Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.
com
Heart Online First, published on June 29, 2015 as 10.1136/heartjnl-2015-307461
1
Department of Emergency
Medicine, Wayne State
University School of Medicine,
Detroit, Michigan, USA
2
Department of Physiology,
Wayne State University School
of Medicine, Detroit, Michigan,
USA
3 where acute uid redistribution is caused by a
Cardiovascular Research
Institute, Wayne State
University School of Medicine,
Detroit, Michigan, USA
Correspondence to
Dr David Viau, Department of
Emergency Medicine, Wayne
State University School of
Medicine, 4201 St. Antoine,
Detroit, MI 48201, USA;
dviau@med.wayne.edu
Received 6 January 2015
Revised 31 May 2015
Accepted 7 June 2015
To cite: Viau DM, Sala-
Mercado JA, Spranger MD,
et al. Heart Published Online
First: [ please include Day
Month Year] doi:10.1136/
heartjnl-2015-307461
Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
The pathophysiology of hypertensive acute heart failure
David M Viau,1,2 Javier A Sala-Mercado,2,3 Marty D Spranger,2,3 Donal S OLeary,2,3
Phillip D Levy1,2,3
ABSTRACT
While acute heart failure (AHF) is often regarded as a
single disorder, an evolving understanding recognises
the existence of multiple phenotypes with varied
pathophysiological alterations. Herein we discuss
hypertensive AHF and provide insight into a mechanism
disturbance in the ventricularvascular coupling
relationship. In this relationship, acute alterations in
vascular elasticity, vasoconstriction and reected pulse
waves lead to increases in cardiac work and contribute
to decompensated LV function with associated
subendocardial ischaemia and end-organ damage.
Chronic predisposing factors (neurohormonal activity,
nitric oxide insensitivity, arterial stiffening) and
physiological stressors (sympathetic surge, volume
overload, physical exertion) that are causally linked to
acute symptom onset are discussed. Lastly, we review
treatment options including both nitrovasodilators and
promising novel therapeutics, and discuss future
directions in the management of this phenotypic variant.
INTRODUCTION
Acute heart failure (AHF) results from the acute
or subacute onset of cardiac dysfunction leading to
pulmonary congestion. Often, AHF is considered a
homogenous disorder (ie, congestive heart failure)
with volume overload serving as the primary medi-
ator of lung uid accumulation. Accordingly,
patients are usually treated based on this assump-
tion. However, an evolution in thinking has
emerged, suggesting that a uniform approach to
therapeutic intervention is not equally benecial
for all patients.1 Closer analysis shows the exist-
ence of several common AHF phenotypes with
distinct pathophysiological distortions that are
potentially amenable to specic, directed treat-
ment. Such phenotypes can occur de novo and in
patients with pre-existing chronic heart failure,
whether EF is preserved (HFpEF) or reduced
(HFrEF). Thus, while all episodes of AHF are
accompanied by an increase in LV end-diastolic
pressure (LVEDP), there are certain patients for
whom volume removal is appropriate and others
where afterload reduction or inotropic support is
most needed. Table 1 introduces concepts such as
elastance, compliance and others, which will be
discussed throughout the text.
HYPERTENSIVE AHF
The hypertensive AHF phenotype is a distinct sub-
group whose primary pathophysiological insult is an
increase in afterload and a decrease in venous cap-
acitance.35 Collectively, these effects lead to
volume redistribution with a shift of uid from the
splanchnic and peripheral vascular beds into the
Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461
Review
pulmonary circulation (gure 1). Hypertensive
AHF manifests as a rapid onset of dyspnoea in
patients with a systolic blood pressure (SBP)
140160 mm Hg, nearly all of whom have a history
of poorly controlled chronic hypertension.6 The
latter is a critical predisposing factor, causing
pressure-mediated cardiac remodelling with LV
hypertrophy, LV stiffness and ultimately diastolic dys-
function.7 Such patients benet greatly from inter-
ventions that improve forward ow and realign their
ventricularvascular coupling relationship; an effect
that may not occur to a sufcient degree by simply
reducing preload through diuresis. Understanding
this is clinically important because >50% of patients
with AHF have an associated SBP >140 mm Hg,
suggesting that the hypertensive AHF phenotype is
quite common.6
The ventricularvascular coupling relationship
While factors such as myocardial ischaemia, worsen-
ing renal function, volume overload and chronic pul-
monary disease may contribute to decompensation,
the primary pathophysiology in hypertensive AHF
centres on a mismatch in the ventricular
vascular coupling relationship. Ventricularvascular
coupling describes the inter-relationship between the
heart and the vasculature in the normal and diseased
state. Normal ventricularvascular interaction
requires the vascular system to complete two func-
tions: (1) transport blood to vital organs and the per-
iphery; and (2) buffer high systolic pressures while
maintaining non-pulsatile diastolic blood ow.8
A powerful model described by Sunagawa
et al9 treats the arterial and ventricular systems as
elastic chambers where arterial elastance (Ea) and
LV end systolic elastance (Ees) work as somewhat
opposing forces affecting and responding to
changes in volume. The ratio of Ea/Ees is often
used to describe interactions between the ven-
tricular and vascular system.2 These values can be
derived from LV pressure volume loops, with Ees
depicting the end systolic pressureend systolic
volume interaction and Ea explaining the end sys-
tolic pressureend diastolic volume relationship
(gure 2AC). The normal Ea/Ees ratio ranges
between 0.6 and 1.0, representing a point where
cardiac contractility and efciency have been opti-
mised to effectively transfer blood to the systemic
circulation.10
Dysfunction in ventricularvascular coupling is
not a novel concept as it has been described in
humans with heart failure and canine models of
cardiac disease. Uncoupling occurs when an imbal-
ance in the system arises and is often ascribed to
vascular stiffening.8 Vascular stiffening has been
demonstrated in elderly populations both with and
without cardiovascular disease.11 While other
1
 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com

Review

Table 1 Key cardiovascular concepts

Term Definition Clinical implication

Compliance Ability of the vessel/heart to increase diameter for a given pressure; Compliant vessels dampen maximum systolic pressure. With decreased
DVolume compliance, pulsatile loads increase maximum systolic pressures in large
vessels and increase vascular resistance in smaller vessels. In the ventricle,
DPressure
decreased compliance will elevate end diastolic pressures.
Elastance Inverse of compliance, ability of vessel/heart to recoil back to original Elastic vessels redistribute systole pressures to diastole, with diminished
DPressure elastance diastolic pressures fall. Ventricular relaxation is dependent on elastic
dimension after a force is applied; properties, without these properties diastolic relaxation parameters are
DVolume
disturbed.
Clinically can be thought of as ventricular opposition to forward flow from the
Impedance Resistance in an oscillatory system. Relationship between pressure change
vascular system. Elevations in afterload and pulse wave reflections will
DPressure
and flow velocity; increase impedance, elevating central systolic pressure and likely lead to
DVelocity elevations in LV end diastolic pressure.
DDistance
Pulse wave Speed of the pulse wave travelling through an artery; Increased velocity through a stiffened conduit (ie, aorta) leads to higher
DTime
velocity maximum systolic blood pressure, increased pulsatile load and early return of
pulse wave reflections. Increased pulsatile load may lead to microcirculatory
damage, especially in susceptible systems such as the renal microvasculature.
Pulse wave As pulsatile flow meets major resistance vessels an attendant reflected Pulse wave reflections occur in all individuals. In healthy vasculature, reflected
reflection pressure wave is generated by Newtons third law. A summation of the waves reach the aortic valve after closure, creating the dicrotic notch and
reflected pressure waves is propagated back towards the LV. elevating diastolic pressure. Elevated diastolic pressure enhances coronary
blood flow. In a stiffened system, pressure waves may reach the LV during late
systole, augmenting pressure (known as augmentation index), leading to
increased afterload, impedance to forward flow and elevated LV end diastolic
pressure.2

conditions such as renal disease and diabetes mellitus may con-
tribute to vascular stiffening, chronic hypertension accelerates
arterial stiffness and is by far the condition most closely
aligned with this phenomenon.12 Chronic hypertension
exposes the vasculature to progressively greater pulsatile loads,
which induce wall stress in large elastic arteries and smooth
Figure 1 Fluid redistribution in hypertensive acute heart failure.
The cardiac and vascular systems are innately coupled together. Acute
vasoconstriction of peripheral arterial and splanchnic vascular beds
reduce compliance in the system and increase pressure, causing a rapid
rise in afterload and preload, respectively. Elevated pressures are
transmitted to the right and left heart. These elevated pressures are
propagated towards the pulmonic circulation. When considering
Starling forces, increased hydrostatic pressures from both the left and
right heart lead to alveolar uid accumulation and pulmonary
congestion.
2 Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461
muscle hypertrophy in small calibre arterioles. In concert, these
effects lead to decreased vascular compliance generating a pro-
gressively greater resistance to forward ow from the LV.12 To
maintain the coupling relationship and dissipate transmural
stress, the LV undergoes hypertrophic remodelling, leading to
alterations in its ventricular geometry and relaxation properties.
Such alterations are accompanied by molecular changes in col-
lagen cross-linking and myocyte protein expression, resulting in
a less compliant LV.13
As the vascular tree becomes progressively non-compliant,
both Ea and Ees increase in tandem, maintaining the Ea/Ees
ratio in the optimal range across widely variable elasticities.
However, a system with baseline elevations in Ea and Ees is
prone to haemodynamic instability and decreased cardiac
reserve.2 In vivo, dynamic perturbations such as static exercise
or anxiety (sympathetic surge) that increase SBP/afterload and
contractility acutely lead to signicant changes in Ea and Ees,
respectively. In non-compliant states, small increases in preload
and afterload alter Ea and produce exaggerated changes to SBP
(represented by SBP) and stress the system. In a normal system
(gure 3A), there is enough cardiac reserve (Ees, contractility
reserve) to compensate for the known rise in Ea (SBP) that
accompanies an increase in heart rate,14 but when LV stiffness is
present, the response (especially preload recruitable stroke
work) is blunted. Consequently, affected patients may exhibit
exertional fatigue as ventricular dysfunction continues to
develop (gure 3B). LV stiffness also renders the system remark-
ably sensitive to loading conditions, with an exaggerated pres-
sure response to smaller volume increases (ie, preload) and an
inability to accommodate even normal volumes with acute
increases in peripheral resistance (ie, afterload). A sharp increase
in LVEDP and an abrupt rise in afterload (gure 3C), causing an
alteration of the pressurevolume relationship, is a particularly
important contributor to hypertensive AHF, as the heart does
not have the ability to increase LV pressures enough to match
vascular resistance and maintain adequate stroke volume.2
Importantly, sensitivity to enhanced afterload occurs in the
setting of HFpEF and HFrEF,15 rendering patients of either
subtype susceptible to episodes of hypertensive AHF.
 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com
Figure 2 Experimental canine pressure volume loops modied to
illustrate the interaction between LV end systolic elastance (Ees), arterial
elastance (Ea) and change in systolic blood pressure (SBP). Derivation of
Ees as the slope of the end systolic pressure and end systolic volume
relationship is shown for a normal ventricle (A). Experimentally the slope
can be calculated with serial preload reduction or using the equation
end systolic pressue
Ees . Ea is derived from the slope
end systolic volume  initial volume
of the end systolic pressure and stroke volume relationship and is dened
end systolic pressue
by the equation Ea . With isolated changes in
stroke volume
preload (B), the slope of Ea remains constant. Isolated changes in
afterload (C) alter the slope of Ea. End diastolic pressure volume
relationship (EDPVR) is shown as the black solid line through all panels.
This is shown essentially as a constant, but EDPVR changes signicantly
with ventricular stiffening.
Central versus peripheral blood pressure
A key to understanding the pathophysiology behind hyperten-
sive AHF is the conuence of central arterial, peripheral
Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461
Review
Figure 3 In vivo, multiple haemodynamic variables can change
during a stress to the cardiovascular system including inotropy, preload
and afterload. A dynamic stress, such as static exercise or aberrant
baroreceptor response (sympathetic activation), may lead to increased
vasoconstriction (afterload) and venous return ( preload). The slope of
LV end systolic elastance (Ees) will increase with increased inotropy
(Ees). In the normal cardiovascular system (A), there is sufcient
cardiac reserve to accommodate these changes because of lower
baseline Ees and Ea. With developing ventricular stiffness (B) and,
ultimately, hypertensive acute heart failure (AHF) (C), the baseline slope
Ees and Ea are much steeper and generate much larger change in
systolic blood pressure (SBP) with similar changes in preload and
afterload and have less room to accommodate a dynamic stress. With
deterioration of the ventricularvascular coupling relationship, the end
diastolic pressure volume relationship (EDPVR) is altered, with higher
end diastolic pressures needed to maintain stroke volumes. This effect
is especially pronounced in AHF (C) when afterload (red arrowhead) is
acutely increased causing an acute stiffening of the LV.
arterial and ventricular pressures. Immediately after birth the
arterial system begins to age. Over time, multiple small insults
3
 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com

Review

to the system add up, exponentially leading to material
fatigue and a progressive loss of vascular elasticity.12 The elas-
ticity is lost in both central vessels (mainly the aorta) and per-
ipheral circulation ( principally the arterioles). As aortic
elastance deteriorates, it loses the ability to function as a cap-
acitor that dampens systolic ventricular load, redistributing it
during diastole. This results in a forward pulsatile load that
travels faster and with more force to the periphery. The speed
of this wave front is known as the pulse wave velocity (PWV).
In contrast, peripheral arterioles generate the majority of resist-
ance to blood ow, absorbing and recoiling with the pulsatile force
encountered during systole. As the arterioles recoil, a reverse pul-
satile wave is reected back towards the central circulation.
Normally, this reected wave reaches the ventricle during early
diastole just after aortic valve closure. With increased vascular stiff-
ness, this waveform is reected earlier, reaching the LV during late
systole (gure 4A, B).8 As a result, excess force is transmitted to
the ventricle during the contraction, causing impedance to outow
and prompting a shortened LV ejection time. In the setting of a
non-compliant ventricle, this excess force (termed the augmenta-
tion index) drives up central aortic pressure, leading to an abrupt
rise in LVEDP with an attendant back ow of uid from the heart
into the pulmonary circulation. Thus, with impaired ventricular
compliance, increases in afterload effectively create a mechanical
barrier to contractile function, precipitating the aforementioned
imbalance in the ventricularvascular coupling relationship seen
with hypertensive AHF.
Mechanisms of vasoconstriction
The excessive afterload that is central to the onset of hyperten-
sive AHF are triggered by periods of acute vasoconstriction. As
shown in box 1, a number of factors can contribute to acute
vasoconstriction, but a few specic mechanisms appear to be
particularly important.
Acute sympathetic surge caused by various stimuli including
muscle metaboreex activation from exertion,16 arterial
baroreceptor insensitivity, sympathomimetic substance abuse
(eg, cocaine or amphetamines), an abrupt rebound from sym-
patholytic medication non-compliance, or even psychosocial stress
or anxiety have been posited as a key contributors. Sympathetic
stimulation results in increased contractility via activation of
cardiac beta-adrenergic receptors and increased peripheral vascular
resistance via activation of vascular alpha-adrenergic receptors.
Additional vasoconstrictor effects may also be mediated by neuro-
hormonal activation of the reninangiotensinaldosterone system
where angiotensin II and vasopressin cause direct vasoconstriction
of vascular beds alongside modulation of central sympathetic
outow.7
Direct endothelial dysfunction (termed acute endothelitis)
may also acutely alter vascular compliance through increased
endothelial oxidative burden. In this proinammatory state,
cytokine release either from infection or other stressors generate
reactive oxygen species, which directly sequester nitric oxide
(NO), thus limiting the ability to vasodilate. These effects
appear to be systemic, involving both arterial and venous beds,
and contribute to enhanced central blood volume mobilisa-
tion.17 This mechanism aligns well with the current patho-
physiological understanding of haemodynamic distortions,
where an increase in pulmonary artery pressure and thoracic
bioimpedance can be observed in the days and weeks prior to
an episode of AHF.18 Further evidence correlating inammation
to decreased vascular compliance have demonstrated a linear

Figure 4 Example of aortic pressure waves (lines) and reected pressure waves (reected , solid shape) from the vasculature plotted as pressure
versus time. As the LV contracts, energy is transferred to the aorta as pressure. Some of this pressure acts to generate the forward ow of blood at a
velocity dependent on the compliance/elastic properties of the aorta. The rest of the energy is stored in the compliant aorta to be redistributed
during diastole. As the incident wave (blood ow) reaches the resistance vessels, an attendant pressure wave is sent backwards, the summation of
these waves creates pressure wave reected back towards the heart. In normal vasculature (A) with a compliant aorta, this reected wave from the
periphery reaches the LV after aortic valve closure. In the less compliant aorta (B), less energy is stored and it is converted to increased velocity of
forward blood ow. This increased velocity of blood ow reaches resistance vessels earlier and sends a reected pressure wave back to the heart.
This pressure wave can reach the heart prior to aortic valve closure acting to increase afterload, creating a mechanical impedance to forward ow,
resulting in a further elevation of LV end diastolic pressure. The illustrations below the panels represent the LV, with aortic valve and aorta. The
incident wave (forward ow) and reected waves (wavy line) are illustrated as well.

4 Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461

 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com

Review

Volume status
Box 1 Mechanisms of vasoconstriction There is increasing appreciation that two distinct pathways can
lead to pulmonary congestion in AHF.3 The rst has been
termed cardiac failure and aligns with a more traditional view
Muscle metaboreex activation
of AHF where excess volume accumulates, leading to an over-
Baroreceptor dysfunction
whelming of the Starling mechanism with ensuing uid over-
Stretch-mediated vasoconstriction
load and congestive heart failure. The second pathway, referred
Angiotensin II
to as vascular failure, results from an abrupt redistribution of
Vasopressin
existing uid from the splanchnic and central circulation into
Endothelins
the pulmonary vasculature rather than an accumulation of
Thromboxanes
volume. This is the principal mechanism of pulmonary conges-
Nitric oxide sequestration
tion in hypertensive AHF. Thus, while both pathways produce
Sympathomimetic use
an increase in lung water content, the pathophysiology behind
Sympatholytic non-adherence
the respective increases differs, suggesting that therapy should
Sympathetic surge (anxiety/stress)
differ as well.

correlation between inammatory markers (especially C reactive Associated myocardial injury?

protein) and measures of increased arterial stiffness (PWV as
well as aortic and brachial pulse pressure).19 Such inammatory
effects mimic the vascular changes of ageing with increased Ea
and Ees, resulting in decreased cardiac reserve, exercise intoler-
ance, volume sensitivity and hyper-reactivity to sympathetic
surge. A summary of the pathophysiological effects of vasocon-
striction in the setting of AHF is provided in gure 5.
As a result of the additional contractile force needed to over-
come the impedance to LV outow, myocardial oxygen demand
increases during hypertensive AHF. While this may be com-
pounded by microcirculatory compression caused by a rising
LVEDP,20 there appears to be a paradoxically protective effect at
the coronary artery level. Peak coronary blood ow occurs pre-
dominantly during diastole and, in the normal heart, coronary

Figure 5 Summary of pathophysiological events in hypertensive acute heart failure. Initial predisposition to altered ventricularvascular (V-V)
coupling secondary to chronic changes such as LV hypertrophy (LVH), arterial smooth muscle cell (SMC) hypertrophy and decreased elastance. Acute
alterations such as static exercise ( perhaps activities of daily living for some), medication non-compliance or acute endothelitis may activate the
sympathetic nervous system (SNS) or through neurohormonal means and induce vasoconstriction. Arterial vasoconstriction leads to decreased
vascular compliance, increasing afterloads and increased pulse wave velocity (PWV), which in turn lead to increased myocardial oxygen (O2) demand
and impedance to forward ow. Venous/splanchnic constriction mobilise central volume and increase preload, elevating right-sided pulmonary
pressure. Combined elevations of left-sided and right-sided pressures increase hydrostatic pressure in the pulmonary system ( pul pressure), and uid
enters alveoli via forces described by Starling equation. Increased myocardial O2 demand and decreased oxygen content from alveolar oedema cause
end-organ ischaemia. This propagates the feed-forward activity of acute heart failure; in the heart, this leads to decreased cardiac output (CO),
kidney increased reninangiotensinaldosterone system (RAAS) activation and brain increased SNS activity, ultimately leading to more
vasoconstriction, more ischaemia and end-organ damage.

Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461 5

 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com
Review
perfusion is enhanced by the reverse pulse wave reecting off
the aortic valve and increasing the pressure gradient in the cor-
onary sinuses. In a study of canine hearts connected to a stiff
aortic bypass graft (mimicking aortic stiffness in humans), left
anterior descending coronary ow was increased by 36% with a
15% increase in perfusion at matched cardiac oxygen consump-
tion with the non-compliant conduit was noted.21 The majority
of the ow increase occurred during systole and was sensitive to
alterations in SBP, with a 56% greater reduction in ow when
the pressure volume area was reduced by 40%. Subsequent
research on the molecular mechanisms suggested that the
observable ow increase within the stiff conduit was secondary
to the release of NO caused by the increased pulsatile load on
the coronary vessels.2 This mechanism may initially be bene-
cial; however, over time prolonged exposure to NO may lead to
insensitivity. Moreover, as Coutsos et al showed in a canine
model of chronic heart failure, this protective mechanism is
likely to be limited by neurogenic coronary vasoconstriction
triggered by exaggerated muscle metaboreex-induced increases
in sympathetic activity.22 With ow probes inserted on the left
circumex artery, such activity resulted in coronary vasocon-
striction and attenuated cardiac contractility. Of note, such
effects on the heart were abolished with use of an alpha-1
antagonist, suggesting the potential for a cardioprotective thera-
peutic approach, particularly in the setting of known coronary
artery disease. Associated myocardial injury does appear to
occur and maybe related to multiple factors including ow
dynamics, subendocardial ischaemia and even coronary
vasoconstriction.
CLINICAL IMPLICATIONS
The past decade has seen signicant advances in the understand-
ing of AHF. There is an increasing emphasis on a directed
approach to management where early therapeutic intervention
is better aligned with underlying precipitants1 and trials focused
on vasodilator therapy in patients with normal to high blood
pressure have now supplanted an all-comer approach. For
hypertensive AHF, the underlying pathophysiology centres on
acute perturbations superimposed on chronically altered ven-
tricularvascular homeostasis. Accordingly, vasodilators ( pre-
dominantly nitrates) are currently recommended as rst-line
therapy for such patients, though as noted in a recent Cochrane
review, existing data on their effectiveness are limited.1 21 That
said, a few small studies have found treatment with high-dose
nitrates to be benecial in preventing consequences of hyperten-
sive AHF such as respiratory failure, myocardial infarction,
endotracheal intubation and intensive care unit admission.4 The
reason for these vascular effects may reside in the fact that
nitrate effects are dose dependent, with increased degrees of
arterial (vs venous) dilation at higher doses. However, even at
lower doses, nitrates appear to provide greater relative reduc-
tions in central aortic (vs peripheral arterial) pressure, largely
through a reduction of the reected waveform and a decrease
in the augmentation index. Accordingly, nitrates can help
modulate perturbations in the ventricularvascular coupling
relationship by diminishing impedance to forward ow.23
Diminishing impedance is a major therapeutic target for rapid
realignment of the ventricularvascular coupling relationship. In
the African-American Heart Failure Trial, treatment of chronic
heart failure with nitrates did demonstrate decreased hospitalisa-
tion and mortality when added to their medication regimen.24
However, similar data are non-existent in the setting of AHF
and, other than symptomatic improvement, the utility of nitrates
in the treatment of hypertensive AHF remains unclear.25
6 Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461
A recent investigation targeting interventions for patients with
hypertensive AHF using serelaxin, a synthetic peptide modelled
after relaxin-2, a vasoactive hormone that aids in maternal adap-
tation to haemodynamic alterations of pregnancy, has shown
promise. Serelaxin has systemic vasodilator effects; increasing
arterial compliance and renal blood ow while decreasing
inammation and brosis. In clinical trials targeting patients
with SBP >125 mm Hg, a 48 h serelaxin infusion was shown to
result in early relative improvements in blood pressure and dys-
pnoea with signals that also suggest downstream mortality bene-
ts at 180 days.26 While the precise mechanism(s) for the latter
have yet to be dened (and the end-point itself, not denitively
proven), biomarker data suggest that it may arise from the
attenuation of both cardiac and renal injury during active treat-
ment.27 Whether this is an effect of serelaxin itself or directed
use of vasodilator therapy in patients who typically receive little
more than diuresis remains to be seen. That greater alleviation
of signs and symptoms of congestion was noted in the serelaxin
group despite lower use of diuretics and other intravenous
agents does suggest clinical benet from efforts to redistribute
rather than remove uid.
Based on this conceptual model, directed therapy with other
vasodilators seems viable as well. The recently completed
PRONTO (An Efcacy and Safety Study of Blood Pressure
Control in Acute Heart Failure) trial was a randomised, open-
label phase IIIa trial of clevidipine, a fourth-generation short-
acting dihydropyridine calcium channel blocker (n=51) versus
standard of care (n=53) for dyspnoea in patients with AHF and
SBP >160 mm Hg.5 Patients receiving clevidipine were more
likely to have their BP reduced to a predened target range by
30 min (70.5% vs 36.6%; p=0.002) and experienced more rapid
improvements in dyspnoea (mean (SD) visual analogue scale at
1 h: 21.7 (18.8) mm vs 33.4 (24.9) mm; p=0.02) than the stand-
ard of care group (86.8% of whom received either nitroglycerin
(56.6%) or nicardipine (30.2%)) without a signicant increase in
hypotension, adverse events or mortality at 30 days.
Despite these ndings, not all vasodilators have been asso-
ciated with benet. In the Acute Study of Clinical Effectiveness
of Nesiritide in Decompensated Heart Failure (ASCEND-HF),
the largest investigation of AHF treatment ever conducted,
patients treated with nesiritide (a b-type natriuretic peptide ana-
logue) showed modest improvement in self-reported dyspnoea
at 6 and 24 h, but there was no difference in 30-day mortality
or rehospitalisation (9.4% vs 10.1%; p=0.31). However, mean
BP was not particularly high in study patients (123 mm Hg for
nesiritide, 124 mm Hg for placebo) and hypotensive episodes
were more frequent in those who received nesiritide (26.6% vs
15.3%, p<0.001), suggesting that perhaps the wrong patient
population (ie, one for whom afterload was not the precipitant)
was targeted for the trial.28 However, ularitide, a natriuretic
peptide analogue that is similar to nesiritide, has shown promise
in the management of AHF. In SIRIUS II, a phase IIb clinical
trial, a 24 h continuous infusion of ularitide led to improvement
in cardiac index, systemic vascular resistance and pulmonary
capillary wedge pressure.29 While the most common side effect
was dose-dependent hypotension, the rate of hypotension was
much lower than in ASCEND-HF. Excess hypotension was also
seen with trials of cinaciguat, a soluble guanylate cyclase activa-
tor that decreases vascular resistance by triggering the produc-
tion of cyclic guanosine monophosphate in a manner that is
independent of NO.30 Similar to ASCEND-HF, the existing
cinaciguat trials did not specically target the hypertensive AHF
phenotype, suggesting that patient selection may be equal, if not
more important, than the specic agent being studied.
 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com
FUTURE DIRECTIONS
AHF is a heterogeneous disorder with multiple pathophysio-
logical causes that all manifest with a common clinical presenta-
tion. In the phenotype of hypertensive AHF, reduction of
impedance to ow in the aorta and modulation of ventricular
vascular relationship are central to treatment. For reasons we
have outlined, vasodilator therapy offers a theoretical advantage
over diuretic-based approaches for treatment of patients with
hypertensive AHF; however, this has not been proven in any
large-scale clinical trial. As shown by the serelaxin studies,
implementation of phenotype tailored treatment in AHF, with
medications that address the cause of ventricularvascular imbal-
ance, could lead to benets beyond merely improving symp-
toms.26 27 Thus, the approach to treatment in the future may be
more focused on directed therapy with a goal of functional pres-
ervation and avoidance of undue damage to organs such as
the heart, liver and kidneys. Ongoing studies involving novel
drugs with known vasodilator properties including serelaxin
(RELAX-AHF-2 (NCT01870778)), ularitide (TRUE-AHF
(NCT01661634)) and TRV027, a biased ligand with combined
angiotensin II receptor blocker and beta-arrestin agonist proper-
ties (BLAST-AHF (NCT01966601)), will help determine this
clinical applicability of such an approach.
CONCLUSIONS
Not all heart failure comes from a single pathophysiology. AHF
is a multifaceted disease and a phenotype-specic approach
could better align treatment with causal factors, offering the
potential to improve patient outcomes. Hypertensive AHF is a
common phenotype with a distinct pattern of cardiac dysfunc-
tion that differs dramatically from volume overload states. To
achieve optimal outcomes, an appreciation of this is important,
particularly the contribution from ow impedance and uncoup-
ling of the underlying ventricularvascular relationship.
Contributors DMV and PDL: conception and design or analysis and interpretation
of data, or both; drafting of the manuscript or revising it critically for important
intellectual content; nal approval of the manuscript submitted. JAS-M, MDS and
DSO: drafting of the manuscript or revising it critically for important intellectual
content.
Competing interests PDL currently serves as a consultant to Novartis
Pharmaceuticals, Cardiorentis and Trevena; he also receives grant funding from
Novartis Pharmaceuticals. DSO and JAS-M also receive grant funding from Novartis
Pharmaceuticals.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Weintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes: emergency
department presentation, treatment, and disposition: current approaches and future
aims. Circulation 2010;122:197596.
2 Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin
2008;4:2336.
3 Cotter G, Metra M, Milo-Cotter O, et al. Fluid overload in acute heart failure
re-distribution and other mechanisms beyond uid accumulation. Eur J Heart Fail
2008;10:1659.
4 Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart
failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis.
Ann Emerg Med 2007;50:14452.
Viau DM, et al. Heart 2015;0:17. doi:10.1136/heartjnl-2015-307461
Review
5 Peacock WF, Chandra A, Char D, et al. Clevidipine in acute heart failure: results of
the A Study of Blood Pressure Control in Acute Heart Failure-A Pilot Study
(PRONTO). Am Heart J 2014;167:52936.
6 Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of
patients hospitalized for heart failure in the United States: rationale, design, and
preliminary observations from the rst 100,000 cases in the Acute Decompensated
Heart Failure National Registry (ADHERE). Am Heart J 2005;149:20916.
7 Gheorghiade M, De Luca L, Fonarow GC, et al. Pathophysiologic targets in the early
phase of acute heart failure syndromes. Am J Cardiol 2005;96:11G7G.
8 Ooi H, Chung W, Biolo A. Arterial stiffness and vascular load in heart failure.
Congest Heart Fail 2008;14:316.
9 Sunagawa K, Maughan WL, Burkhoff D, et al. Left ventricular interaction with
arterial load studied in isolated canine ventricle. Am J Physiol 1983;245:
H77380.
10 Starling MR. Left ventricular-arterial coupling relations in the normal human heart.
Am Heart J 1993;125:165966.
11 Redeld MM, Jacobsen SJ, Borlaug BA, et al. Age-and gender-related
ventricular-vascular stiffening a community-based study. Circulation
2005;112:225462.
12 ORourke MF. Arterial aging: pathophysiological principles. Vasc Med
2007;12:32941.
13 Lorell BH, Carabello BA. Left ventricular hypertrophy pathogenesis, detection,
and prognosis. Circulation 2000;102:4709.
14 Fox JM, Maurer MS. Ventriculovascular coupling in systolic and diastolic heart
failure. Curr Cardiol Rep 2006;8:2329.
15 Schwartzenberg S, Redeld MM, From AM, et al. Effects of vasodilation in heart
failure with preserved or reduced ejection fraction implications of distinct
pathophysiologies on response to therapy. J Am Coll Cardiol 2012;59:44251.
16 OLeary DS. Altered reex cardiovascular control during exercise in heart failure:
animal studies. Exp Physiol 2006;91:737.
17 Colombo PC, Onat D, Sabbah HN. Acute heart failure as acute endothelitis
Interaction of uid overload and endothelial dysfunction. Eur J Heart Fail
2008;10:1705.
18 Yu C-M, Wang L, Chau E, et al. Intrathoracic impedance monitoring in patients
with heart failure correlation with uid status and feasibility of early warning
preceding hospitalization. Circulation 2005;112:8418.
19 McEniery CM, Wallace S, Mackenzie IS, et al. C-reactive protein is associated with
arterial stiffness in apparently healthy individuals. Arterioscler Thromb Vasc Biol
2004;24:96974.
20 Kociol RD, Pang PS, Gheorghiade M, et al. Troponin elevation in heart failure
prevalence, mechanisms, and clinical implications. J Am Coll Cardiol
2010;56:10718.
21 Wakai A, McCabe A, Kidney R, et al. Nitrates for acute heart failure syndromes.
Cochrane Database Syst Rev 2013;8:Cd005151.
22 Coutsos M, Sala-Mercado JA, Ichinose M, et al. Muscle metaboreex-induced
coronary vasoconstriction limits ventricular contractility during dynamic exercise in
heart failure. Am J Physiol Heart Circ Physiol 2013;304:H102937.
23 Cohn JN. Vasodilator therapy for heart failure. The inuence of impedance on left
ventricular performance. Circulation 1973;48:58.
24 Franciosa JA, Taylor AL, Cohn JN, et al. African-American Heart Failure Trial
(A-HeFT): rationale, design, and methodology. J Card Fail 2002;8:12835.
25 Metra M, Teerlink JR, Voors AA, et al. Vasodilators in the treatment of acute heart
failure: what we know, what we dont. Heart Fail Rev 2009;14:299307.
26 Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2,
for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled
trial. Lancet 2013;381:2939.
27 Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and
hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development
program: correlation with outcomes. J Am Coll Cardiol 2013;61:196206.
28 OConnor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with
acute decompensated heart failure. N Engl J Med 2011;365:3243.
29 Mitrovic V, Seferovic PM, Simeunovic D, et al. Haemodynamic and clinical effects of
ularitide in decompensated heart failure. Eur Heart J 2006;27:282332.
30 Gheorghiade M, Greene SJ, Filippatos G, et al. Cinaciguat, a soluble
guanylate cyclase activator: results from the randomized, controlled, phase IIb
COMPOSE programme in acute heart failure syndromes. Eur J Heart Fail
2012;14:105666.
7
 Downloaded from http://heart.bmj.com/ on July 3, 2015 - Published by group.bmj.com

The pathophysiology of hypertensive acute

heart failure
David M Viau, Javier A Sala-Mercado, Marty D Spranger, Donal S
O'Leary and Phillip D Levy

Heart published online June 29, 2015

Updated information and services can be found at:

http://heart.bmj.com/content/early/2015/06/28/heartjnl-2015-307461

These include:

References This article cites 30 articles, 9 of which you can access for free at:
http://heart.bmj.com/content/early/2015/06/28/heartjnl-2015-307461
#BIBL
Email alerting Receive free email alerts when new articles cite this article. Sign up in the
service box at the top right corner of the online article.

Topic Articles on similar topics can be found in the following collections

Collections Review articles (50)

Notes

To request permissions go to:

http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to:

http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to:

http://group.bmj.com/subscribe/