Circulation: Heart Failure

ON MY MIND

Heart Rate and Heart Failure With

Preserved Ejection Fraction
Time to Slow β-Blocker Use?

T
here is a widely held belief that pharmacological heart rate (HR) lowering Markus Meyer, MD, PhD
provides patients with heart failure with preserved ejection fraction (HFpEF) Martin M. LeWinter, MD
a benefit because it results in more time for ventricular filling.1 This view
seems to influence medication choices. In recent large HFpEF trials, about 80% of
patients were receiving β-blockers.2 Some patients may have appropriate indica-
tions, for example, a mildly reduced EF. However, in many, the indication is hyper-
tension, stable coronary artery disease, or atrial fibrillation, for which β-blockers
are no longer considered a preferred long-term treatment and have an uncertain
benefit. Our goal in this article is to discuss how changes in resting HR influence
cardiac function, especially relaxation and filling, in large animals, normal human
subjects and patients with HFpEF (defined based on EF ≥50%) and whether there
is a role for pharmacological HR lowering in HFpEF. Because their daily activity
levels are very low,3 we focus on resting HR as being most relevant to patients
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with HFpEF.

EFFECTS OF ACUTE HR CHANGES IN NORMAL

MYOCARDIUM AND THE INTACT LEFT VENTRICLE
The effects of stimulation frequency on myocardial contraction and relaxation
have been well-characterized in isolated human myocardium. Isometrically con-
tracting normal myocardium displays an increase in systolic force up to 130 to
170/min, above which force declines. As frequency increases, the relaxation rate
also increases. Under these fixed preload and afterload conditions, diastolic force
eventually rises when the diastolic interval becomes so short that relaxation cannot
be completed despite the increase in relaxation rate. These cumulative changes
in contraction-relaxation dynamics are largely accounted for by cellular calcium
handling.4,5
There is limited in vivo information about how isolated increases in HR, usu-
ally produced by atrial pacing, affect contraction-relaxation dynamics in normal
hearts. Findings from animal studies are that higher HRs reduce left ventricular
(LV) end-diastolic pressure and accelerate contraction and relaxation, reflected in
a higher dP/dt and a shortened τ (time constant of isovolumic pressure decline).6
The opinions expressed in this article are
Less well-recognized is the fact that LV diastolic and systolic dimensions progres- not necessarily those of the editors or
sively decrease at higher HRs. At very high HRs, this leads to stroke volumes that of the American Heart Association.
approach zero, a physiological response commonly used during transcatheter aor- Key Words: atrial fibrillation
tic valve replacement procedures. ◼ beta blockers ◼ heart failure ◼ heart
rate ◼ hypertension
Results in normal human subjects generally parallel observations in large ani-
mals.7 With atrial pacing, LV diastolic and systolic volumes typically decrease © 2019 American Heart Association, Inc.
while dP/dt and Ees, the slope of the end-systolic pressure-volume relation, an https://www.ahajournals.org/journal/
index of contractility, increase. Although not all studies report a decrease in circheartfailure

Circ Heart Fail. 2019;12:e006213. DOI: 10.1161/CIRCHEARTFAILURE.119.006213 August 2019 1

 Meyer and LeWinter; Heart Rate and HFpEF
τ, lower filling pressures have been a uniform find-
ing at higher HRs.8 Between-study differences may be
explained by the actual HRs used, loading conditions
and neurohumoral background. The best approach to
estimate τ is also a matter of debate.
What accounts for observed changes in diastolic
volumes and pressure with acute increases in HR in
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normal hearts? Smaller ES volumes at higher HRs
can be explained by increased intracellular calcium
levels,9 which move the systolic volume to a left-
ward-shifted, steeper end-systolic pressure-volume
relation. Volume and pressure at the beginning of
diastole are reduced and, all else being equal, the
pressure remains reduced throughout diastole. At
smaller systolic volumes, there is also an increase in
elastic recoil including torsional deformation respon-
sible for filling by suction and hence lower diastolic
pressures. The decrease in end-diastolic volume at
higher HRs is usually explained by shortening of the
cardiac cycle primarily at the expense of diastole,
with a decrease in time available for filling. How-
ever, this is likely not the whole story because the
reduction in filling time most prominently affects
mid-diastole or diastasis, when transmitral flow is at
its lowest. Other contributors may include a preload-
dependent decrease in the atrial contribution to fill-
ing and changes in afterload. In addition, it is con-
ceivable that increased myocardial oxygen demand
combined with reduced coronary flow at high HRs
leads to ischemia, which could confound the effects
of HR on volume and pressures. However, a loss in
time available for coronary flow is typically overcome
by coronary vasodilation.10 Conversely, it is also well
documented that pharmacological HR lowering does
not improve coronary arterial flow.11
Circ Heart Fail. 2019;12:e006213. DOI: 10.1161/CIRCHEARTFAILURE.119.006213
Figure. Illustration of the acute effects of
an increase in heart rate in heart failure
with preserved ejection fraction.
EFFECTS OF HR CHANGES IN HFPEF
The hemodynamic effects of increasing HR to 120/
min by atrial pacing in patients with HFpEF have been
reported (Figure).8 Compared with resting HR, LV end-
diastolic pressure strikingly decreased (from 17 to 8
mm Hg) at 120/min while end-diastolic, end-systolic,
and stroke volumes all declined. Compared with control
subjects, as HR increased the rise in dP/dt was blunted,
but shortening of τ was preserved.
The acute hemodynamic effects of lower HRs in HFpEF
have not been studied. Because LV end-diastolic pres-
sure declines substantially with HR elevations in HFpEF, it
is likely that slowing the resting HR will raise filling pres-
sures. As increases in HR in patients with HFpEF are asso-
ciated with LV volume reductions that result in a blunted
HR—cardiac output relationship, slowing of resting HR
will likely modestly reduce cardiac output.8 This, along
with increased filling pressures, is obviously undesirable
in patients with HFpEF and suggests that higher resting
HRs might provide hemodynamic benefits.
The potential benefits of higher HRs in HFpEF might be
related to the level of basal contractility, assessed as systolic
stiffness. For example, patients with very steep end-systolic
pressure-volume relations, typified by some elderly women
with HFpEF, would be expected to have a reduced capacity
to shift this relationship leftward with increasing HR, that
is, reduced contractile reserve, and thus smaller decreases
in diastolic pressure and volume mediated by increased
HR. If these patients also had higher basal relaxation rates
(which we do not know), their ability to potentially speed
relaxation further as a function of HR might also be limited.
It is important to not confuse HR-induced changes
produced by pacing with the much more complex
changes that occur during exercise. Principal differ-
August 2019 2
 Meyer and LeWinter; Heart Rate and HFpEF
ences include increased adrenergic tone, which results
in larger changes in contractility-relaxation dynam-
ics, and the action of skeletal muscle pumps which
increase systemic venous return. During exercise in
normal subjects, these combine to maintain LV vol-
umes with little change in filling pressure. In contrast,
in patients with HFpEF filling pressure increases mark-
edly.12 In addition, patients with HFpEF are reported to
have a blunted HR response to exercise (chronotropic
incompetence) that is further exacerbated by pharma-
cological HR lowering.13
Chronic resting HR elevations have also not been stud-
ied in HFpEF. However, the guideline-influencing RACE II
trial (Rate Control Efficacy in Permanent Atrial Fibrillation:
a Comparison Between Lenient Versus Strict Rate Control
II) trial provides insights into the chronic effects of higher
HRs in patients with atrial fibrillation, who also frequently
have hypertensive heart disease and diastolic dysfunc-
tion.14 This trial demonstrated that a more lenient HR con-
trol strategy of up to 110 per minutes was noninferior to
a HR of <80 per minutes with a numerical signal towards
better outcomes at higher HRs. Although the findings of
RACE II cannot be directly extended to HFpEF, they may
provide a clue that higher HRs are not always detrimental.
PHARMACOLOGICAL HR LOWERING
IN HFPEF
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There are no hemodynamic studies of the effects of HR
lowering in HFpEF but clinical experience with β-blockers
and ivabradine provides insights into the chronic effects
of pharmacological HR lowering. As discussed earlier, pro-
longed diastolic filling increases ventricular volumes and
pressures, thus raising the ventricular load. This increases
myocardial wall stress and provides an explanation for the
observation that natriuretic peptide levels are elevated in
patients receiving β-blockers in population studies.15 In
the E:LANDD study (Effects of Long-term Administration
of Nebivolol on the Clinical Symptoms, Exercise Capacity,
and Left Ventricular Function of Patients With Diastolic
Dysfunction) which assessed the effect of nebivolol on
clinical symptoms and exercise capacity in patients with
diastolic dysfunction, β-blocker use was associated with
a trend toward higher levels of natriuretic peptides.16
Higher N-terminal-pro hormone brain natriuretic peptide
(NT-proBNP) levels were also reported in the CIBIS-ELD
study (Cardiac Insufficiency Bisoprolol Study in Elderly)
which evaluated the tolerability of β-blocker uptitration
in HFpEF.17 In addition to higher natriuretic peptide levels,
neither study demonstrated any benefits of β-blockers.
Finally, in the SWEDIC (Swedish Doppler-echocardio-
graphic Study) echocardiographic study of patients with
diastolic dysfunction randomized to carvedilol or placebo,
BNP levels were higher with carvedilol, and the authors
reported an unexpected worsening in heart failure symp-
Circ Heart Fail. 2019;12:e006213. DOI: 10.1161/CIRCHEARTFAILURE.119.006213
toms.18 Taken together, these studies raise the possibil-
ity that β-blockers actually exacerbate HFpEF. However,
worse outcomes were not in fact observed in the only
2 randomized, controlled, long-term trials of β-blockers
in HFpEF. The SENIORS trial Randomized Trial to Deter-
mine the Effect of Nebivolol on Mortality and Cardiovas-
cular Hospital Admission in Elderly Patients With Heart
Failure) trial used an EF cutoff >35% to define HFpEF. It
enrolled 752 participants, approximately half with an EF
<50%. Although the trial reported benefits in all patients,
a recent reanalysis did not find a benefit in patients with
EF ≥50%.19,20 The trial may well have been underpow-
ered to detect any significant change in patients with EF
≥50%, and it is noteworthy that a key outcome, heart
failure hospitalizations, was not specifically documented.
The open-label, randomized J-DHF trial (Japanese Dia-
stolic Heart Failure) tested carvedilol in 245 patients with
EF >40% and did not detect any beneficial or adverse
effects even after limiting the analysis to patients with
EF ≥50%.21 However, the total daily dose of carvedilol
averaged only 8.5 mg, which likely resulted in modest
β-adrenergic blockade at best. Thus, it is unlikely that any
definitive conclusions can be derived from these 2 trials
that can be applied to patients with a modern, EF ≥50%
definition of HFpEF.
Ivabradine has little in the way of cardiovascular effects
other than HR lowering. The functional effects of selective
HR lowering with ivabradine in patients with HFpEF were
evaluated in 2 studies.22,23 These studies were contradicto-
ry. The first22 found an improvement in functional capacity
while the second23 demonstrated a reduction in exercise
capacity. The only randomized, placebo-controlled, long-
term outcomes trial of ivabradine in HFpEF, the EDIFY
(Preserved Left Ventricular Ejection Fraction Chronic Heart
Failure With Ivabradine Study) enrolled 179 patients with
resting HRs above 70 bpm. An HR reduction of 8 per min-
utes failed to improve E/e′ ratio, walk distance or NT-proB-
NP levels in patients with HFpEF.24 Thus, pharmacological
HR lowering with ivabradine does not appear to provide
any consistent benefit in HFpEF. Last, it is concerning that
in a much larger ivabradine trial in patients with coronary
artery disease without heart failure a 20% increase in
heart failure admissions was observed.25
CONCLUSIONS
The weight of evidence gleaned from normal subjects and
patients with HFpEF indicates that within the physiological
range, an acute increase in resting HR results in LV volume
reduction and lower, not higher filling pressures. Moreover,
we have argued elsewhere that pharmacological HR low-
ering in general in patients with normal EFs has adverse
effects on exercise capacity and outcomes.26–28 According-
ly, it is our contention that pharmacological HR lowering
almost certainly has no benefit in most patients with HFpEF
August 2019 3
 Meyer and LeWinter; Heart Rate and HFpEF
and may well be deleterious. Nonetheless, there are select-
ed indications for which pharmacological HR lowering is
likely beneficial, including protection from excessive ven-
tricular rates in atrial fibrillation, prophylaxis of tachyarryth-
mias and symptomatic treatment of effort angina, albeit
with uncertain effects on long-term outcomes. For the
specific case of rate control in atrial fibrillation, if the results
of RACE-2 can indeed be extended to patients with HFpEF,
a more lenient rate strategy may be indicated in these
patients, with consideration given to weaning β-blockers
and other rate-lowering drugs in selected cases. Such an
approach should ideally be tested in a controlled fashion.
With respect to β-blockers, considering the high preva-
lence of their use in HFpEF, it is unlikely that a large, defini-
tive outcome trial can realistically be undertaken. A with-
drawal trial may be the only practical way to test whether
β-blockers have a role in HFpEF. For now—in light of a
questionable rationale and an uncertain evidence basis—it
is our belief that it is prudent to avoid the use of β-blockers
in HFpEF in the absence of a clear and specific indication.
ARTICLE INFORMATION
Correspondence
Martin M. LeWinter, MD, Larner College of Medicine University of Vermont,
UVMMC, McClure 1, Cardiology, 111 Colchester Ave, Burlington, Vermont
05401. Email martin.lewinter@uvmhealth.org
Affiliation
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Cardiology Unit, Department of Medicine, Larner College of Medicine at the
University of Vermont, Burlington.
Sources of Funding
This research was supported by National Institutes of Health grants R01 HL-
118524 (Dr LeWinter) and R01 HL-122744 (Dr Meyer).
Disclosures
Dr Meyer and the University of Vermont have licensed patents for the use of
pacemakers for the prevention and treatment of heart failure with preserved
ejection fraction. The other author reports no conflicts.
REFERENCES
1. Topol EJ, Traill TA, Fortuin NJ. Hypertensive hypertrophic cardio-
myopathy of the elderly. N Engl J Med. 1985;312:277–283. doi:
10.1056/NEJM198501313120504
2. Solomon SD, Rizkala AR, Lefkowitz MP, Shi VC, Gong J, Anavekar N,
Anker SD, Arango JL, Arenas JL, Atar D, Ben-Gal T, Boytsov SA,
Chen CH, Chopra VK, Cleland J, Comin-Colet J, Duengen HD,
Echeverría Correa LE, Filippatos G, Flammer AJ, Galinier M,
Godoy A, Goncalvesova E, Janssens S, Katova T, Køber L, Lelonek M,
Linssen G, Lund LH, O’Meara E, Merkely B, Milicic D, Oh BH, Perrone SV,
Ranjith N, Saito Y, Saraiva JF, Shah S, Seferovic PM, Senni M, Sibulo AS Jr,
Sim D, Sweitzer NK, Taurio J, Vinereanu D, Vrtovec B, Widimský J Jr,
Yilmaz MB, Zhou J, Zweiker R, Anand IS, Ge J, Lam CSP, Maggioni AP,
Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL,
Van Veldhuisen DJ, Zannad F, Zile MR, McMurray JJV. Baseline char-
acteristics of patients with heart failure and preserved ejection frac-
tion in the PARAGON-HF Trial. Circ Heart Fail. 2018;11:e004962. doi:
10.1161/CIRCHEARTFAILURE.118.004962
3. Snipelisky D, Kelly J, Levine JA, Koepp GA, Anstrom KJ, McNulty SE,
Zakeri R, Felker GM, Hernandez AF, Braunwald E, Redfield MM. Accel-
Circ Heart Fail. 2019;12:e006213. DOI: 10.1161/CIRCHEARTFAILURE.119.006213
erometer-measured daily activity in heart failure with preserved ejec-
tion fraction: clinical correlates and association with standard heart
failure severity indices. Circ Heart Fail. 2017;10:e003878. doi: 10.1161/
CIRCHEARTFAILURE.117.003878
4. Pieske B, Kretschmann B, Meyer M, Holubarsch C, Weirich J, Posival H,
Minami K, Just H, Hasenfuss G. Alterations in intracellular calcium han-
dling associated with the inverse force-frequency relation in human di-
lated cardiomyopathy. Circulation. 1995;92:1169–1178.
5. Runte KE, Bell SP, Selby DE, Häußler TN, Ashikaga T, LeWinter MM,
Palmer BM, Meyer M. Relaxation and the role of calcium in isolated
contracting myocardium from patients with hypertensive heart dis-
ease and heart failure with preserved ejection fraction. Circ Heart Fail.
2017;10:e004311. doi: 10.1161/CIRCHEARTFAILURE.117.004311
6. Karliner JS, LeWinter MM, Mahler F, Engler R, O’Rourke RA. Pharmacolog-
ic and hemodynamic influences on the rate of isovolumic left ventricular
relaxation in the normal conscious dog. J Clin Invest. 1977;60:511–521.
doi: 10.1172/JCI108803
7. Wainstein RV, Sasson Z, Mak S. Frequency-dependent left ventricu-
lar performance in women and men. Am J Physiol Heart Circ Physiol.
2012;302:H2363–H2371. doi: 10.1152/ajpheart.01125.2011
8. Wachter R, Schmidt-Schweda S, Westermann D, Post H, Edelmann F,
Kasner M, Lüers C, Steendijk P, Hasenfuss G, Tschöpe C, Pieske B. Blunted
frequency-dependent upregulation of cardiac output is related to impaired
relaxation in diastolic heart failure. Eur Heart J. 2009;30:3027–3036. doi:
10.1093/eurheartj/ehp341
9. Selby DE, Palmer BM, LeWinter MM, Meyer M. Tachycardia-induced di-
astolic dysfunction and resting tone in myocardium from patients with
a normal ejection fraction. J Am Coll Cardiol. 2011;58:147–154. doi:
10.1016/j.jacc.2010.10.069
10. Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercise.
Physiol Rev. 2008;88:1009–1086. doi: 10.1152/physrev.00045.2006
11. Nayler WG, Carson V. Effect of stellate ganglion stimulation on myo-
cardial blood flow, oxygen consumption, and cardiac efficiency dur-
ing beta-adrenoceptor blockade. Cardiovasc Res. 1973;7:22–29. doi:
10.1093/cvr/7.1.22
12. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise
hemodynamics enhance diagnosis of early heart failure with preserved
ejection fraction. Circ Heart Fail. 2010;3:588–595. doi: 10.1161/
CIRCHEARTFAILURE.109.930701
13. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, Kass DA.
Impaired chronotropic and vasodilator reserves limit exercise capacity in
patients with heart failure and a preserved ejection fraction. Circulation.
2006;114:2138–2147. doi: 10.1161/CIRCULATIONAHA.106.632745
14. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM,
Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA,
Van Veldhuisen DJ, Van den Berg MP; RACE II Investigators. Lenient ver-
sus strict rate control in patients with atrial fibrillation. N Engl J Med.
2010;362:1363–1373. doi: 10.1056/NEJMoa1001337
15. Luchner A, Burnett JC Jr, Jougasaki M, Hense HW, Riegger GA,
Schunkert H. Augmentation of the cardiac natriuretic peptides by beta-
receptor antagonism: evidence from a population-based study. J Am Coll
Cardiol. 1998;32:1839–1844.
16. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J,
Vardas PE, Böhm M, Dei Cas L. Effects of the long-term administration of
nebivolol on the clinical symptoms, exercise capacity, and left ventricu-
lar function of patients with diastolic dysfunction: results of the ELANDD
study. Eur J Heart Fail. 2012;14:219–225. doi: 10.1093/eurjhf/hfr161
17. Edelmann F, Musial-Bright L, Gelbrich G, et al. Tolerability and feasibility of
beta-blocker titration in HFpEF versus HFrEF: Insights from the CIBIS-ELD
Trial. JACC Heart Fail. 2016;4:140–149.
18. Bergström A, Andersson B, Edner M, Nylander E, Persson H, Dahlström U.
Effect of carvedilol on diastolic function in patients with diastolic heart
failure and preserved systolic function. Results of the Swedish doppler-
echocardiographic study (SWEDIC). Eur J Heart Fail. 2004;6:453–461. doi:
10.1016/j.ejheart.2004.02.003
19. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A,
Borbola J, Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J,
Tavazzi L, Spinarova L, Toman J, Böhm M, Anker SD, Thompson SG,
Poole-Wilson PA; SENIORS Investigators. Randomized trial to determine
the effect of nebivolol on mortality and cardiovascular hospital admission
in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215–
225. doi: 10.1093/eurheartj/ehi115
20. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS,
Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, von Lueder TG,
August 2019 4
 Meyer and LeWinter; Heart Rate and HFpEF
Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H,
Hjalmarson Å, Wikstrand J, Kotecha D; Beta-blockers in Heart Failure
Collaborative Group. Beta-blockers for heart failure with reduced, mid-
range, and preserved ejection fraction: an individual patient-level analy-
sis of double-blind randomized trials. Eur Heart J. 2018;39:26–35. doi:
10.1093/eurheartj/ehx564
21. Yamamoto K, Origasa H, Hori M; J-DHF Investigators. Effects of carvedilol
on heart failure with preserved ejection fraction: the japanese diastolic
heart failure study (J-DHF). Eur J Heart Fail. 2013;15:110–118. doi:
10.1093/eurjhf/hfs141
22. KosmalaW, Holland DJ, Rojek A,Wright L, Przewlocka-Kosmala M,
Marwick TH. Effect of I f-channel inhibition on hemodynamic status and
exercise tolerance in heart failure with preserved ejection fraction: a ran-
domized trial. J Am Coll Cardiol. 2013;62:1330–1338. doi:10.1016/j.
jacc.2013.06.043
23. Pal N, Sivaswamy N, Mahmod M, Yavari A, Rudd A, Singh S,
Dawson DK, Francis JM, Dwight JS, Watkins H, Neubauer S, Frenneaux M,
Ashrafian H. Effect of selective heart rate slowing in heart failure with
preserved ejection fraction. Circulation. 2015;132:1719–1725. doi:
10.1161/CIRCULATIONAHA.115.017119
Downloaded from http://ahajournals.org by on October 8, 2023
Circ Heart Fail. 2019;12:e006213. DOI: 10.1161/CIRCHEARTFAILURE.119.006213
24. Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P,
Voors AA, Dominjon F, Henon-Goburdhun C, Pannaux M, Böhm M; prE-
serveD left ventricular ejectIon fraction chronic heart Failure with ivabradine
studY (EDIFY) Investigators. Effect of ivabradine in patients with heart failure
with preserved ejection fraction: the EDIFY randomized placebo-controlled
trial. Eur J Heart Fail. 2017;19:1495–1503. doi: 10.1002/ejhf.876
25. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R; SIGNIFY Inves-
tigators. Ivabradine in stable coronary artery disease without clini-
cal heart failure. N Engl J Med. 2014;371:1091–1099. doi: 10.1056/
NEJMoa1406430
26. Meyer M, Rambod M, LeWinter M. Pharmacological heart rate lowering
in patients with a preserved ejection fraction-review of a failing concept.
Heart Fail Rev. 2018;23:499–506. doi: 10.1007/s10741-017-9660-1
27. Nambiar L, Meyer M. β-Blockers in myocardial infarction and coronary
artery disease with a preserved ejection fraction: recommendations,
mechanisms, and concerns. Coron Artery Dis. 2018;29:262–270. doi:
10.1097/MCA.0000000000000610
28. Epstein S, Robinson BF, Kahler RL, Braunwald E. Effects of beta-adrenergic
blockade on the cardiac response to maximal and submaximal exercise in
man. J Clin Invest. 1965;44:1745–1753. doi: 10.1172/JCI105282
August 2019 5