Download Ancient Gunpowder and Novel Insights Team Up Against

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 66, NO. 15, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2015.08.028
EDITORIAL COMMENT
Ancient Gunpowder and Novel Insights
Team Up Against Heart Failure With
Preserved Ejection Fraction*
Walter J. Paulus, MD, PHD,y Loek van Heerebeek, MD, PHDyz
E
xercise intolerance due to dyspnea or muscle
These beneficial effects of sodium nitrite on exercise
fatigue is the most common clinical symptom
hemodynamics are consistent with novel insights on
in heart failure with preserved ejection frac-
inadequate myocardial availability of NO and cyclic
tion (HFpEF). Improvement of exercise tolerance is
therefore correctly used as the primary endpoint in
recent HFpEF trials. In this issue of the Journal,
Borlaug et al. (1) report on invasively established
improvement of exercise hemodynamics when HFpEF
patients received an intravenous infusion of sodium
nitrite before the exercise stress test.
SEE PAGE 1672
guanosine monophosphate (cGMP) in HFpEF (3,4).
EXERCISE INTOLERANCE AND NITRITE
High left ventricular (LV) diastolic stiffness, LV systolic
shortening deficit, chronotropic incompetence, and
deficient pulmonary or systemic vasodilation have all
been proposed as mechanisms critically limiting exercise tolerance in HFpEF (5,6). Their involvement in
the beneficial effect of nitrite deserves closer scrutiny.
Inorganic nitrite originates from the reduction of
First among the proposed mechanisms for exercise
inorganic nitrate, a compound known since ancient
intolerance in HFpEF is high LV diastolic stiffness (5),
times as gunpowder. In the human body, both inor-
which elicits a prompt and large increase in PCWP (7),
ganic nitrate and nitrite are converted to nitric oxide
even at low-level exercise, as illustrated in the study
(NO), with nitrate requiring 2 reductions and nitrite
by Borlaug et al. (1). High LV diastolic stiffness results
only 1 reduction (2). In contrast to organic nitrates,
from a modest deposition of interstitial collagen and
tolerance does not develop because there is no need
from cardiomyocytes with a less distensible cyto-
for enzymatic separation from small carbon-based
skeletal protein titin (4,8,9). Low titin distensibility
molecules (2). The improvement of exercise toler-
is presumed to derive from hypophosphorylation
ance observed by Borlaug et al. (1) was evident at a
by protein kinase G (PKG), a presumption supported
comparable workload from a lower pulmonary capil-
by in vitro experiments in which PKG administration
lary wedge pressure (PCWP), pulmonary artery pres-
corrects distensibility of isolated HFpEF cardiomyo-
sure, and systemic vascular resistance (SVR), as well
cytes and by the presence in HFpEF myocardium of
as from increased cardiac output (CO), left ventricular
low PKG activity and an impressive 10-fold reduction
stroke work (LVSW), oxygen consumption (V O2), and
of the concentration of cGMP, the cofactor of PKG (3).
slope of the D CO/D VO 2 relation (exercise factor).
The low cGMP concentration derives from deficient
upstream activation of soluble guanylate cyclase by
*Editorials published in the Journal of the American College of Cardiology
NO and of particulate guanylate cyclase by natriuretic
reflect the views of the authors and do not necessarily represent the
peptides. In HFpEF myocardium, both NO and natri-
views of JACC or the American College of Cardiology.
uretic peptide contents are low, respectively, because
From the yInstitute for Cardiovascular Research, VU University Medical
of microvascular endothelial inflammation induced
Center, Amsterdam, the Netherlands; and the zOnze Lieve Vrouwe
by comorbidities and because of low wall stress in a
Gasthuis, Amsterdam, the Netherlands. Supported by grants from the
European Commission (FP7-Health-2010; MEDIA-261409) and CVON
concentrically remodeled left ventricle (3,4). In the
(ARENA, RECONNECT). Both authors have reported that they have no
absence of LV volume measurements, the current
relationships relevant to the contents of this paper to disclose.
study (1) did not directly assess diastolic LV stiffness.
1684
Paulus and van Heerebeek
JACC VOL. 66, NO. 15, 2015
OCTOBER 13, 2015:1683–6
Nitrite for Exercise Intolerance in HFpEF
The large increase after nitrite infusion in exercise LV
of titin can explain the improved LV diastolic stiff-
stroke volume (7 ml), however, strongly suggests
ness after nitrite infusion. Nitrite infusion apparently
improvement of LV diastolic stiffness with lower
did not improve LV diastolic stiffness at rest given
PCWP (11 mm Hg) at comparable or larger LV end-
that the small reduction in PCWP (3 mm Hg) was
diastolic volumes. In HFpEF, increased LV stroke
accompanied by a reduced LV stroke volume (5 ml).
volume is more likely to arise from a larger end-
The difference between exercise and rest is compat-
diastolic volume than from a smaller LV end-systolic
ible with nitrite administration delivering more NO to
volume because of high end-systolic elastance,
the myocardium during exercise than at rest because
which only allows for limited end-systolic volume
of the presence of myocardial hypoxia, which boosts
reductions during LV unloading or positive inotropic
conversion of nitrite to NO.
interventions. Increased NO delivery, replenished
The drastic reduction of cGMP in HFpEF myocar-
cGMP stores, and restored PKG-mediated destiffening
dium is also relevant to the LV systolic shortening
F I G U R E 1 Exercise Intolerance and Microvascular Dysfunction
PVREX = or
Comorbidities
•Obesity, MS, DM
•Renal Insufficiency
• Salt-Sensitive HT
Titin-PO4
Collagen
Diastolic LV
StiffnessRest
LV Contractile
ReserveEX
Microvascular
Inflammation/
Rarefaction
Na+ RetentionRest
Δ(CaO2 - CvO2)EX
Microvascular dysfunction in lungs, skeletal muscle, heart, and kidneys induces exercise intolerance in patients with heart failure with preserved
ejection fraction through organ-specific mechanisms. CaO2 CvO2 ¼ arteriovenous oxygen content difference; DM ¼ diabetes mellitus;
EX ¼ exercise; HT ¼ hypertension; LV ¼ left ventricular; MS ¼ metabolic syndrome; Naþ ¼ sodium; PVR ¼ pulmonary vascular resistance;
Titin-PO4 ¼ titin phosphorylation.
Paulus and van Heerebeek
JACC VOL. 66, NO. 15, 2015
OCTOBER 13, 2015:1683–6
Nitrite for Exercise Intolerance in HFpEF
deficit frequently reported in HFpEF, both at rest and
circulation. This produces impaired oxygen delivery
during exercise (6). The dose-response curve for
to exercising muscles, as evident by a smaller arte-
cGMP and cardiac muscle contractile performance has
riovenous oxygen content difference (Ca O 2 Cv O2)
an ascending and descending limb explained by
(12). The present study partially confirms the im-
competing effects of cGMP on calcium handling and
portance of blunted muscle perfusion for exercise
myofilamentary desensitization (10). At the very low
intolerance in HFpEF as it observed lower SVR
cGMP levels observed in HFpEF myocardium, the
and higher V O 2 but unaltered Ca O2 Cv O2 after nitrite
cardiomyocytes could well be operating on the
infusion.
ascending limb of the dose-response curve with a
concomitant LV systolic shortening deficit and the
large increase in LVSW during exercise after nitrite
infusion could be consistent with increased myocardial cGMP eliciting a move up the ascending limb.
Another mechanism recently suggested to contribute to exercise intolerance in HFpEF is chronotropic incompetence (6). Evidence suggests that
chronotropic incompetence not only reduces CO
during exercise because of a blunted heart rate
response, but also forces the left ventricle at the onset
of exercise to use its preload reserve because the
surge in venous return is not matched by an appropriate increase in heart rate. The latter phenomenon
profoundly impairs exercise tolerance in transplant
recipients. In the current study, there was no difference in the heart rate response to exercise, suggesting
that chronotropic incompetence does not seem to
be involved in the effects of nitrite on exercise
tolerance.
Deficient pulmonary and systemic vasodilation
have also been implicated in HFpEF exercise intol-
EXERCISE INTOLERANCE AND
MICROVASCULAR DYSFUNCTION
Microvascular dysfunction induced by comorbidities
appears to be a common denominator for most of the
mechanisms responsible for exercise intolerance in
HFpEF as it is involved in high LV diastolic stiffness,
LV systolic shortening deficit, and blunted pulmonary
or systemic vasodilation (Figure 1). It is also involved
in renal sodium retention because low renal NO content shifts the renal perfusion pressure–natriuresis
curve to the right. The extent of microvascular dysfunction in pulmonary, systemic, coronary, and renal
beds probably varies in relation to the duration of
HFpEF or comorbidity profile. This supports the
hemodynamic evaluation of exercise intolerance in
individual HFpEF patients to guide personalized
treatment, as illustrated in this new study (1), which
showed nitrite improved PCWP, CO, and LVSW but not
PVR and Ca O2 CvO 2 during exercise.
CONCLUSIONS
erance (11–13). Patients with exertional pulmonary
venous hypertension have a limited ability to lower
Borlaug et al. (1) deserve to be commended for the
pulmonary vascular resistance (PVR) during exercise
current study. It demonstrates the clinical relevance
and one-third of patients even experience a para-
of invasive exercise hemodynamics before assigning
doxical increase in PVR (11). The current study (1)
HFpEF patients to therapy, establishes inorganic ni-
observed a similar inability to lower PVR, which
trite as acutely improving exercise hemodynamics in
unfortunately remained unaffected by a previous
HFpEF, and, because inorganic nitrite lacks tolerance
nitrite infusion. Patients in both studies share an
development, paves the way for its use in long-term
important clinical characteristic: obesity, with an
HFpEF trials.
average body mass index of 33 kg/m 2. Obesity and
metabolic syndrome are known to cause microvas-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
cular inflammation, reduced density of the micro-
Walter J. Paulus, Department of Physiology, Institute
vascular network (i.e., microvascular rarefaction),
for Cardiovascular Research VU (ICaR-VU), VU Uni-
and increased PVR. In obese HFpEF patients, micro-
versity Medical Center Amsterdam, Van der Boe-
vascular inflammation and rarefaction not only af-
chorststraat 7, 1081 BT Amsterdam, the Netherlands.
fect the pulmonary circulation but also the systemic
E-mail: [email protected].
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Nitrite for Exercise Intolerance in HFpEF
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KEY WORDS nitrate, nitric oxide, nitrite