation — publisher (Circulation 1983;68(6):1212–21)
• Masood Akhtar — senior author; the Mount Sinai/Milwaukee electrophysiology group's later work (references 9, 21, 23) is cited within the paper for technique

Wiki Pages Updated

• Created: wiki/sources/denker-hps-refractoriness-circ-1983.md
• Created: wiki/concepts/Cardiac-Refractoriness.md
• Updated: wiki/concepts/Left-Bundle-Branch-Area-Pacing.md
• Updated: wiki/sources/denker-pes-lbbap-jce-2020.md
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md
• Updated: ECG-Physiology-index.md (hub) — concepts/Cardiac-Refractoriness added to the Electrophysiology block
• Updated: tools/convert.py and tools/README.md — the conversion repair and its guards