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Ventricular Arterial Stiffening
Integrating the Pathophysiology
David A. Kass
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Abstract—Vascular stiffening of the large arteries is a common feature of aging and is exacerbated by many common
disorders such as hypertension, diabetes, and renal disease. This change influences the phasic mechanical stresses
imposed on the blood vessels that in turn is important to regulating smooth muscle tone, endothelial function, and
vascular health. In addition, the heart typically adapts to confront higher and later systolic loads by both hypertrophy
and ventricular systolic stiffening. This creates altered coupling between heart and vessel that importantly affects
cardiovascular reserve function. In this overview, I discuss the notion of a coupling disease in which stiffness of both
heart and arteries interact to limit performance and generate clinical symptoms. This involves changes in the mechanical
interaction of both systems, changes in signaling within the arteries themselves, and alterations in coronary flow
regulation. Lastly, I briefly review recent development in de-stiffening strategies that may pave the way to treat this
syndrome and its clinical manifestations. (Hypertension. 2005;46:185-193.)
Key Words: arteries 䡲 compliance 䡲 ventricular function
W
idening of the arterial pulse is common in the elderly
and is generally a reflection of arterial stiffening. It is
a dominant circulatory hemodynamic risk factor for cardiac
disease and stroke.1–3 Pulsatility of blood flow and pressure is
also an intrinsic feature of the circulation. For example,
during aerobic exercise, the arterial pulse can increase
⬎100% in peripheral arteries and by ⬇50% in central arteries
(Figure 1A).4 Short-term widening of the pulse pressure
under these circumstances might be considered physiological
and not a source for vascular or ventricular disease. One
might even anticipate increased pulsatile mechanical stimulation of the arteries to enhance endothelial regulation of
vascular tone to improve blood flow where needed. As
discussed later in this review, there is a growing body of data
supporting such signaling and its role in enhancing organ
perfusion. However, this may require normal vascular distensibility and thus may be compromised in stiff arteries. In
contrast, chronic increases in pulse pressure (Figure 1A)
caused by age-related arterial damage and/or diseases that
stimulate vascular stiffening (eg, diabetes, renal disease)
worsen cardiovascular risk.
When considering the pathophysiologic implications of
vascular stiffening, it is important not to overlook the role
played by the heart to which the blood vessels are coupled.
Evidence shows that ventricular systolic and diastolic stiffness also increase with age, which increase in tandem with
large-artery stiffening.5,6 This is likely linked to the interaction of heart and vascular load, and also by intrinsic changes
in the heart itself, and common comorbidities such as diabe-
tes, hypertension, renal disease, and neurohumoral stress that
impact both systems. Importantly, such combined stiffening
alters how the heart–arterial system interacts at rest, but
particularly under stress by exertional demands, salt loading,
and abrupt changes in heart function. In this broad sense,
combined ventricular–arterial stiffening potently impacts on
cardiovascular reserve, blood pressure lability and diastolic
dysfunction, coronary and peripheral flow regulation, endothelial function, and mechanical signaling, and undoubted
other factors. It is in this broader context that I propose the
concept of stiff heart artery coupling disease. These changes
occur to some extent with aging5 and may be particularly
prominent in patients with cardiac hypertrophy in whom heart
failure symptoms develop despite having a preserved ejection
fraction.6 In this review, I discuss the pathophysiology of
coupling disease and suggest some novel approaches to
treating it.
Ventricular–Arterial Stiffening
Age-dependent increases in vascular stiffening are well established with evidence from multiple large cross-sectional
studies involving various ethnicities.7,8 Mechanisms underlying this stiffening, methodologies to assess it, and new
approaches to treat it have all been subjects of recent
reviews9 –11 and are not discussed here. What has been only
more recently revealed is that age-related vascular stiffening
is also accompanied by changes in the left ventricle (LV) that
increase end-systolic chamber stiffness.5 This does not require renal disease and/or cardiac hypertrophy to be present,5
Received February 15, 2005; first decision February 23, 2005; revision accepted April 13, 2005.
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to David A. Kass, MD, Ross 835, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205. E-mail
[email protected]
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000168053.34306.d4
185
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Figure 1. A, Physiological versus pathologic causes for higher artery pulse pressure. Upper panel, Radial and central
arterial pressures increasing with aerobic
exercise in a young subject. Lower
panel, Arterial pulse pressure increases
with vascular aging. B, Increased ventricular end-systolic stiffness (Ees) accompanies arterial stiffening with age. Pressure–volume loops from young and
elderly individual show increases in Ees
that match increases in arterial loading
indexed by arterial elastance (Ea). C,
Inverse correlation between total arterial
compliance and ventricular end-systolic
stiffness in humans. D, Increased load
sensitivity of systolic pressure by ventricular–arterial stiffening in the elderly. From
Chen et al5 and Kawaguchi et al.6
although both play important roles in vascular and ventricular
stiffening.10 Importantly, this combination of ventricular–arterial stiffening alters the way in which the cardiovascular
system can respond to stress demands and changes in volume
and pressure loading. Furthermore, it appears common in
patients with heart failure and preserved ejection fraction and
may importantly contribute to the clinical features of this
disorder.6
Figure 1B shows example pressure–volume (PV) relations
measured invasively in a young and elderly individual, with
neither having any demonstrable clinical heart disease at the
time of study. Each set of loops was obtained by transient
obstruction of venous return, with the baseline condition
reflected by the most rightward loop of the set. The 2
relations depicted are the end-systolic PV relation and slope
(Ees) and the ratio of end-systolic pressure to stroke volume— or effective arterial elastance (Ea). These are often
equal in absolute magnitude, a combination yielding optimal
and efficient matching of heart and artery. However, the
elderly patient displays marked increases in both elastances,
with Ea reflecting vascular stiffening and Ees LV systolic
stiffening. The change in loop shape (trapezoidal) in the
elderly subject reflects stiff arteries with a wider pulse
pressure. The diastolic PV relation (lower boundary of the
loops) is also somewhat steeper. As reported by Chen et al,5
Ea, Ees, and diastolic stiffness increase with age and correlate
with one another. Figure 1C shows such an inverse relation
between Ees and total arterial compliance, with the latter a
component of Ea (Ea increases as compliance declines).
Patients with low arterial compliance display increased Ees.6
Higher ventricular and arterial stiffness has important
implications to blood pressure lability and loading sensitivity.
This is shown by example in Figure 1D, with the data derived
from the same set of PV loops shown in Figure 1B. Decreasing preload results in only a modest decline in systolic blood
pressure in the younger individual but a much greater change
in the older subject. As previously reported,5 the slope of such
relations is determined by both arterial and ventricular stiffness and increases with age.
Another implication of combined ventricular–arterial stiffening is that exertional capacity can be limited and this may
play a role in patients with heart failure and normal-range
ejection fraction. An example from the recent study of
Kawaguchi et al6 is shown in Figure 2A. This patient has
increased Ees and Ea at baseline, and on performance of
sustained hand-grip exercise (solid loop) displayed a marked
hypertensive response and elevated diastolic pressures. The
steep basal Ees means that contractile reserve, normally
reflected by further increases in Ees, is limited, whereas
pressure-loading changes are amplified. Evidence that such
pathophysiology likely contributes to exertional intolerance
was reported by Hundley et al (Figure 2B).12 There is a direct
relation between arterial distensibility (ie, compliance) and
peak oxygen consumption during exercise testing. Patients
with cardiac failure symptoms and preserved ejection fraction
(EF) are shown by the white triangles and have the stiffest
arteries. This study did not determine whether these patients
also had increased Ees, although a more recent study found
such elevations that exceeded that predicted from age alone in
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Figure 2. A, Effect of increased demand
(handgrip exercise) on LV function
depicted by pressure–volume loop in
subject with ventricular–arterial stiffening
and cardiac failure with preserved ejection fraction. From Kawaguchi et al.6 B,
Positive correlation between arterial stiffness and metabolic exercise capacity.
From Hundley et al.12 C, Loss of
afterload-dependence of pressure relaxation in transgenic mice with activated
PKA–phosphorylation sites on troponin I
(PKA-TnI TG). NTG indicates nontransgenic control. From Takimoto et al.15
such patients.6 Gender differences in ventricular arterial
stiffening may also impact exercise performance.13
Cardiac relaxation is delayed when hearts are exposed to
elevated systolic pressure during ejection (ie, increased afterload), as occurs with vascular stiffening or enhanced systemic
resistance.14 As noted in Figures 1 and 2A, ventricular–
vascular stiffening exacerbates the load–pressure interaction,
worsening the potential impact on diastole. A correlation
between greater prolongation of diastolic relaxation and
ventricular vascular (VV) stiffening was found in a recent
study.6 Underlying mechanisms for load-dependence of relaxation have been previously unclear, although recent murine studies in which protein kinase A–phosphorylation sites
on troponin I were constitutively active has yielded new
insights.15 As shown in Figure 2C, normal mice show marked
relaxation delay when cardiac afterload is increased by partial
aortic constriction, whereas the mutant animals display little
effect, highlighting a key role of TnI-PKA phosphorylation
state as a coupler between load and relaxation.
Impact of Blood Flow Pulsatility
A major hemodynamic consequence of arterial stiffening is
widening of the arterial pulse, which also increases cyclic
changes of arterial flow. In studies performed over the past
decade, we and other investigators have found that such
pulsatility itself triggers vasodilator responses and contributes
to flow reserve. In vitro studies suggest this may be blunted
by loss of wall distension (ie, vascular stiffening), although
this has not yet been tested in vivo.
The initial observation that enhancing flow pulsatility itself
triggers vasodilation in vivo came in an experiment testing
effects of systemic vascular stiffening on cardiac function and
mechanoenergetics.16,17 In canine hearts ejecting into a stiff
conduit substituting for the thoracic aorta, total compliance
was reduced and central arterial pulse pressure increased 2- to
3-fold. At matched cardiac oxygen consumption, hearts
ejecting into this stiff load displayed ⬇15% increase in mean
coronary blood flow.17 Subsequent studies using a servocontrolled perfusion pump to selectively vary pulse pressure
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Figure 3. A, Change in phasic coronary
pressure and flow waveforms with
increased pulse perfusion. B, Augmentation of coronary flow by pulse perfusion
is enhanced by concomitant coronary
vasodilation from adenosine. C, Role of
NO and KCa-dependent signaling in pulse
perfusion enhancement of mean coronary flow; raw tracings (upper) and summary results (lower). L-NMMA indicates
NG-monomethyl-L-arginine. Monoacetate
(NO synthase inhibitor) and CbTX
(charybdotoxin) and AP (apamin) (KCa-inhibitors). From Paolocci et al.19 D, Effect
of acute coronary occlusion on LV function in canine model with heart ejection
directed into a stiff (wide pulse pressure)
or compliant aorta. With the former,
there is a marked decline in LV pressure
and increase in chamber volumes (dilation) induced by the acute ischemia. This
is minimal if the heart ejects into a compliant vasculature, despite identical sites
of coronary occlusion. Modified from
Saeki et al17 and Kass et al.24
in a given vascular bed18 –20 confirmed this and clarified the
biochemical mechanisms. Figure 3A shows the effect of
altering pulse pressure in a coronary artery and consequent
changes in phasic flow. Diastolic flow increased slightly with
the higher pulse pressure despite a decline in mean pressure
during this period, and there was a greater increase in flow
during the systolic period. Net flow increased ⬇15%, confirmed by both coronary sinus and microsphere flow, and is
not associated with changes in regional function or metabolic
demand.
A 15% change in coronary flow from higher perfusion
pulsatility, although significant, was not large, raising doubts
that such a mechanism would play an important physiological
role. However, the situation changed markedly when distal
vascular tone is modestly lowered by adenosine involving
activation of ATP-sensitive potassium channels20 (Figure
1B). Under such conditions, the same augmentation of pulse
pressure results in a marked increase in mean flow, with a
peak response nearly doubling flow over that at the normal
(40 mm Hg) pulse pressure. This was specific to vasodilators
that were active in the distal microvessels (ie, ⬍150 ␮m) by
mechanisms involving activation of KATP channels (adenosine, pinacidil). Alternative dilators operating on more prox-
imal vessels (calcium channel blockers, acetylcholine, bradykinin) did not replicate this synergistic interaction with
perfusion pulsatility.20
Endothelial-dependent vasodilation caused by elevated
perfusion pulsatility has been confirmed in vascular beds
other than the coronary arteries. For example, Nakano et al21
reported that augmenting pulse perfusion in skeletal muscle
triggers primary nitric oxide (NO)-dependent vasodilation.
More recently, studies using external muscle compression to
enhance central coronary blood flow revealed enhanced
endothelial-dependent flow dilation in upper arm vascular
beds exposed to the resulting higher perfusion pulsatility.22
Steady shear stress induces vasodilation largely by activating NO synthase (NO release) and by stimulating factors that
induce hyperpolarization.23 Although the precise mediators
for the latter remain unclear and likely vary with the vascular
tissue and site, they commonly stimulate calcium-dependent
potassium channels (KCa) and can be inhibited by KCablocking toxins. Both NO and KCa signaling are involved with
pulse perfusion-mediated dilation as shown by Paolocci et
al19 (Figure 3C). Inhibiting either pathway alone reduced the
pulse perfusion response by half, whereas when combined
this response was virtually eliminated.
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Pathophysiology of Ventricular–Vascular Stiffening
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Figure 4. A, Phasic pressure waveforms
generated in vitro to stimulate vascular
pulse perfusion in distensible or stiff vessels; left tracings are from compliant
silastic tube, right tracings from stiff
tube. B, Differential activation of the
serine/threonine kinase Akt by pulse perfusion in compliant versus stiff tubes. C,
Similar differential response in endothelial
NO synthase phosphorylation in stiff vs
compliant tubes.
Although normally compliant arteries can dilate in response to pulse perfusion, in the coronary circulation, this is
also coupled to changes in the phasic pattern of flow, as noted
in Figure 3A, and this has potentially detrimental consequences on cardiac reserve. Normal coronary perfusion is
principally diastolic, and reducing systolic pressure has less
impact on mean flow. However, this may not hold in hearts
ejecting into a stiff arterial system with consequent increases
in flow during systole. This shift can render the heart more
sensitive to a decline in systolic pressure as occurs with
loading changes or acute dysfunction (eg, myocardial infarction). An example is shown in Figure 3D. On the right are
data from an in vivo heart ejecting into a stiff (bypass) arterial
system resulting in high arterial pulsatility. Acute coronary
occlusion led to a rapid decline in LV pressure and marked
chamber dilation (LV volume), ultimately triggering cardiac
demise. After full resuscitation, the experiment was repeated
but with the same heart now ejecting into the compliant
vascular system. The magnitude of cardiac dysfunction was
markedly attenuated (data from Kass et al24). Thus, high
perfusion pulsatility can benefit vascular tone yet have
detrimental effects on myocardial flow regulation. As discussed in the next section, the benefits may diminish in
vessels that are not compliant, so that the net balance tips
further toward pathophysiology in such settings.
Role of Wall Distensibility
Another feature of ventricular–arterial stiffening is that it
changes the mechanical forces to which endothelial cells and
arterial smooth muscle cells are exposed. Because these
mechanical forces play key roles in regulating wall tone,
atherogenesis, angiogenesis, and other features of vascular
homeostasis, understanding their impact is important. Using
perfusion systems that expose cultured endothelial cells to
controlled levels of phasic flow with or without distension,
studies have revealed effects of pulsatility on NO synthase
gene expression,25–27 endothelin, and other signaling cascades28 that tend to favor a vasorelaxant response.
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Arterial and Ventricular Destiffening Strategies
Reduce smooth muscle tone
Nitrates, ACE inhibitors, ARBs, calcium channel blockers
Enhance endothelial function/relaxation
Exercise
Antioxidants
Tetrahydrobiopterin
Statins
Rho kinase inhibitors
Alter structural properties
Reduce fibrosis (ARBs, aldosterone blockers, TGF-␤1 inhibitors)
Limit or reverse hypertrophy
Advanced glycation end-product cleavage
Enhance elasticity (elastin, fibrillin, etc)
ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor
blocker; TGF, transforming growth factor.
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Recent studies used more physiological waveforms (Figure
4A) and assessed post-translational changes in signaling
proteins.29 Endothelial cells cultured on the inner surface of
distensible tubes were exposed to pulse perfusion with the
degree of wall distensibility varied. These studies found
important differences in signaling related to distensibility
(Figure 4B and 4C). The enzyme Akt is stimulated in
response to mechanical shear stress30 and cyclic stretch,31 and
by receptor-coupled growth factors (eg, IGF-1).32 Activated
Akt phosphorylates NO synthase to enhance NO release30 and
stimulates proteins controlling vasculogenesis, endothelial
cytoprotection, and apoptosis.32 When cyclic stretch and
shear were combined in normally compliant tubes, Akt was
activated much more than with steady shear alone (Figure
3B).33 This was lacking if wall compliance was reduced,
however. Downstream targets of Akt such as NO synthase
also displayed this differential activation. (Figure 3C). This is
further supported by data showing enhanced NO release from
endothelial cells grown in distensible tubes exposed to
pulsatile flow from external compression.34
Destiffening Strategies
Past and evolving strategies to counter vascular stiffening
have been recently reviewed35 and are summarized in the
Table. To date, the major emphasis has been on inhibitor
smooth muscle tone, working through the NO/cGMP pathway, or by blocking neurohormones such as angiotensinconverting enzyme and angiotensin II. Calcium channel
blockers have also been used. For example, verapamil has
been shown to acutely lower ventricular systolic stiffness and
arterial stiffness and, in association with these changes,
improve aerobic exercise capacity in aged volunteers.36 This
exercise benefit was not reproduced when smooth muscle
tone only was reduced using an intravenous nitrate.37 Ongoing studies using angiotensin II receptor-blocking agents in
patients with heart failure and normal-range EF may help
clarify the role of such drugs for this disorder. Previous data
from the substudy CHARM (Preserved) trial found only
slight clinical benefits38 but the study population was not
really representative.
Exercise remains an important factor and has been shown
to reduce vascular stiffening with aging.39 Whether it can also
lower ventricular systolic stiffening remains unknown. There
is increasing interest in the use of 3-hydroxy-3-methylglutaryl– coenzyme A reductase inhibitors (statins). Studies have
shown that statins augment Akt activity in vessels,40 improve
blood flow by increasing NO synthase activation,41 and may
reduce vascular stiffening.42 Statins also inhibit small GTPbinding proteins Rac1 and RhoA and thereby may impede
development of cardiac hypertrophy.43– 45 Other strategies
may involve enhancing NO synthase signaling by increasing
substrate availability (arginase inhibition) or its cofactor
tetrahydrobiopeterin (BH4).46
Another tactic gaining interest is to reduce fibrosis and/or
modify structural proteins thought linked to stiffness. Drugs
that inhibit angiotensin II and particularly aldosterone47,48 are
intriguing in this regard. Both may have the added advantages
to targeting both vascular and ventricular changes. Efforts to
enhance elastin by blocking neutrophil elastace have yielded
very exciting results in both the heart and vasculature.49
However, translation to human trials has remained limited by
the toxicity of these drugs, and this avenue remains one
undergoing investigation.
A different strategy that may also target both heart and
arteries relates to the cleavage of advanced glycation endproducts (AGEs). AGEs are highly stable glucose—protein
links that accumulate with normal aging but are enhanced in
settings of glucose excess (diabetes) and/or molecular stress
such as from oxidation.50,51 These cross links form in collagen and other long-lived structural molecules resulting in
reduced turnover by metalloproteinases and likely increased
tissue stiffness. Proof for the involvement of AGEs in
structural stiffness remains fairly indirect but has been fueled
by animal and a recent clinical trial found that a breaker of
AGE (ALT-711) improves vascular distensibility,52,53 and
perhaps ventricular diastolic distensibility (Figure 5A).54
Last, we recently reported that enhancement of protein
kinase G activation by inhibiting PDE5a may provide a novel
approach to ventricular–arterial stiffening.55 PDE5a is the
enzymatic target of sildenafil, which is widely used to treat
erectile dysfunction. In the vasculature, PDE5a inhibition
increases cGMP to activate protein kinase G-I, leading to
reduced vascular tone. PDE5a inhibitors also appear to lower
vascular stiffness,56 although the extent to which this is
independent of mean pressure remains somewhat unclear.
cGMP plays an important role as a negative modulator of
vascular proliferation and fibrosis. Similarly, increasing
cGMP/PKG activation in the heart reduces fibrosis and can
be anti-hypertrophic.57,58 In mice, PDE5a inhibition markedly
inhibits the development of cardiac hypertrophy and fibrosis
while improving ventricular function despite sustained ventricular afterload increase59 (Figure 5B). Furthermore, this
treatment reversed hypertrophy and fibrosis once established
(Figure 5C). It remains to be determined whether this strategy
will prove efficacious for treating humans with ventricularvascular stiffening (coupling disease).
Perspectives
This brief review is meant to place recent studies regarding
pulsatile perfusion, arterial, and ventricular stiffening in
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Pathophysiology of Ventricular–Vascular Stiffening
191
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Figure 5. Novel de-stiffening strategies.
A, Effect of advanced glycation endproduct cross-link breaker (ALT-711) on
human arterial total compliance as a
function of changes in mean arterial
pressure over a 2-month treatment
period. From Kass et al.52 B, Inhibition of
pressure load-induced cardiac hypertrophy (traverse aortic constriction [TAC]) in
mice treated with the PDE5a inhibitor
sildenafil (left). Right panel shows capacity of sildenafil to reverse pre-established
ventricular hypertrophy (also triggered by
pressure load) over subsequent 2 weeks.
From Takimoto et al.55
perspective. Although many previous reviews have focused
on stiffening of the arteries themselves, and much of this
special issue highlights this pathophysiology, such changes
have major ramifications on the heart and the manner in
which it interacts with the rest of the body. Cardiac maladaptations such as hypertrophy and increased ventricular
end-systolic elastance make the net effects of vascular stiffening even worse, particularly from the standpoint of net
cardiovascular reserve, blood pressure regulation, and blood
volume distribution. It is in the context of the coupling
between these altered systems that one best understands the
physiological manifestations observed in many affected patients. New de-stiffening strategies are needed, and some are
presently undergoing development and entering clinical trials.
Greater appreciation of the impact of coupling disease in the
elderly should help us apply even the known therapies with
better focus and hopefully improve our approach to this
disorder.
Acknowledgments
Supported by National Institutes of Health grants HL-47511
and AG-18324.
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Ventricular Arterial Stiffening: Integrating the Pathophysiology
David A. Kass
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Hypertension. 2005;46:185-193; originally published online May 23, 2005;
doi: 10.1161/01.HYP.0000168053.34306.d4
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