htn

1. Hypertension &
Vascular protection
DR :Adel Sallam

6.  Learning Objectives
After completion of this volume, the reader should:
1. Update the pathophysiology of hypertensive heart disease
and coronary atherothrombosis, particularly regarding
their relationship with hypertension.
2. Review the methods applicable to the diagnosis of heart
disease and their indications in the hypertensive patient.
3. Review the indications, and the prevention and treatment
patterns for patients with cardiac and coronary hypertension.

7. TRANSLATIONAL APPROACH TO
HYPERTENSIVE HEART DISEASE
The spectrum of the cardiac complications of arterial
hypertension includes
 heart failure (HF),
 sudden death, and
cardiac dysrrhythmias,
as well as the exacerbation of coincidental
diseases. As ATHEROSCLEROSIS AND CHRONIC
RENAL DIS EASE

8. Systemic and local
humeral deregulation
 Hemodynamic
overload
Increased LV
wall tension
 Unbalance between pro- and
anti-remodeling factors
Altered biophysiology of
cardiac cells and ECM
Genetic reprogramming and
growth of cardiomyocytes
Myocardial
remodeling
LV wall
thickening
Genetic background
Increased blood pressure
Local physico-chemical factors
Environmental factors
Hypertensive heart disease

9. Structural Remodeling of the Myocardium
The conception of remodeling was initially created to de-
scribe the anatomic changes in the left ventricle that
occur after myocardial infarction.
Today, myocardial remodeling is used to qualify a
variety of changes in :
-the cardiomyocyte
-the volume and composition of the non cardiomyocyte
compartment that alter myocardial structure and
function
Remolding occurring in response to :
-myocardial infarction,
-pressure or volume overload,
-cardiomyopathic states,
-exposure to infectious or cardio toxic agents.

11. Table 1. Molecules Involved in Myocardial Remodeling in HHD
Proremodeling molecules
Vasoactive substances (norepinephrine, angiotensin II) Hormones
(thyroid hormone, aldosterone)
Growth factors (transforming growth factor-13)
Cytokines (cardiotrophin 1)
Other (reactive oxygen species, endogenous peroxisome
proliferator-activated receptor-y ligands)
Antiremodeling molecules
Vasoactive substances (NO, prostacyclin, angiotensin-)
Hormones (glucocorticoids)
Growth factors (insulin-like growth factor 1)
Cytokines (tumor necrosis factor-a)
Other (endogenous peroxisome proliferator-activated receptor—a

12. Altered
Ca2+metabolism
Increased Perivascular
stiffness compression
Decreased
blood supply
 Cardiomyocyte
apoptosis
Cardiomyocyte
hypertrophy
Alterations of the
microcirculation
Decreased
number
 Myocardial
fibrosis
Altered
energetics
Altered
relaxation
Altered
conduction
Impaired Impaired Focal Impaired
systolic diastolic re-entry coronary
contraction filling mechanisms
flow reserve
LV dysfunction/failure Arrhythmias Ischemia
Figure 3. Pathways linking myocardial remodeling with clinical manifestations in hypertensive heart disease.

13. Proposed New Aims for the Clinical Handling of HHD
To identify patients prone to develop LVH
24-h monitoring of blood pressure
Insertion/deletion polymorphism of ACE gene
Circulating cardiotrophin 1
To optimize the diagnosis of LVH
3D echocardiography
MRI
To detect noninvasively myocardial remodeling
Speckle tracking echocardiography
MRI
Nuclear molecular imaging techniques
ELISA of circulating biochemical markers
To provide therapeutic benefit beyond reduction of LVM
Agents (i.e., antihypertensive and non antihypertensive agents)
that repair myocardial remodeling
Antihypertensive agents that preserve cardiac function, electrical
activity, and intramyocardial perfusion

14. Experimental and Clinical Evidence-Based Effects of Antihypertensive Agents in HHD
Pharmacological Class Decrease of Blood Pressure Regression of LVH Repair of Remodeling
Diuretics Yes Mild effect Proven for torsemide
B-Blockers Yes Mild-moderate effect Apparently not
a-Blockers Yes Mild effect Untested
Calcium antagonists Yes Marked effect Apparently not
ACE inhibitors Yes Marked effect Yes
Angiotensin receptor blockers Yes Marked effect Yes
Aldosterone antagonists Yes Mild-moderate effect Apparently yes
Direct renin inhibitors Yes Marked effect Untested

15. Kazuomi Kario, MD, PhD
Morning Surge in Blood Pressure
and Cardiovascular Risk
Evidence and Perspectives
Key points
• There is marked diurnal
variation in the onset time
of cardiovascular events,
with the peak being
exhibited in early morning.
Blood pressure (BP) also
exhibits a similar diurnal
variation, with a decrease
during sleep and a surge
in the morning.
• Because current study
demonstrated that
exaggerated morning
surge in BP constitutes
a risk for stroke
independent of
24-hour BP, there has
been a steady increase
in cross-sectional
and prospective evidence
supporting the idea
that morning BP surge
is an independent risk
factor for cardiovascular
disease.

16. Prospective findings
on cardiovascular events
• Normal morning BP surge
is a physiological
phenomenon,
but an exaggerated
morning BP surge
is a cardiovascular risk.
Thus, the association
between the degree
of morning BP surge
and cardiovascular risk
is not linear but rather
has a threshold.
Definition of morning surge in blood pressure.

17. Six prospective studies demonstrating the association between
morning surge in BP (based on ABPM) and cardiovascular events

18. Cross-sectional evidence
on target organ
Risk factors and target organ damage associated
with morning surge in blood pressure.
• There is
compelling
evidence
suggesting
a significant
association
between morning
BP surge and
various
surrogate markers
of target organ
damage.

19. Associations of morning BP surge
Associations of morning surge in blood pressure

20. Unresolved issues
on morning BP surge
Unresolved issues on morning surge in blood pressure

21. Unresolved issues
on morning BP surge
• Morning BP surge is usually assessed using ambulatory
blood pressure monitoring (ABPM);
however, there is no consensus on a single definition or on the
threshold of pathological morning BP surge.
• Sleep-trough surge is one of the dynamic diurnal surges during the
specific period from sleep to early morning, when the cardiovascular
risk is exaggerated.
• Recently, the ME difference (morning systolic BP minus evening
systolic BP) was reported to be associated with cardiovascular risk
independent of the mean of morning and evening BPs.
 Definition and threshold of morning BP surge

22. • The ME difference of ABPM was shown to be an independent
predictor of future stroke events in elderly hypertensives,
whereas the ME difference of HBP was associated with LVMI
and the risk of concentric hypertrophy, as well as with
increased pulse wave velocity.
• The morning HBP self-measured in the standing position
may be better to detect the risk of morning BP surge than
sitting HBP.
Unresolved issues
on morning BP surge
 Definition and threshold of morning BP surge

23. Intervention on morning surge
• There has been no study that scientifically tested the hypothesis that
selective suppression of exaggerated morning BP surge leads to the
regression of target organ damage and the reduction of subsequent
cardiovascular events.
• From a practical point of view, antihypertensive treatment targeting
morning BP 135/85 mm Hg leads to strict 24-hour BP control, which would
achieve more effective protection than conventional antihypertensive treatment
based on clinic BP.
• Nonspecific medications for morning BP surge include long-acting calcium
channel blockers, such as amlodipine.
• More specific chronological treatment for morning BP surge
may be achieved by bedtime dosing of antihypertensives that
reduce the pressor effect of the RAS or sympathetic nervous
system potentiated in the morning.

24. Visceral Obesity
The Link Among Inflammation, Hypertension, and
Cardiovascular Disease
• Obesity-associated disorders, such as diabetes mellitus, an
atherogenic dyslipidemia, and hypertension, contributed to create an
atherosclerosis-prone environment and thereby the development of
cardiovascular disease .
• The adipose tissue, is now regarded as a complex organ not only
contributing to the management of energy flux within the body but
also interacting with the inflammatory system and the vascular wall.
Key points
• A growing body of evidence indicates that obesity is a heterogeneous
condition in which body fat distribution is closely associated with
metabolic perturbations and, thus, with CVD risk.

25. Visceral fat and inflammation
• Studies have highlighted that, in addition to its metabolic activity,
visceral adipose tissue produces large amount of interleukin-6 and by
doing so promotes the secretion of acute-phase proteins by the liver,
e.g., C-reactive protein (CRP).
• Clinical studies have demonstrated that CRP levels are associated with
coronary events. Whether there is a cause-and-effect relationship
between CRP and coronary heart disease event remains unclear, but
studies have shown that CRP levels are markedly increased in individuals
with abdominal obesity, particularly among subjects with a selective
excess of visceral adipose tissue.

26. Visceral fat and metabolism
 Small, dense low-density lipoprotein
• Small, dense LDL is 1 key feature of visceral obesity and is closely
associated with the hypertriglyceridemic state of insulin resistance.
• Studies have shown that small, dense LDL particles have a greater
ability to penetrate within the vascular wall and have a high
susceptibility to oxidation and are thereby potentially highly atherogenic.
• Although it is presently unclear whether small LDL particles predict
CAD risk beyond classic lipid variables, a high proportion/number of
small LDL particles is clearly associated with an increased CAD risk.

27. Visceral fat and metabolism
 High-density lipoprotein
• Epidemiological prospective studies have conclusively shown that low
plasma levels of high-density lipoprotein (HDL) cholesterol are
associated with an increased CVD risk.
In the viscerally obese individual, through the successive actions of
cholesteryl ester transfer protein and hepatic lipase, HDL levels are
decreased,and, more important perhaps, the particles become smaller
and more dense.

28. Visceral fat and metabolism
 Endocannabinoid system:
a new player in the control of body fat distribution and
related metabolism
• Although further studies will be needed to confirm the direct role
played by endocannabinoids (ECs) in the regulation of body fat
distribution, these recent observations suggest that the activity of the
EC system is related not only to energy balance but also to insulin
resistance and to atherogenic dyslipidemic states.

29. Visceral obesity and hypertension
• Hypertension, a major cardiovascular risk factor, is closely associated
with obesity. Indeed, it is estimated that between 65 % and 78 % of
cases of hypertension could be attributed to obesity.
Physiopathologic relationships between obesity and hypertension.

30.  Visceral obesity: a new target in hypertension?
Visceral obesity and hypertension
• When compared with the subcutaneous adipose tissue, the gene
expression profile indicates that visceral fat expresses more
proinflammatory cytokines and more AGN.
• In an animal experimental model, surgical removal of visceral fat has
been associated with a reversal of insulin resistance.
• In viscerally obese individuals, resistance to antilipolytic activity of
insulin results in greater FFA flux, which, in turn, is significantly related
to the mean blood pressure and vascular resistance.

31. Visceral obesity and hypertension
 Visceral obesity:
a new target
in hypertension?
Diastolic and systolic
blood pressures
according
to waist circumference
and body mass
index (BMI) among
men (A) and
women (B) of the
Quebec Health Survey.
1, 2, 3, 4, and 5 indicate
significantly different
from the corresponding
subgroup. Men (A), all
P <0.0001; age-
adjusted all P <0.03;
women (B), all
P <0.0001; age-
adjusted all P <0.05.

32. Therapeutic options
for the viscerally obese patient
 Lifestyle interventions
• Keeping in mind the relevance of visceral obesity and related
metabolic perturbations in the pathophysiology of CVD, along with an
expanding pool of patients, it is likely that interventions targeting the
loss of visceral fat maysignificantly decrease global cardiovascular risk.
• Exercise training, per se, is independently associatedwith blood
pressure reduction. Thus, decreasingweight and, more importantly, the
waistline are likely to yield significant improvements in the metabolic
profile and a considerable reduction of CVD risk.

33. • Given the crucial links
between visceral
obesity and the
atheroinflammatory
process, it is likely that
targeting a reduction
of the waistline instead of
body weight may provide
a better assessment
of the efficacy of the
intervention; the point
being that, in some
individuals, regular
exercise will increase
the fat-free mass resulting
in an apparent modest
weight reduction, which
may mask a very significant
loss of visceral fat.
Therapeutic options
for the viscerally obese patient
 Lifestyle interventions
An illustrative case showing an individual
having undergone a lifestyle intervention
program with a modest weight loss (body
mass index reduced from 33 to 31 kg/m2)
but with a substantial reduction of visceral
fat (66%) and, therefore, a significant
improvement of the metabolic risk factors.

34.  Pharmacological treatment
Therapeutic options
for the viscerally obese patient
• The glitazones
are a class of drug
that activates peroxisome
proliferator-activated
receptor (PPAR)-γ,
a transcription factor
regulating glucose
homeostasis and having
anti-inflammatory
activities, as well as
potentially
antiatherosclerotic
properties.
• No less significant
is the observation
that glitazones
increase the deposition
of subcutaneous fat
and by doing so prevent
the accumulation
of harmful intra-abdominal
fat, possibly
the phenomenon
explaining how this class
of drugs improves insulin
sensitivity.
• Fibrates are weak
activators of PPAR-
and are routinely
used to treat
hypertriglyceridemia
in mice, weight loss is
associated with an
increased expression
of PPAR- and PPAR-
in the adipose tissue
and atherosclerotic
plaques, which is, in turn,
inversely related to plaque
volume, suggesting that
PPARs are in some ways
related to the burden of
atheroma.

35. METABOLIC SYNDROME
WHO CRITERIA
MADE ON THE BASIS OF SEVERAL MARKERS OF INSULIN
RESISTANCE PLUS ADDITIONAL RISK FACTORS INCLUDING
1-OBESITY
2-HYPERTENSION
3-HIGH TRIGLYC ERIDE LEVEL
4-REDUCED HIGH DENSITY LIPOPROTEIN CHOLESTEROL
5-LEVEL OR MICROALBUMINURIA .
ATP III CRITERIA
MADE THE PRESENCE OF 3 OF 5 THE FOLLOWING FACTORS :
1-ABDOMINAL OBESITY WHICH IS HIGHLY CORRELATED WITH INSULIN
RESISTANCE
2- ELEVATED TRIGLYCERIDE
3- REDUCED HIGH DENSITY LIPOPROTEIN CHOLESTEROL
4- ELEVATED BLOOD PRESSURE
5- ELEVATED FASTING GLUCOSE IMPAIRED FASTING GLUCOSE OR TYPE
DIABETES MELLITUS )

38. Treatment of Hypertension
in the Prevention and Management
of Ischemic Heart Disease
• The optimal choice
of antihypertensive agents
remains controversial,
and there are only partial
answers to important
questions in the treatment
of hypertension
in the prevention
and management
of ischemic heart
disease (IHD).
• This scientific statement
attempts, on the basis
of the best available
evidence, to develop
recommendations
that will be appropriate
for both BP reduction
and the management
of coronary artery
disease (CAD) in its various
manifestations.

39. Summary of main recommendations

40. Hypertension is a major independent risk factor for CAD, stroke, and
renal failure.
The Framingham Heart Study has estimated the 20-year risk of
developing hypertension as >90% for men and women not yet
hypertensive by middle age (55 to 65 years of age).
• At all ages, the relationship between SBP or DBP and IHD mortality
is consistent, robust, and continuous, with no apparent threshold
value.
• The risk of cardiovascular disease in the patient with hypertension
can be greatly reduced with effective antihypertensive therapy.
• Randomized trials have shown that BP lowering produces rapid
reductions in cardiovascular risk that are highly consistent with
predictions of risk reduction that can be inferred from observational
studies.
Epidemiology of hypertension and CAD

41. Guidelines
APPENDIX
Calculating a 10-year
risk for coronary heart
disease using Framing-
ham point scores.
Reprinted from The National Heart,
Lung, and Blood Institute as a part
of the National Institutes of Health
and the US Department of Health
And Human Services, NIH
Publication No. 01-3305.
Available
at:http://www.nhlbi.nih.gov/
guidelines/cholesterol/risk_tbl.htm.

42.  Effects of treatment
Epidemiology of hypertension and CAD
• A 10-mm Hg–lower usual SBP (or a 5-mm Hg–lower usual DBP) would
predict a 50% to 60% lower risk of stroke death and an approximately
40% to 50% lower risk of death due to CAD or other vascular causes at
middle age, benefits that are only slightly less in older people.

43.  Physical forces and hemodynamics
Mechanisms of hypertension and CAD
• In hypertension, there is both an increased myocardial oxygen
demand and a diminished coronary blood flow or, at least, a
diminished coronary flow reserve.
• When SBP is elevated, there is an increase in both LV
output,impedance and intramyocardial wall tension, which increase
myocardial oxygen demand.
• IHD can be prevented or reversed when aggressive targets are achieved
for major cardiovascular disease risk factors.

44.  BP and treatment goals
Primary prevention of CAD
in hypertension
• The current consensus target for BP is <140/90 mm Hg in general and
<130/80 mm Hg in individuals with diabetes mellitus or chronic kidney disease.
• Recently, it has been found that treatment of prehypertension(BP 120 to
139/80 to 89 mm Hg) reduces the incidence of subsequent hypertension.
• At present, there are no clinical trials specifically designed to answer the
question of what the most appropriate BP target(s) should be in individuals
with latent or overt CAD.
• We recommend a target BP of <130/80 mm Hg for individuals with
demonstrated CAD, or CAD risk equivalents (carotid artery disease, peripheral
arterial disease, abdominal aortic aneurysm), and for high-risk patients, defined as
those with diabetes mellitus, chronic renal disease, or a 10-year Framingham risk
score of ≥10%.

45. Primary prevention of CAD
in hypertension
 Clinical trials
• In the Hypertension Optimal Treatment (HOT) trial, lower BPs did not further
decrease or increase the incidence of adverse cardiovascular events, except
for a small increase in mortality in those whose diastolic pressures were
reduced to <70 mm Hg.
• In the International Verapamil-Trandolapril Study (INVEST), DBP values
lower than 70 mm Hg were associated with increased risk for MI.
• In the Irbesartan Diabetic Nephropathy Trial (IDNT), the incidence of MI
was increased in those with DBP values <80 mm Hg.

46.  Pharmacological therapies
Primary prevention of CAD
in hypertension
• The most important strategy for lowering the burden of atherosclerotic
disease is fastidious BP control.
• Meta-analyses have demonstrated that BP lowering is more important
than choice of drug class in the primary prevention of the complications of
hypertension.
• Effective combination antihypertensive drug therapy is usually required
to achieve and sustain effective long-term BP control.
• It is reasonable to assume that there are class effects for thiazide-type
diuretics, ACE inhibitors, and ARBs, which have a high degree of homogeneity
in their mechanisms of action and side effects. It is equally clear that
there are major differences between drugs within more heterogeneous
classes of agents, such as β-blockers or CCBs.

47.  Pharmacological therapies
Primary prevention of CAD
in hypertension
• Thiazides are highly effective in reducing BP
and preventing cerebrovascular events, as demonstrated most
convincingly in early studies.
• β-blocker administration remains a standard of care in patients
with angina pectoris, those who have had an MI, and those who
have LV dysfunction with or without HF symptoms, unless
contraindicated.
• ACE inhibitors, a relatively homogeneous class of antihypertensive
agents, are effective in reducing initial IHD events and are
recommended for consideration in all patients after MI.

48.  Pharmacological therapies
Primary prevention of CAD
in hypertension
•In HOPE, treatment with ramipril was associated with a 22% reduction in the
composite end point of cardiovascular death, MI, and stroke (P0.001)
• In EUROPE, perindopril therapy (target dose 8 mg/d) was associated with a
20% relative risk reduction in the primary end point, a composite of
cardiovascular death,MI, or cardiac arrest (P = 0.003).
• In PEACE, the investigators concluded that ACE inhibitors might not be
necessary as routine therapy in low-risk CAD patients with preserved LV
function, especially those who have received intensive treatment with
revascularization and lipid-lowering agent
• ARBs are generally considered to be appropriate therapy in individuals
with cardiovascular disease who are intolerant of ACE inhibitors.

49.  Pharmacological therapies
Primary prevention of CAD
in hypertension
• As add-on to conventional antifailure therapy, spironolactone and
eplerenone lowered BP and had a secondary protective effect in
patients with severe HF in the Randomized Aldactone Evaluation Study
(RALES) and in patients with LV dysfunction after MI in the Eplerenone
Post-acute myocardial infarction HEart failure efficacy and Survival
Study (EPHESUS) trial.
• Primary prevention of cardiovascular events with the dihydropyridine
CCB amlodipine was equivalent to that produced by thiazide diuretic or
ACE inhibitor–based therapy in ALLHAT, and superiority over a β-
blocker was claimed in ASCOT.

50.  Pharmacological therapies
Primary prevention of CAD
in hypertension
• There is a strong tendency to find that combination or add-on
therapies are more effective than single agents. These important
caveats limit the applicability of trial results to everyday practice
and make physician judgment a major factor in choosing optimal
therapy for individual patients.
• There is a general consensus that the amount of BP reduction, rather
than the choice of antihypertensive drug, is the major determinant of
reduction of cardiovascular risk; however, there is sufficient evidence
in the comparative clinical trials to support the use of an ACE inhibitor
(or ARB), CCB, or thiazide diuretic as first-line therapy, supplemented
by a second drug if BP control is not achieved by monotherapy.

51. Management of hypertension
in patients with CAD and stable
angina
• Management of hypertension in patients with chronic CAD and chronic stable
angina is directed toward the prevention of death, MI, and stroke; a reduction
in the frequency and duration of myocardial ischemia; and the amelioration
of symptoms.
• β-blockers are the drugs of first choice for the treatment of hypertension in
patients with CAD that causes angina. Cardioselective (β1) agents without
intrinsic sympathomimetic activity are used most frequently.
• A reasonable BP target for hypertensive patients with demonstrated CAD
or with CAD risk equivalents (carotid artery disease, peripheral arterial
disease, abdominal aortic aneurysm, diabetes mellitus, or chronic
renal disease) is <130/80 mm Hg.
 Pharmacological therapies

52. Management of hypertension
in patients with CAD and stable
angina
 Pharmacological therapies
• Long-acting dihydropyridine agents are preferred over Nondihydropyridines
for use in combination with β-adrenoreceptor blockers, to avoid excessive
bradycardia or heart block.
• The use of β-blockers for secondary prevention in all but the lowest-risk
patients is a Class I American College of Cardiology (ACC)/AHA recommendation.
• CCBs are added to, or substituted for, β-blockers when BP remains elevated,
when angina persists, or when drug side effects or contraindications mandate.
• Diltiazem or verapamil should not be used in patients with HF or LV systolic
dysfunction, and short-acting nifedipine should be avoided because it causes
reflex sympathetic activation and worsening myocardial ischemia.
• Although CCBs are useful in the management of angina, there is no consensus
about their role in preventing cardiovascular events in patients with established
CAD.

53. Management of hypertension
in patients with CAD and stable
angina
 Pharmacological therapies
• The long-term use of ACE inhibitors in patients with CAD who also have diabetes
mellitus and/or LV systolic dysfunction is a Class I ACC/AHA recommendation.
• Long-acting nitrates are indicated for the treatment of angina not controlled
with adequate doses of -blockers and CCBs in hypertensive CAD patients.
• The management of symptomatic CAD, particularly angina pectoris, is directed
to the relief of the angina and the prevention of both the progression of CAD and
coronary events.
• ARBs are indicated during hospitalization and at discharge for STEMI patients
who are intolerant of ACE inhibitors and have HF or LOW ejection fraction.
• The combination of ACE inhibitors and ARBs has been used for the treatment
of advanced or persistent HF in the convalescent or chronic phase
after STEMI.
• Thiazide diuretics reduce cardiovascular events, as demonstrated most
convincingly in early studies.

54. Management of hypertension in HF
of ischemic origin
• Although guidelines from the ACC and the AHA exist for the treatment
of chronic HF, evidence on which to base guidelines for the treatment
•of hypertension in patients with HF of ischemic origin is limited.
•Hypertension is a major risk factor for IHD and can lead to the development
of HF by causing LV hypertrophy, impaired cardiac myocyte contractility,
ventricular chamber remodeling, and eventually diastolic and systolic
dysfunction.

55. Management of hypertension in HF
of ischemic origin
• The therapeutic goals in patients presenting with HF are to reverse
Hemodynamic abnormalities, relieve symptoms, and initiate treatments that
will decrease disease progression and improve survival.
 Therapeutic strategies
• Thiazide diuretics are effective in preventing HF in hypertensive patients.
• Thiazide diuretics are the drugs of choice in patients with mild HF because of
a more sustained natriuretic and diuretic action than loop diuretics, particularly
in those individuals in whom BP control may be more important than correction
of volume overload.

56. Management of hypertension in HF
of ischemic origin
 Therapeutic strategies
• By inducing sodium and water loss, diuretics also activate several
adverse mechanisms. There may be a decrease in right ventricular filling
pressure, with a fall in stroke volume and activation of the RAAS and the
sympathetic nervous system, effects that would be expected to be harmful.
• This problem is avoided by combining diuretic therapy with an ACE
inhibitor or ARB, a -blocker, and/or an aldosterone antagonist, all of which
have been shown to provide effective therapy in HF.

57. Management of hypertension in HF
of ischemic origin
 Therapeutic strategies
• ACE inhibitors have been shown in many trials to be beneficial in
patients with LV dysfunction of ischemic origin.
• The VALIANT trial found valsartan to be noninferiorto captopril,
althoug it did not show superiority.
• In the combination arm of VALIANT, valsartan and captopril together
showed no increased effect over captopril alone and had a higher incidence
of discontinuation due to adverse effects.

58. Management of hypertension in HF
of ischemic origin
 Therapeutic strategies
• The addition of hydralazine to a nitrate reduces this tolerance. Interest in this
combination for HF has been revived by a recent trial that suggested
that a combination of a fixed dose of both isosorbide dinitrate and hydralazine
provides additional benefit in black patients with advanced HF.
• The role of β-blockers in the management of patients with HF is well
established.
• Four clinical trials of carvedilol in HF were stopped prematurely because of a
highly significant 65% reduction in mortality in patients treated with carvedilol
compared with placebo.
• Aldosterone has been shown to promote myocardial fibrosis.
Long-term treatment with ACE inhibitors has not been associated with
suppression of plasma aldosterone levels. This had led to an interest in
evaluating aldosterone receptor antagonists as adjunctive therapy to ACE
inhibition in patients with HF.

59. Management of hypertension in HF
of ischemic origin
 Target BP
• BP targets in HF have not been firmly established, but in most successful
trials, SBP was lowered to the range of 110 to 130 mm Hg.
• There are several classes of drugs that should be avoided patients
with ischemic systolic HF with hypertension.
• Because of their negative inotropic properties and the increased likelihood of
worsening HF symptoms, nondihydropyridine CCBs such as diltiazem and
verapamil should be avoided.
• In patients with HF, α-blockers should be used only if other agents used for the
management of hypertension and HF are inadequate to achieve good BP control,
and even then, they should be used with caution.
 Drugs to avoid

60. Management of hypertension in HF
of ischemic origin
 Recommendations
• The treatment of hypertension in patients with HF should include behavioral
modification, such as sodium restriction, and a closely monitored exercise program.
• Drugs that have been shown to improve outcomes for patients with HF generally
also lower BP. Patients should be treated with diuretics, ACE inhibitors (or ARBs), β-
blockers, and aldosterone receptor antagonists.
• Thiazide diuretics shouldbe used for BP control and to reverse volume overload
and associated symptoms. In severe HF, or in patients with severe renal
impairment, loop diuretics should be used for volume control, but these are less
Effective than thiazide diuretics in lowering BP. Diuretics should be used together
with an ACE inhibitor or ARB and a β-blocker.
• Consider the addition of hydralazine/isosorbide dinitrate to the regimen
of diuretic, ACE inhibitor or ARB, and β-blocker in black patients with NYHA class III
or IV heart failure. Others may benefit similarly, but this has not yet been tested.

61. Aspirin for Primary Prevention of Cardiovascular Events
in People With Diabetes
The burden of cardiovascular disease (CVD) among patients with diabetes
is substantial.
Individuals with diabetes are at two- to fourfold increased risk of cardiovascular
events compared with age and sex-matched individuals without diabetes.
In diabetic patients over the age of 65 years, 68% of deaths are from coronary
heart disease (CHD) and 16% are from stroke.
A number of mechanisms for the increased cardiovascular risk with diabetes
have been proposed, including increased tendency toward intracoronary
thrombus formation increased platelet reactivity, and worsened endothelial
dysfunction,

62. Aspirin for Primary Prevention of Cardiovascular Events in People With
Diabetes
1. What is the evidence regarding aspirin to prevent initial
cardiovascular events in people with diabetes?
2. How can we reconcile the results of the different primary
prevention trials?
3. What are the risks of aspirin, and are these similar or
different for people with diabetes compared to those without?
4. What do we know about the recommended dosage or dosage
range?
5. How can we integrate potential benefits and risks of aspirin to
determine which patients with diabetes should receive aspirin
for the primary prevention of cardiovascular events?
6. What are the needs for future research?

64. •The Antithrombotic Trialists’
(ATT) Collaboration recently
published an individual patient-
level meta-analysis of the six
large trials of aspirin for
primary prevention in the
general population. Overall, the
meta-analysis found that
aspirin reduced the risk of
vascular events by 12%
Aspirin for Primary Prevention of Cardiovascular Events in People
With Diabetes
There was some evidence
of a difference in aspirin
effect by sex. Aspirin
reduced CHD events in
men but not in women.
Conversely, aspirin had no
effect on stroke in men
but reduced stroke in
women.
•Based on data from primary and
secondary prevention trials
conducted in mixed populations of
patients with and without diabetes,
low-dose aspirin appears to be
associated with an absolute risk of
hemorrhagic stroke of ~1 in 10
000 people annually.
For extra cranial (mainly
gastrointestinal) bleeding, aspirin
use is associated with a 54%
increase in risk based on meta-
analysis of the six primary
prevention trials.

65. •Low-dose (75 to 162 mg/day)
aspirin use for prevention is
reasonable for adults with
diabetes and no previous
history of vascular disease who
are at increased CVD risk and
who are not at increased risk for
bleeding.
Aspirin should not be
recommended for CVD
prevention for adults with
diabetes at low CVD risk as the
potential adverse effects from
bleeding offset the potential
benefits.
Low-dose (75 to 162 mg/day)
aspirin use for prevention might
be considered for those with
diabetes at intermediate CVD risk
until further research is available.

67.  Learning Objectives
After completion of this volume, the reader should:
1. Review brain flow physiology, its disturbances in the
presence of hypertension, and its clinical implications.
2. Update the diagnostic procedures of cerebrovascular
diseases, particularly regarding hypertension.
3. Review the indications, and the prevention and treatment
patterns for patients with hypertension and cerebrovascular
disease.

68. Venkatesh Aiyagari, MBBS, DM, and Philip B. Gorelick, MD, MPH
Management of Blood Pressure
for Acute and Recurrent Stroke
Key points
• Hypertension is the most important modifiable risk factor for stroke.
• Because many patients with stroke have mild hypertension or
prehypertension, we have shifted our focus and now think of stroke on a
continuum of risk based on blood pressure (BP) level rather than on a
threshold effect.
• Although the role of longer-term BP controlto improve outcomes in
patients with stroke is undisputed, BP management immediately after a
stroke remains controversial.

69. Blood pressure management after
intracerebral hemorrhage
• Patients with intracerebral hemorrhage (ICH) often have elevated BP.
Approximately one third of all patients with ICHpresenting within 3
hours of symptom onset have a significant expansion of the hematoma
over the next 20 hours.
• Recent studies indicate that low blood flow around the hematoma
may be a consequence of reduced cerebral metabolism in this area
rather than a primary reduction of blood flow.
• Hypertensive patients with ICH may have heart failure or elevated
cardiac troponin in which lowering BP might be helpful.

70.  The evidence
Blood pressure management after
intracerebral hemorrhage
• The results of three prospective pilot trials on acute BP reduction
after ICH indicate that intensive BP-lowering in the acute phase is
clinically feasible and well tolerated. Larger trials are planned to test
the hypothesis that hematoma expansion can be limited by acute
treatment of hypertension.
 Questions and answers about blood pressure
management after acute intracerebral hemorrhage
• What blood pressure level is considered to be too high and
requiring immediate reduction?
Despite absence of definitive supportive evidence,
some experts believe that a SBP of >180 mm Hg or a mean arterial
pressure (MAP) of >130 mm Hg would warrant immediate lowering.

71. • What is the appropriate target blood pressure in patients with ICH?
Immediately after an ICH, it is perhaps more appropriate to tailor the target BP to
each patient rather than using a “one size fits all” approach.
Blood pressure management after
intracerebral hemorrhage
 Questions and answers about blood pressure
management after acute intracerebral hemorrhage
• The AHA/ASA guidelines suggest maintaining a cerebral perfusion pressure of 60
to 80 mm Hg in patients with possible increased ICP and a BP of 160/90 or a MAP
of 110 mm Hg in other patients.
• How fast should blood pressure be lowered?
Results of small studies suggest that rapidly lowering MAP by approximately 15%
does not lower cerebral blood flow, whereas reductions of >20% can do so.
• What antihypertensive agents are appropriate for use in the acute
setting?
Short and rapidly acting intravenous antihypertensive agents are preferred.

72. Blood pressure management after
intracerebral hemorrhage
AHA/ASA recommendations for BPmanagement in acute cerebral
hemorrhage

73. Blood pressure management
after acute ischemic stroke
 Questions and answers on BP management immediately
after an acute ischemic stroke
• Should blood pressure be lowered in patients with evated BP after an
ischemic stroke?
As per the AHA/ASA guidelines, it is recommended that before intravenous
thrombolytic treatment, BP should be lowered if >185 mm Hg systolic or >110
mm Hg diastolic.
• Should blood pressure be elevated to improve cerebral perfusion in
patients with ischemic stroke?
A few small case series have shown neurological improvement with induced
hypertensive therapy.
• It is reasonable to try volume expansion and/or vasopressors in patients
with hypotensive stroke or in patients who have had a worsening of the
neurological deficit in association with a drop in BP.
.

74. • Should patients on antihypertensive agents have their
medications held or continued?
The AHA/ASA guidelines recommend restarting antihypertensives at 24
hours in previously hypertensive neurologically stable patients unless
contraindicated

75. AHA/ASA recommendations
for BP management in acute
ischemic stroke
Blood pressure
management
after acute ischemic
stroke

76. Blood pressure management
and prevention of recurrent stroke
 The evidence
• A key message derived from PROGRESS is that greater BP-
lowering may be associated with more significant benefit in
terms of reducing major vascular events.
• Patients eligiblefor treatment with intravenous thrombolytics
or other acute reperfusion intervention and SBP >185 mm Hg or
DBP >110 mm Hg should have BP lowered before the
intervention.
• A persistent SBP of >185 mm Hg or a DBP >110 mm Hg is
a contraindication to intravenous thrombolytic therapy.
• In hypotensive patients, the cause of hypotension should be sought.
Hypovolemia and cardiac arrhythmias should be treated and in
exceptional circumstances, vasopressors may be prescribed in an
attempt to improve cerebral blood flow.

77. Blood pressure management
and prevention of recurrent stroke
 Questions and answers about BP management for
recurrent stroke prevention
• When is it safe to lower BP after an acute ischemic stroke for the
purpose of recurrent stroke prevention?
While awaiting the arrival of more definitive data, the available evidence
suggests that it might be reasonable to start oral antihypertensives as soon
as 24 to 72 hours after onset of symptoms provided there are no
contraindications such as a presumed hemodynamic mechanism of stroke.
• The AHA/ASA guideline supports BP-lowering therapy as soon as 24 hours after
acute ischemic stroke.
• What is the target BP goal?
The precise target goal is not definitively known. In the PROGRESS trial, BP was
lowered by approximately 10/5 mm Hg, and this BP target has been suggested as
a reasonable one for patients according to the AHA/ASA guideline.
• A reasonable goal, if it can be safely achieved after ischemic stroke, is the JNC
7 target of <140/90 mm Hg for uncomplicated hypertensive patients and ≤130/80
mm Hg for those with diabetes mellitus or chronic kidney disease

78. Blood pressure management
and prevention of recurrent stroke
• Which BP-lowering agent is most effective?
In general, all major classes of BP-lowering agents may diminish recurrent
stroke risk.
• Although some studies have suggested that angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers may be more effective in
recurrent stroke prevention than other antihypertensive agents, this
assertion has not been validated in more recent studies.
• The AHA/ASA guideline recommends consideration of a
diuretic in combination with an angiotensin-converting enzyme
inhibitor.

79. AHA/ASA recommendations for BP management for prevention of
recurrent stroke
Blood pressure management and
prevention of recurrent stroke

80. Suraj Kapa, MD; Fatima H. Sert Kuniyoshi, PhD, and Virend K.
Somers, MD, PhD
Sleep Apnea and Hypertension:
Interactions and Implications
for Management
Key points
• In recent years, there has been a large body of work assessing the role
of OSA as an independent risk factor for hypertension.
• As many as half of all patients with sleep apnea may have underlying
hypertension, and many patients with hypertension, particularly
resistant hypertension, may have OSA.
• There seems to be an interaction between OSA severity and resistance
to antihypertensive medications.
• OSA patients may not always exhibit elevated systolic pressures but
may have a high prevalence of isolated diastolic hypertension.

81. Systolic and diastolic hypertension
Effects of gender and Age
• A recent study by Drager et al. suggested that increasing age, body
mass index, a family history of hypertension, and female gender
independent of menopause and obesity may be risk factors for
hypertension in patients with OSA.
• In a subgroup analysis of the Sleep Heart Health Study, patients 60
years of age with sleep apnea were more likely to demonstrate a
significant relationship between minimum oxygen saturation and the
development of hypertension.

82. Nocturnal nondipping blood pressure
patterns
• Even in the absenceof day time hypertension, sleep apnea patients
may not exhibit the normal nocturnal dip in blood pressure during
sleep because of apnea-induced sympathetic activation.
• Even in normotensive patients, a nocturnal nondipping blood
pressure profile may suggest increased cardiovascular risk.
Subclinical OSA and prehypertension
• The relationship between OSA and hypertension could extend beyond
OSA alone and may reflect a broader interaction between disturbed
sleep and blood pressure.

83. Sleep duration and hypertension
Mechanisms mediating OSA-associated
hypertension
• Sleep duration of <5 hours per night was shown to significantly
increase risk for hypertension in patients <60 years of age, even after
controlling for obesity and diabetes.
• Improving duration and quality of sleep in sleep apnea patients may
conceivably help decrease the risk of developing hypertension.
• Hypertension because of OSA may be multifactorial in origin and may
depend on systemic inflammation, oxidative stress, endogenous
vasoactive factors, endothelial dysfunction, increased sympathetic
activation, and metabolic dysregulation.
• A growing body of evidence suggests that obesity and sleep apnea, in
part via effects on blood pressure and also via direct effects on the
heart, may have long-term effects on cardiac structure and function in
adults and in children.

84. Management
• The first-line treatment for OSA-induced hypertension is treatment
of OSA and antihypertensive medications as indicated.
• Sleep apnea treatments, including positional therapy, oral appliances,
and bariatric surgery, have been suggested to improve hypertension in
OSA patients.

85. Continuous positive airway pressure
• The mainstay of therapy for sleep apnea patients is CPAP,
administered
during sleep via a face mask or nasal mask.
• CPAP treatment of OSA may attenuate several of the mechanisms
believed to be responsible for development of hypertension in these
patients, including inflammation and endothelial and metabolic
dysfunction.
• CPAP can acutely decrease systemic blood pressure at night and
seems to also lower daytime blood pressure in hypertensive patients
but less so in normotensive patients.
• A reduction of >50 % in the apnea-hypopnea index may be needed
to decrease blood pressure.

86. Continuous positive airway pressure
Effect of CPAP vs. supplemental oxygen on 24-hour ambulatory
blood pressure.

87. Continuous positive airway pressure
Effect of CPAP usage on change in blood pressure.

89.  Learning Objectives
After completion of this volume, the reader should:
1. Update the pathophysiology of arterial and renal disorders
in hypertension.
2. Review the diagnostic approaches to both silent and
clinical renal vascular involvement.
3. Review the indications, and the prevention and treatment
patterns for hypertensive kidney and peripheral artery
disease.

90. Ernesto L. Schiffrin, MD, PhD, FRSC, FRCPC; Mark L. Lipman, MD,
FRCPC, and Johannes F. E. Mann, MD
Chronic Kidney Disease
Effects on the Cardiovascular System
• It is increasingly
apparent
that individuals
with chronic kidney
disease (CKD)
are more likely to die
of cardiovascular (CV)
disease (CVD)
than to develop kidney
failure.
Key points
ESRD is defined as the need for renal replacement
therapy (i.e., need for dialysis or renal transplantation).
*Stage 1 CKD is mostly recognized by either
albuminuria or structural renal abnormality
(e.g., hyperechoic renal parenchyma on ultrasound).
ESRD = end-stage renal disease; GRF = glomerular rate
filtration.
Stages of chronic kidney disease (CKD)

91. • Beyond the effects
of lack of appropriate
therapy, it is clear
that accelerated CVD
is prevalent in subjects
with CKD.
CV risk according
to stages of CKD
The increase in risk in comparison with people free
of CKD depends on the age of the population studied:
The younger the person, the higher the relative risk.
Microalbuminuria increases the CV risk 2- to 4-fold.
CKD = chronic kidney disease; CV = cardiovascular;
ESRD = end-stage renal disease.

92. • Evidence for the relationship between renal dysfunction and adverse
CV events was perhaps first recognized in the dialysis population in
whom the incidence of CV death is strikingly high.
Epidemiological links
between impaired GFR and adverse
cardiovascular events
• A growing number of studies have demonstrated that the relationship
between renal dysfunction and increased CV morbidity and mortality
extends across the spectrum of renal dysfunction to encompass the
mildest degrees of renal impairment. Moreover, this relationship
appears to hold across populations with widely varying degrees of
baseline CV health.

93. CVD associated with renal
disease in the general population
• The Framingham Heart Study was among the first to assess mild renal
insufficiency and its association with death and adverse CV events in
the general
population.
• More recently, Go et al., in a large study clearly demonstrated an
independent and graded (inverse) correlation between decreasing
levels of renal function and increasing event rates of CV morbidity and
death.
• The association between renal function and mortality in the
hypertensive population was evaluated by the Hypertension Detection
and Follow-up Program Cooperative Group. Data from the HOT study
support this finding.

94. Effect of renal disease on individuals
with preexisting stable CVD or risk
factors for CVD
• A post hoc analysis of the HOPE study examined the impact of
baseline serum creatinine on the incidence of the composite primary
outcome (CV death, MI, or stroke). The impact of renal insufficiency
was independent of both the baseline CV risk factors as well as the
treatment group.
• A similar relationship between renal function and CV events was
demonstrated in the PEACE trial. Interestingly, unlike in HOPE, there
was a significant interaction between GFR and treatment group
with respect to CV and all-cause mortality in that the
angiotensinconverting Enzyme inhibitor benefited only those individuals
with a GFR 60 mL/min per 1.73 m2.

95. Effect of renal disease in patients with
established heart failure or postmyocardial
infarction
• renal dysfunction was a predictor of mortality in stable patients with
advanced heart failure. GFR was the strongest predictor of mortality of
all factors analyzed, which included parameters of neurohormonal
activation.
• In a post hoc analysis of the Valsartan in Acute Myocardial
InfarctionTrial (VALIANT), found that, irrespective of treatment
group, there was a progressive increase in both the primary end point
as well as each of the secondary end points as GFR declined
• Similar to GFR, the link between albuminuria and adverse CV events
was first recognized in the more overt situations of macroalbuminuria
(urine albumin:creatinine ratio [ACR]>300 mg/g), and then this link
was extended to more modest elevations such as microalbuminuria
(ACR, 30 to 300 mg/g)

96. CVD in patients with macroalbuminuria
• The Irbesartan Diabetic Nephropathy Trial (IDNT) enrolled subjects
with type 2 diabetes, hypertension, and macroalbuminuria. patients who
experienced the CV end point progressively increased with increasing quartiles of
baseline urine albumin:creatinine ratio confirmed albuminuria as an independent
risk factor for CV events with a 1.3-fold increased relative risk for each natural log
increase of 1 U in urine ACR.
• RENAAL trial , baseline albuminuria was again shown to be a predictor of both
the prespecified composite CV end point (composite of MI, stroke, first
hospitalization for heart failure or unstable angina, coronary or peripheral
revascularization, or CV death) as well as of heart failure alone.
• Albuminuria is not only a risk factor for adverse CV outcomes but may also be
a therapeutic target or an indicator of therapeutic response.
• Recently, serum cystatin C has gained recognition as an excellent endogenous
marker of kidney function

97. Hypertension
• Hypertension in and of itself represents a powerful risk factor for
CVD in CKD and is almost invariably present in patients with renal
failure.
• Hypertension also plays a major role in cardiac damage in CKD via
LVH induction. In addition, a reduction in coronary reserve and
capillary density that occurs in CKD patients exposes them to coronary
ischemia, which in turn leads to worsening of ventricular dysfunction.
• Sodium retention and activation of the renin-angiotensin system
have been considered the most important mechanisms involved in
the elevation of blood pressure in subjects with kidney disease.

98. Markus P. Schlaich, MD; Paul A. Sobotka, MD; Henry Krum, MB, PhD;
Robert Whitbourn, MD; Anthony Walton, FRACP, and Murray D. Esler,
MD, PhD, FRACP
Renal Denervation as a Therapeutic
Approach for Hypertension
Novel Implications for an Old Concept
• On the basis of several findings in both preclinical and human experiments, and
in view of the demand for alternative treatmentoptions, targeting
the renal sympathetic nerves as a major player in the pathophysiology
of hypertension, kidney disease, and heart failure is a very attractive
therapeutic approach.

99. Role of renal sympathetic
nerves in cardiovascular and kidney
disease
• The renal sympathetic nervous system has been identified as a major
contributor to the complex pathophysiology of hypertension, states of volume
overload (such as heart failure), and progressive renal disease, both
Experimentally and in humans.
• Studies using radiotracer dilution methodology to measure overflow of
norepinephrine (NE) from the kidneys to plasma revealed increased renal NE
spillover rates in patients with essential hypertension.
• Activation of cardiorenal sympathetic nerve activity is even more pronounced in
heart failure, as demonstrated by an exaggerated increase of NE overflow
from the heart and the kidneys to plasma in this patient group.

100. Several forms of renal injury can induce activation of sensory
afferent signals.

101. Novel developments: catheter-based
renal denervation
• In a recently published safety and proof-of-concept trial, a novel,
percutaneous, catheter-based approach was applied to selectively ablate
the renal sympathetic nerves without affecting other abdominal, pelvic, or
lower extremity innervation.
• In this approach, renal sympathetic nerve ablation is achieved
percutaneously via the lumen of the main renal artery using a catheter
connected to a radiofrequency (RF) generator.
• Renal denervation achieved via this novel catheter-based approach has
the potential to improve blood pressure control and alleviate the sequelae
of elevated blood pressure, most likely via interference with both efferent
sympathetic and afferent sensory nerves and potentially further central
mechanisms.