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Current Hypertension
Reviews
ISSN: 1573-4021
Current Hypertension Reviews
Volume 5, Number 3, August 2009
Contents
Editorial Pp.166-167
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Article]
Blood Pressure Lowering and Outcomes in type 2 Diabetes:
Implications of the Blood Pressure-Lowering Arm of the Advance
Trial Pp. 168-180
Richard J. MacIsaac, David Barit and
George Jerums
[Abstract] [Purchase
Article]
Hypertension and Diabetes: Emphasis on
the Renin-Angiotensin System in Atherosclerosis Pp.
181-201
Riccardo Candido, Stella Bernardi and
Bruno Fabris
[Abstract] [Purchase
Article]
The ONTARGET Trial Programme: Facts and
Lessons Pp. 202-209
Thomas Unger, Ulrich Kintscher, Kai Kappert
and Ulrike M. Steckelings
[Abstract] [Purchase
Article]
Hypertension and Diabetes: Emphasis on
the Renin–Angiotensin System and Insulin Resistance
Pp. 210-221
Puja Nistala, Ravi Nistala, Camila Manrique,
Guido Lastra and James R. Sowers
[Abstract] [Purchase
Article]
Losing Control: Positive and Negative
Feedback in the Renin Angiotensin System Pp.
222-226
Merlin C. Thomas and Chris Tikellis
[Abstract] [Purchase
Article]
Functional Cardiovascular Effects of
Angiotensin Peptides: Focus on Atherosclerosis and Hypertension
Pp. 227-236
Antony Vinh, Tracey A. Gaspari, Emma S.
Jones and Robert E. Widdop
[Abstract] [Purchase
Article]
Does Handle Region Peptide Provide Benefits
in Chronic Kidney Disease? Pp. 237-240
Atsuhiro Ichihara, Fumiaki Suzuki, Tadashi
Inagami and Hiroshi Itoh
[Abstract] [Purchase
Article]
Blood Pressure Control and Diabetic Retinopathy
Pp. 241-244
Tien Y. Wong and Paul Mitchell
[Abstract] [Purchase
Article]
Prorenin and the (Pro)renin Receptor
in Retinal Pathology Pp. 245-250
Jennifer L. Wilkinson-Berka, Terri J. Allen
and Antonia G. Miller
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Article]
Abstracts
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Editorial: Current Hypertension Reviews: Hot Topics
Hypertension and Diabetes: An Emphasis on the RAS
In this “Hot Topic” issue of Current
Hypertension Reports we focus on the role of blood pressure
control in diabetes and novel aspects of the renin angiotensin
system. This issue includes current experimental and clinical
evidence and covers important “burning” issues
such as, 1. what is the optimal blood pressure target in diabetes
and hypertension, 2. is there superiority of inhibitors of
the renin angiotensin system (RAS) over other antihypertensive
agents, 3. does combination therapy have additional benefits
in terms of vascular protection and 4. which novel therapeutic
options are on the horizon for better treatment and prevention
of vascular complications in diabetes and hypertension?
There is overwhelming evidence for an increased cardiovascular
risk in the setting of concomitant hypertension and diabetes.
Therefore, excellent blood pressure control is particularly
important in patients who also suffer from diabetes or insulin
resistance.
The article by R. MacIsaac et al. addresses the question
as to which blood pressure target should be aimed for. Various
United States and European guidelines including the American
Diabetes Association (ADA) recommendations suggest BP targets
< 130/80
mm Hg for patients with diabetes. There is new evidence that
further blood pressure (BP) reduction may confer superior
cardiovascular benefits as shown in the recently published
ADVANCE study. The ADVANCE study showed that BP reduction
with perindopril and indapamide in patients usually not considered
hypertensive resulted in further significant cardiovascular
and renal benefits. However, the ADVANCE study did not include
a comparator combination group and can therefore not answer
the question as to which combination medications may be superior
in preventing cardiovascular (CV) events.
However, as already suggested in previous studies such as
in HOPE, EUROPA, LIFE and UKPDS, the results of the ADVANCE
study support current BP lowering guidelines which recommend
a target BP of <
130/80 mm Hg in patients with type 2 diabetes. The ongoing
BP lowering arm of the ACCORD trial will also help to substantiate
the evidence supporting a continuous relationship between
BP levels and the development of diabetes related vascular
complications. In that trial, a group of patients with systolic
blood pressures of less than 120 mm Hg is being compared to
a less intensively treated group where the aim is a systolic
blood pressure of less than 140 mm Hg.
The article by Candido et al. addresses the question
as to which antihypertensives should be used in diabetes and
hypertension and if there is superiority of inhibitors of
the RAS over other antihypertensive agents in terms of cardiovascular
protection. There is substantial evidence that overactivation
of the RAS plays a key role in endothelial dysfunction and
macrovascular complications in hypertensive diabetic subjects.
RAS blockade confers vasculoprotection not only via effects
on BP, but also through attenuation of inflammation, oxidative
stress and cellular proliferation independent of blood pressure
effects. Therefore, it has been suggested that inhibitors
of RAS may be superior to other antihypertensive agents in
preventing cardiovascular disease, in particular in the context
of concomitant diabetes and hypertension. Indeed, they have
become first line treatment to prevent CV disease in patients
with diabetes and hypertension.
RAS blockade has also been associated with prevention of new
onset diabetes development via effects on reducing insulin
resistance and preserving beta cell function. Such an anti-diabetic
effect should theoretically translate to further reduction
in cardiovascular events although the clinical evidence for
such an effect is still lacking. This issue has been further
addressed in 2 recently published studies exploring the potential
preventative effect of RAS inhibition on new onset diabetes.
Firstly, in the DREAM study there was no significant prevention
of diabetes with ramipril treatment, although ramipril treatment
was associated with a trend towards regression to normoglycemia.
Secondly, in the TRANSCEND study no effect on prevention of
diabetes was observed with the ARB, telmisartan. In addition,
the ONTARGET study failed to show any benefit of the combination
of ramipril and telmisartan in the prevention of diabetes
when compared to either agent as monotherapies. Finally, the
results of the NAVIGATOR trial that include investigaton of
valsartan on new onset diabetes are still awaited and may
further clarify this potentially important effect of RAS inhibition.
The question as to whether angiotensin receptor blockade is
equivalent to ACE inhibition in preventing cardiovascular
disease in hypertension and diabetes has been addressed in
the ONTARGET trial and is discussed in the article by Unger
et al.. In the ONTARGET study telmisartan proved
to be non-inferior to ramipril with respect to the combined
primary endpoint and all secondary endpoints and was better
tolerated than ramipril. This study is the first to demonstrate
that an ARB can be used as an alternative to the gold standard
of an ACE inhibitor in patients at high cardiovascular risk
with or without hypertension. Furthermore, the combination
treatment of ramipril and telmisartan was not superior to
ramipril treatment alone in terms of endpoints but was associated
with more side effects. However, it needs to be considered
that only 30% of patients included in this trial had diabetes.
Therefore, the question as to whether combination treatment
is superior to ACE inhibitor alone cannot be conclusively
answered for the diabetic patient.
In the chapter by Nistala et al. the role of the
renin angiotensin system in terms of insulin resistance and
hypertension is discussed. Hypertension and type 2 diabetes
are two main components of the cardiometabolic syndrome and
both conditions are linked by chronic inflammatory processes
and insulin resistance. Inappropriate activation of the renin
angiotensin aldosterone system (RAAS) may further link insulin
resistance to diabetes and hypertension. There is increasing
clinical evidence that RAAS blockade attenuates certain features
of insulin resistance. Novel insights into the effects of
aldosterone blockade and renin inhibitors on insulin resistance
are also discussed, although they are still in the early stages
of clinical evaluation.
The renin angiotensin system (RAS) is a key homeostatic regulator
of vascular function and blood pressure that relies on feedback
regulation to achieve and sustain the delicate balance required
for healthy physiological function. The phenomenon of the
so-called “escape phenomenon” observed with chronic
RAS inhibition has been addressed in the article by M. Thomas
et al. A number of negative feedback loops exist
within the RAS that counterbalance the effects of conventional
RAS blockade, leading to a paradoxical elevation in many patients
treated with RAS blockers. The association between adverse
outcomes and activation of feedback pathways provides a strong
rationale for specifically targeting feedback as part of any
vasculo-protective strategy. These feedback pathways are partially
mediated by recently discovered components of the RAS.
The main effector peptide of the RAS is angiotensin II, also
known as Ang 1-8, and is a major contributor to CV disease.
However, there is an emerging concept that shorter peptide
fragments such as Ang 1-7, Ang III or Ang IV are also active
components of the RAS with their own biological profile. The
article by Vinh et al. describes the cardiovascular
functions of those newly discovered Ang peptides, including
Ang 1-7, Ang III and Ang IV. Furthermore, it has been suggested
the recently identified angiotensin converting enzyme 2 (ACE2)
which may also contribute to increased Ang1-7 formation, is
involved in counteracting some of the deleterious effects
mediated by activation of AT1 receptors by AII. A role for
Ang peptides such as A1-7 and the enzyme ACE2 in cardiovascular
disease, hypertension and diabetes remains as yet unresolved.
Furthermore, the effect of ACE inhibition or ARB blockade
on these components is still subject to ongoing investigation
with some evidence emerging that effects on these vasodilatory
angiotensins may contribute to the beneficial effects of ACE
inhibitors and ARBs on cardiovascular disease.
The discovery of the prorenin receptor has unravelled a novel
function of renin/prorenin as receptor ligands in addition
to their function as enzymes and this is discussed in the
chapter by Ishihara et al.. Binding of renin and prorenin
to the (pro)renin receptor activates two major signalling
pathways, firstly an angiotensin II dependent pathway as a
result of enzymatic activation and secondly an AII independent
(pro)renin receptor mediated intracellular pathway leading
to hypertrophy, hyperplasia and fibrosis.
A putative specific blocker of this receptor has been reported
also called “handle region protein (HRP)” which
leads to non-proteolytic alteration of prorenin. It has been
shown that infusion of this molecule into animal models of
diabetes and low renin hypertension reduced the development
of nephropathy, whereas it was not effective in high renin
hypertension in the 2 kidney, 1 clip model. The reno- and
vasculoprotective effects of prorenin blockade in hypertension
and diabetes remain to be clearly characterised.
The association of diabetes and hypertension with retinopathy
is addressed in the article by Wong et al. The association
of hypertension with retinopathy does not appear to be as
strong as that seen between type 2 diabetes and retinopathy.
Nevertheless, as reported in the UKPDS study, a 10 mmHg blood
pressure reduction was associated with less retinopathy. As
suggested in the ABCD and ADVANCE trials there may be a threshold
effect for blood pressure reduction in terms of effects on
retinopathy. Lowering of blood pressure beyond this threshold
does not appear to lead to further improvements in retinopathy.
RAS blockade has been suggested to have beneficial effects
on development and progression of diabetic retinopathy. The
DIRECT trial demonstrated beneficial effects of the ARB candesartan
on retinopathy in both, type 1 and 2 diabetes, although in
this trial the drug failed to reach the pre-specified endpoint.
Nevertheless, although the effects appeared to be modest,
candesartan was shown to prevent progression of retinopathy
in type 1 diabetes and to promote regression of retinopathy
in type 2 diabetes. The article by Wilkinson-Berka et
al. presents some experimental evidence that prorenin
may have a pathogenic role in the eye in diabetes and hypertension.
Studies exploring the effect of prorenin binding protein blockers
and renin inhibitors such as aliskiren will further define
potential benefits and strategies to treat and prevent ocular
pathology such as diabetic retinopathy and retinopathy or
prematurity in the absence or presence of hypertension.
In summary, this Hot Topic issue gives a comprehensive overview
about our current understanding of the role of the renin angiotensin
system in pathophysiology and treatment of hypertension and
diabetes.
Karin A.M. Jandeleit-Dahm and Terri J. Allen
Baker IDI Heart and Diabetes Institute
75 Commercial Road
Melbourne
Victoria 3004
Australia
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Blood Pressure Lowering and Outcomes in type 2 Diabetes:
Implications of
the Blood Pressure-Lowering Arm of the Advance Trial
Richard J. MacIsaac, David Barit and George Jerums
This review focuses on trials that have examined the
relationship between blood pressure (BP) lowering strategies
and cardiovascular and renal outcomes in subjects with type
2 diabetes. In particular, we highlight the results of the
recently completed BP-arm of the ADVANCE (Action in Diabetes
and Vascular Disease: Preterax and Diamicron-MR Controlled
Evaluation) study. Active therapy with perindopril and indapamide
compared with placebo significantly reduced blood pressure
(134.7/74.8 vs 140.4/77.0 mmHg) and the primary endpoint
of the trial, a composite of major macrovascular and microvascular
events. Active therapy also reduced the secondary end points
of cardiovascular death and development of renal events. Importantly,
the study shows that in a group of patients with BP levels
within the range that would not usually be classified as hypertensive,
further reductions in BP resulted in clinically significant
cardiovascular and renal benefits. It supports the combination
of perindopril and indapamide as an effective BP lowering
strategy in type 2 diabetes. However, as other BP lowering
strategies were not compared, the BP-lowering arm of the ADVANCE
study does not answer the question as to what is the best
medication or combination of medications that should be employed
to reduce BP levels in type 2 diabetes.
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Hypertension and Diabetes: Emphasis on the Renin-Angiotensin
System in
Atherosclerosis
Riccardo Candido, Stella Bernardi and Bruno Fabris
Cardiovascular diseases (CVDs) are the major causes
of morbidity and mortality in persons with diabetes, and many
factors, including hypertension, contribute to this high prevalence
of macrovascular complications. Hypertension is approximately
twice as frequent in subjects with diabetes compared with
non-diabetic patients. Furthermore, up to 75% of CVD in diabetes
may be attributable to hypertension, leading to recommendations
for more aggressive treatment (i.e. reducing blood pressure
to <
130/80 mmHg) in persons with coexistent diabetes and hypertension.
Macroangiopathy in diabetes is manifested by accelerated atherosclerosis
which affects heart, brain and peripheral arteries. The pathogenesis
of this accelerated atherosclerosis is multifactorial and
includes a very complex interaction. Several data suggest
a key role for renin-angiotensin system (RAS) activation in
the pathophysiology of macrovascular complications in diabetic
hypertensive subjects. Consequently, RAS blockade exerts potent
antiatherosclerotic effects, which are mediated by their anti-hypertensive,
anti-inflammatory, antiproliferative, and oxidative stress
lowering properties. Inhibitors of the system, ie, angiotensin
converting enzyme inhibitors and angiotensin receptor blockers,
are now first line treatment to prevent CVD in patients with
diabetes and hypertension. In addition, recent clinical trials
have suggested that RAS blockade may protect against the development
of de-novo diabetes in at-risk patients. Finally, the recent
identification of new components of the RAS should provide
fertile territory to not only examine new targets linked to
the RAS but potentially to design more rational treatments
for the prevention of CVD in patients with diabetes and hypertension.
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The ONTARGET Trial Programme: Facts and Lessons
Thomas Unger, Ulrich Kintscher, Kai Kappert and
Ulrike M. Steckelings
The ONTARGET trial programme tested the effects of the
angiotensin AT1 receptor blocker (ARB), telmisartan, alone
or in combination with the angiotensin converting enzyme (ACE)
inhibitor, ramipril, in more than 25.000 patients at high
cardiovascular risk including diabetes on a combined endpoint
consisting of cardiovascular death, non-fatal stroke or myocardial
infarction and hospitalisation for congestive heart failure.
Patient selection and study procedures followed the previous
HOPE trial. In the parallel TRANSCEND study, nearly 6.000
patients, all intolerant to ACE inhibition, were subjected
to telmisartan or placebo.
In ONTARGET, telmisartan proved to be non-inferior to ramipril
with respect to the combined primary endpoint and all secondary
end-points, and was better tolerated than ramipril. Combination
treatment (dual RAS blockade) was not superior to ramipril
(and telmisartan-) treatment but associated with more side
effects. In TRANSCEND, telmisartan was not superior to placebo
when applying the above combined primary endpoint but was
significantly better with respect to the predefined main secondary
endpoint corresponding to HOPE, i.e. excluding hospitalization
for congestive heart failure.
Telmisartan thus proved to be the first and so far the only
representative of the ARB class that can be used as an alternative
to the “gold standard” ACE-inhibitor, ramipril,
in patients at high cardiovascular risk with or without hypertension.
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Hypertension and Diabetes: Emphasis on the Renin–Angiotensin
System
and Insulin Resistance
Puja Nistala, Ravi Nistala, Camila Manrique, Guido Lastra
and James R. Sowers
Type 2 Diabetes Mellitus (T2DM) and hypertension (HTN)
both increase cardiovascular disease (CVD) morbidity and mortality,
and impose a tremendous burden on worldwide heath care systems
in recent years. The mechanisms underlying the frequent coexistence
of T2DM and HTN, two main components of the Cardiometabolic
Syndrome (CMS), remain to be fully uncovered. Interestingly,
both conditions are linked by chronic inflammatory processes
and insulin resistance that are instigated by enhanced activation
of the Renin Angiotensin Aldosterone System (RAAS). Inappropriate
activation of the RAAS and insulin resistance with compensatory
hyperinsu-linemia trigger numerous pathophysiological pathways
that ultimately result in endothelial dysfunction, inflammation,
proliferation, and remodeling in cardiovascular and renal
tissue. Blockade of RAAS has proven beneficial in the management
of T2DM and HTN as well as associated CVD and chronic kidney
diseases. This review focuses on current knowledge about the
role of RAAS and insulin resistance and accompanying inflammation
and oxidative stress in the pathophysiology that links DM
and HTN.
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Losing Control: Positive and Negative Feedback in the Renin
Angiotensin System
Merlin C. Thomas and Chris Tikellis
The renin angiotensin system (RAS) is a key homeostatic
regulator that relies on feedback regulation to achieve and
sustain the delicate balance required for healthy physiological
function. A number of negative feedback loops exist within
the RAS that counterbalance the effects of conventional RAS
blockade. Indeed, instead of reducing levels of Ang II and
aldosterone, exaggerated feedback responses lead to a paradoxical
elevation in many patients treated with RAS blockers. This
‘escape’ has been used to explain a number of
clinically-relevant phenomena including progressive left ventricular
hypertrophy, deteriorating cardiac and renal function in the
face of full-dose RAS blockade. Escape has been thought to
be mediated by reactive increases in renin activity and Ang
I, which is then converted to Ang II, via non- ACE
pathways (or by ACE when inhibitors are cleared). The reduced
expression and activity of the angiotensinase Angiotensin
Converting Enzyme 2 (ACE2) following RAS blockade may have
a role. Bystander activation of the uninhibited AT2
receptor during long-term angiotensin receptor blockade (ARB)
can also increase aldosterone synthesis. Feed forward or positive
feedback loops also exist within the RAS, which exaggerate
the effects of signaling and contribute to progressive hypertension
and vascular damage. For example, Ang II acts to increase
the expression of angiotensinogen in the kidney and the liver.
The strong association between adverse outcomes and activation
of feedback pathways provide a strong rationale for specifically
targeting feedback as part of any vasculo-protective strategy.
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Functional Cardiovascular Effects of Angiotensin Peptides:
Focus on
Atherosclerosis and Hypertension
Antony Vinh, Tracey A. Gaspari, Emma S. Jones and
Robert E. Widdop
The renin-angiotensin system (RAS) is a major physiological
regulator of body fluid volume, electrolyte balance, and arterial
blood pressure. The octapeptide, angiotensin (Ang) II, is
the main effector of the RAS and overactivity of Ang II is
a major contributor to pathological changes in cardiovascular
disease; exemplified by the vasoprotective effects observed
with RAS inhibition that extend beyond blood pressure reduction.
However, an emerging concept of the RAS is the unique roles
of shorter peptide fragments other than Ang II, such as Ang
(1-7), Ang III and Ang IV. These peptides were initially thought
to be inactive breakdown products of Ang II; however, they
are now recognized as active components of the RAS, often
with their own unique biological profile. This review will
focus on the cardiovascular functions of these and other newly-discovered
Ang peptides. The effects of these peptides will be discussed
in the context of their actions at a number of non-AT1
receptors and the likely interplay with RAS inhibition.
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Does Handle Region Peptide Provide Benefits in Chronic Kidney
Disease?
Atsuhiro Ichihara, Fumiaki Suzuki, Tadashi Inagami and
Hiroshi Itoh
Discovery of (pro)renin receptor uncovered a novel function
of renin/prorenin as the receptor ligands in addition to enzyme
and its precursor. Binding of renin and prorenin to the (pro)renin
receptor activate two major signaling pathways: the locally
generate-dangiotensin II-dependent pathway as a result of
the enzymatic activation of renin/prorenin, and the angiotensin
II-independent (pro)renin receptor mediated intracellular
pathway, involving hypertrophic, hyperplasic, and profibrotic
signals. A specific blocker of the receptor was discovered
through identification of amino acid sequence of prorenin
pro-segment which binds to the receptor and leads to non-proteolytic
alteration of prorenin to its active form. A peptide which
contains this sequence was found to block the binding of prorenin
to its receptor. Its continuous infusion in animal models
of diabetes and low-renin hypertension significantly inhibited
the development and progression of nephropathy, but (pro)renin
receptor blockade was not effective on the clipped kidney
of 2K1C rats or rat models of high-renin hypertension. Since
renin is still active without a (pro)renin receptor, (pro)renin
receptor blockade provides a maximum benefit under low-renin
conditions. Thus, (pro)renin receptor blockade can be a effective
therapeutic approach for chronic kidney disease with low renin
levels in the plasma.
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Blood Pressure Control and Diabetic Retinopathy
Tien Y. Wong and Paul Mitchell
Diabetic retinopathy affects a significant proportion
of people with diabetes. Epidemiological studies suggest that
hypertension is related to diabetic retinopathy, and major
clinical trials has provided clear evidence that controlling
blood pressure in diabetic patients with hypertension reduces
the incidence and progression of retinopathy and visual loss.
The United Kingdom Prospective Diabetes Study (UKPDS) showed
that a 10 mmHg reduction in systolic blood pressure is associated
with a 10% reduction in the risk of retinopathy. However,
the UKPDS suggest that adequate blood pressure control must
be maintained over time for sustained benefits on retinopathy
and other microvascular complications. Recent trials suggest
that there is a limit to retinopathy risk reduction achievable
through lowering blood pressure to near normal levels. Newer
trials also provide initial evidence that specific inhibition
of the renin angiotensin system (RAS), particularly with angiotensin
II-receptor blockers (ARB), may have an additional protective
effect against retinopathy. Early detection of retinopathy
through comprehensive dilated eye examinations by eye care
providers, controlling modifiable risk factors (glucose, blood
pressure and lipids) and appropriate referral for treatment
are the cornerstones in management of diabetic retinopathy
in the community.
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Prorenin and the (Pro)renin Receptor in Retinal Pathology
Jennifer L. Wilkinson-Berka, Terri J. Allen and
Antonia G. Miller
Blockade of angiotensin II (Ang II) has potential therapeutic
benefit for ocular diseases including diabetic retinopathy
and retinopathy of prematurity. Perhaps the most studied is
diabetic retinopathy where angiotensin converting enzyme inhibition
and angiotensin type 1 receptor blockade (AT1-RB) is beneficial.
The importance of Ang II has recently been highlighted with
DIRECT (DIabetic REtinopathy Candesartan Trial) reporting
that the AT1-RB, candesartan, reduced the incidence of retinopathy
in type 1 diabetic patients and enhanced regression in type
2 diabetic patients. Prorenin may also be a causative factor
in diabetic retinopathy in humans, with early studies reporting
that prorenin is elevated in both plasma and vitreous. Recently,
interest in prorenin has re-emerged with the identification
of a prorenin receptor [(P)RR] which binds both renin and
prorenin and induces signal transduction pathways that are
independent of Ang II. Studies by one group have reported
that a particular (P)RR inhibitor provides protective effects
in experimental retinopathy of prematurity and uveitis. However,
controversy exists about the effectiveness of this (P)RR inhibitor
with other groups failing to find organ protection. This review
discusses these findings and evaluates whether prorenin and
the (P)RR may be relevant for certain ocular diseases and
a possible target for therapeutic intervention.
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