Accepted Manuscript

Title: Hypertension and cardiovascular risk: general aspects

Author: Sverre E. Kjeldsen

PII: S1043-6618(17)31118-0
DOI: https://doi.org/10.1016/j.phrs.2017.11.003
Reference: YPHRS 3718

To appear in: Pharmacological Research

Received date: 8-9-2017

Revised date: 6-11-2017
Accepted date: 6-11-2017

Please cite this article as: Kjeldsen Sverre E.Hypertension and cardiovascular risk:
general aspects.Pharmacological Research https://doi.org/10.1016/j.phrs.2017.11.003

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Pharmacological Research - Special Issue on Hypertension Ms. YPHRS_2017_942

Hypertension and cardiovascular risk: general aspects

Sverre E. Kjeldsen*

on behalf of the 2013 Task Force for the Management of Arterial Hypertension of the
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)
* Department of Cardiology, University of Oslo Hospital, Ullevaal, N-0407 Oslo, Norway.
Telephone +47 22119100
Fax + 47 22119181
Email sverrkj@online.no or s.e.kjeldsen@medisin.uio.no or uxsvkj@ous-hf.no

Contents
Introduction……………..
Relationship of blood pressure to cardiovascular and renal damage…………..

Definition and classification of hypertension……………..

Prevalence of hypertension………………

Hypertension and total cardiovascular risk……………………….

Assessment of total cardiovascular risk………………..

Discussion…………….

Conclusions……………….

References

1
Graphical Abstract

ABSTRACT
Hypertension is the strongest or one of the strongest risk factors for almost all different

cardiovascular diseases acquired during life, including coronary disease, left ventricular

hypertrophy and valvular heart diseases, cardiac arrhythmias including atrial fibrillation,

cerebral stroke and renal failure. The continuous relationship between blood pressure and

cardiovascular and renal events makes the distinction between high normal blood pressure

and hypertension based on arbitrary cut-off values for blood pressures. Overall the prevalence

of hypertension in different European countries appears to be around 30–45% of the general

population, with a steep increase with ageing. The prevention of cardiovascular disease and

treatment recommendations should be related to quantification of total cardiovascular risk

which could be estimated from several different models. However the impact of age on risk is

so strong that young adults (particularly women) are unlikely to reach high-risk levels even

when they have more than one major risk factor and a clear increase in relative risk. Therefore

2
age-adjusted models, models assessing relative risks compared to others of same age and

models including thorough assessments of target organ damage and ambulatory 24 hour blood

pressure are needed together with national models because of the large variations between

countries.

Keywords: Blood Pressure

Cardiovascular risk

Cerebral stroke

Hypertension

Target organ damage

Renal disease

Introduction

The Global Burden of Disease Study organized by the World Health Organization has since

2003 pointed towards hypertension as the most important global risk factor for morbidity and

mortality. Hypertension does not cause cancer like smoking, but hypertension is the strongest

or one of the strongest risk factors for almost all different cardiovascular diseases acquired

during life, including coronary disease, left ventricular hypertrophy and valvular heart

diseases, cardiac arrhythmias including atrial fibrillation, cerebral stroke and renal failure.

The European Society of Hypertension has in cooperation with the European Society of

Cardiology issues hypertension guidelines in 2003, 2007 and 2013. 1, 2 The 2003 guidelines

are the most quoted guidelines in the world – regarding any field of medicine. For example,

the 2003 version of the hypertension guidelines was the most quoted article in medical

literature in 2003 and 2004, and the 2007 and 2013 are also extensively quoted.

The hypertension guidelines have comprehensively summarized the relationship between

hypertension and cardiovascular, cerebral and renal risk. This overview is a slightly modified

and updated version.

Relationship of blood pressure to cardiovascular and renal damage

3
The relationships between blood pressure and cardiovascular and renal morbid and mortality

have been addressed in a large number of observational studies.3 Office blood pressure shows

an independent continuous relationship with the incidence of several cardiovascular events

such as stroke, myocardial infarction, sudden death, heart failure, and peripheral arterial

disease as well as of end stage renal disease.3,4,5 This has been shown for all ages and in all

ethnic groups.6, 7

The relationship with blood pressure extends from high blood pressure levels to relatively low

values of 110-115 mmHg for systolic blood pressure and 70-75 mmHg for diastolic blood

pressure. Systolic blood pressure is a stronger predictor of events than diastolic BP after the

age of 50 years,8, 9 and in the elderly pulse pressure has an additional prognostic role.10 This is

indicated also by the particularly high cardiovascular risk in patients with an elevated systolic

and a normal or low diastolic BP (isolated systolic hypertension).11*

A continuous relationship with cardiovascular events is also exhibited by out-of-office blood

pressures obtained by 24-hour ambulatory blood pressure monitoring and home blood

pressure measurements. Metabolic risk factors including lipid abnormalities and glucose

intolerance or type 2 diabetes are more common when blood pressure is high than when it is

low. 12, 13 The relationship between blood pressure and cardiovascular morbidity and mortality

is modified by the concomitant presence of such cardiovascular risk factors.

Definition and classification of hypertension

The continuous relationship between blood pressure and cardiovascular and renal events

makes the distinction between high normal blood pressure and hypertension based on

arbitrary cut-off values for blood pressures. This is further the case because in the general

population systolic and diastolic blood pressure values have a unimodal distribution.14

However, cut-off blood pressure values are universally accepted both to simplify the

diagnostic approach and to facilitate the decision about treatment. The recommended

4
classification is summarized in Table 1 and it has been kept unchanged from the 2003 and

through the 2007 and 2013 European Society of Hypertension and European Society of

Cardiology hypertension guidelines. Hypertension is defined as systolic blood pressure values

≥140 mmHg and/or diastolic blood pressure values ≥90 mmHg. The definition is based on the

evidence from randomized clinical trials showing that in patients with these blood pressure

values treatment-induced reductions are beneficial. The same classification is used in young,

middle-aged, and elderly subjects, whereas different criteria, based on percentiles are adopted

in children and teenagers in whom data from large interventional trials are not available.

Details on blood pressure classification in boys and girls according to their age and height can

be found in the European Society of Hypertension report on the diagnosis, evaluation and

treatment of high blood pressure in children and adolescents.15

Prevalence of hypertension

Overall the prevalence of hypertension in different European countries16 appears to be around

30–45% of the general population, with a steep increase with ageing. There also appear to be

noticeable differences in the average blood pressure levels across countries, with no

systematic trends towards blood pressure changes in the past decades.17

Owing to the difficulty of having comparable results among countries and over time,

the use of a surrogate of hypertension status has been suggested.18 Stroke mortality is a good

candidate, because hypertension is by far the most important risk factor for fatal cerebral

stroke. A close relationship between prevalence of hypertension and fatal stroke has been

reported.19 The incidence and trends of stroke mortality in Europe have been analyzed by use

of World Health Organization vital statistics. Western European countries exhibit a downward

trend, in contrast to Eastern European countries, which show a strong increase in death rates

from stroke.20

5
Hypertension and total cardiovascular risk

For a long time, hypertension guidelines focused on blood pressure values as the only or main

variables determining the need for and the type of treatment. In 1994, the European Society of

Hypertension, the European Society of Cardiology, and the European Atherosclerosis Society

developed joint recommendations on prevention of coronary heart disease in clinical

practice,21 and the societies emphasized that prevention of coronary heart disease should be

related to quantification of total (or global) cardiovascular risk. This approach is now

generally accepted and has been integrated in the various versions of the European Society of

Hypertension/European Society of Cardiology guidelines for the management of arterial

hypertension.1, 2 The concept is based on the fact that only a small fraction of the hypertensive

population has an isolated elevation of blood pressure, with the majority exhibiting additional

cardiovascular risk factors. Furthermore, when concomitantly present, blood pressure and

other cardiovascular risk factors may potentiate each other, leading to a total cardiovascular

risk, which is greater than the sum of its individual components. Finally, in high-risk

individuals, antihypertensive treatment strategies such as initiation and intensity of treatment,

use of drug combinations, etc., as well as other treatments may be different from those to be

implemented in lower risk individuals. There is evidence that in high-risk people blood

pressure control is more difficult and requires more frequently the combination of

antihypertensive drugs together with other therapy first of all statin treatment. The therapeutic

approach should consider total cardiovascular risk in addition to blood pressure levels in order

to maximize the cost benefit efficacy of the management of hypertension.

Assessment of total cardiovascular risk

Estimation of total cardiovascular risk is easy in certain subgroups of patients such as those

with antecedents of established cardiovascular disease, diabetes, coronary heart disease or

with severely elevated single risk factors. In all of these conditions the total cardiovascular

6
risk is high or very high, calling for intense cardiovascular risk-reducing treatments. However,

a large number of patients with hypertension do not belong to any of the above categories and

the identification of those at low, moderate, high or very high risk requires the use of models

to estimate total cardiovascular risk in order to be able to adjust the therapeutic approach

accordingly.

Several computerized methods have been developed for estimating total cardiovascular risk.21-
28*
Their values and limitations have also been reviewed.29 The SCORE model 23 has been

developed based on large European cohort studies. The SCORE model 23 estimates the risk of

dying from cardiovascular and not just coronary disease over 10 years based on age, gender,

smoking habits, total cholesterol, and systolic blood pressure. The SCORE model allows

calibration of the charts for individual countries, which has been done for numerous European

countries. At the international level two sets of charts are provided: one for high-risk and one

for low-risk countries. The electronic interactive version of SCORE – Heart Score

(www.heartscore.org) is adapted to allow also adjustment for the impact of high-density

lipoprotein cholesterol on total cardiovascular risk.

The charts and their electronic versions can assist in risk assessment and management, but

must be interpreted in the light of the clinician’s knowledge and experience, especially with

regard to local conditions. Furthermore, the implication that total cardiovascular risk

estimation is associated with improved clinical outcomes when compared with other strategies

has not been adequately investigated in a randomized design.

The cardiovascular risk may be higher than indicated in the charts in sedentary persons and in

people with central obesity; the increased relative risk associated with overweight is greater in

the younger than in older persons. Socially deprived individuals and those from certain ethnic

minorities may also have higher cardiovascular risk. Persons with elevated fasting glucose

and/or an abnormal glucose tolerance test who do not meet the diagnostic criteria for type 2
7
diabetes are in the same category. The same is the case for individuals with increased

triglycerides, fibrinogen, apolipoprotein B, lipoprotein (a) levels, and high-sensitivity C-

reactive protein. And also individuals with a family history of premature cardiovascular

disease before the age of approximately 60 years may have high cardiovascular risk.

In the SCORE model, total cardiovascular risk is expressed as the absolute risk of dying from

cardiovascular disease within 10 years. Because of its heavy dependence on age, in young

patients absolute total cardiovascular risk can be low even in the presence of high blood

pressure with additional risk factors. If insufficiently treated, however, this condition may

lead to a partly irreversible high-risk condition years later. In younger persons treatment

decisions should better be guided by quantification of relative risk or by estimating heart age.

A relative-risk chart is available in the Joint European Societies’ Guidelines on cardiovascular

disease prevention in clinical practice,30 which is helpful when advising young persons.

Further emphasis has been given to identification of asymptomatic organ damage, since

hypertension-related asymptomatic alterations in several organs indicate progression in the

cardiovascular disease continuum, which markedly increases the risk beyond that caused by

the simple presence of risk factors. Thus, searching for asymptomatic organ damage may be

essential31-33 whenever evidence for additional risk is discussed.

International guidelines for the management of hypertension like the 1999 and 2003

World Health Organization/International Society of Hypertension guidelines, and the 2003,

2007 and 2013 European Society of Hypertension/European Society of Cardiology guidelines

1,2,34,35
and the 2012 European Society of Cardiology prevention guidelines30 have stratified

cardiovascular risk in different categories based on blood pressure category, cardiovascular

risk factors, asymptomatic organ damage, and presence of diabetes or symptomatic

cardiovascular disease or chronic kidney disease. The classification in low, moderate, high

and very high risk (Figure 1) refers to the 10-year risk of cardiovascular mortality as defined
8
by the 2012 European Society of Cardiology prevention guidelines30. The factors on which

the stratification is based are summarized in Table 2.

Discussion

All currently available models for cardiovascular risk assessment have limitations that must

be considered. The significance of target organ damage in determining calculation of overall

risk is dependent on how carefully the damage is assessed, based on available facilities.

Maybe the most typical example is detection of left ventricular hypertrophy which is much

more common when investigated by echocardiography compared to electrocardiography.

Conceptual limitations should also be mentioned. For example the rationale of estimating total

cardiovascular risk is to take advantage of the best use of limited resources to prevent

cardiovascular disease, or in other words to grade preventive measures in relation to the

increased risk. Yet, stratification of absolute risk is often used by private or public healthcare

providers to establish a barrier below which treatment is discouraged. One should keep in

mind that any threshold to define high total cardiovascular risk is arbitrary, as well as the use

of a cut-off values leading to intense interventions above this threshold and no action at all

below.

One should be aware of the strong effect of age on total cardiovascular risk models. It

is so strong that younger adults (particularly women) are unlikely to reach high-risk levels

even when they have more than one major risk factor and a clear increase in relative risk. By

contrast, many elderly men (e.g. >70 years) reach a high total risk level whilst being at very

little increased risk relative to their peers. The consequences are that most resources are

concentrated in older people, whose potential lifespan is relatively short despite intervention,

and little attention is given to young individuals at relatively high relative risk despite the fact

that, in the absence of intervention, their long-term exposure to an increased risk may lead to

a high and partly irreversible risk situation in middle age, with potential shortening of their

9
otherwise longer life expectancy.

For the future, national models for prediction of 10-year risk of incident acute

myocardial infarction or cerebral stroke based should be developed. A new such model36 was

based on 10-year follow-up of a large population based cohort through linkage to a database

of cardiovascular disease hospital discharge diagnoses of morbidity and mortality in Norway

1994-2009. Estimations of 10-year risks were adjusting for competing risk. The model

population consisted of participants 1994-1999 and the external validation population of

participants 2000-2003. The Norwegian model showed good validity in an external data set

and it is already included in new national preventive cardiovascular guidelines37 to help

making decisions about preventive interventions in people without known previous

cardiovascular disease.

Conclusions

Hypertension is the strongest or one of the strongest risk factors for almost all different

cardiovascular diseases acquired during life, cerebral stroke and renal failure. The distinction

between high normal blood pressure and hypertension is based on arbitrary cut-off values,

hypertension being the level at which intervention to lower blood pressure has documented

preventive benefits. The prevention of cardiovascular disease and treatment recommendations

for mildly elevated blood pressure should be related to quantification of total cardiovascular

risk. The effect of age on total cardiovascular risk models is however so strong that young

adults (particularly women) are unlikely to reach high-risk levels even when they have more

than one major risk factor and a clear increase in relative risk. Therefore age-adjusted models,

models assessing relative risks compared to peers of same age and models including thorough

assessments of target organ damage and ambulatory 24 hour blood pressure are needed

together with national models because of the large variations between countries.

10
Conflicts of Interest

SEK has received speaking and consultancy honoraria from ABDiiBRAHiM, Bayer, MSD,

and Takeda.

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Table 1 Definitions and classification of office blood pressure levels (mmHg)*

Category Systolic Diastolic
Optimal <120 and <80
Normal 120–129 and/or 80–84
High normal 130–139 and/or 85–89
Grade 1 hypertension 140–159 and/or 90–99
Grade 2 hypertension 160–179 and/or 100–109
Grade 3 hypertension ≥180 and/or ≥110
Isolated systolic hypertension ≥140 and <90

*The blood pressure category is defined by the highest level of blood pressure, whether systolic
or diastolic. Isolated systolic hypertension should be graded 1, 2, or 3 according to systolic BP
values in the ranges indicated.

16
Table 2 Factors influencing prognosis other than office blood pressure, used for
stratification of total cardiovascular risk in Figure 1

Risk factors
Male sex
Age (men ≥55 years; women ≥65 years)
Smoking
Dyslipidaemia
Total cholesterol >4.9 mmol/L and/or
Low-density lipoprotein cholesterol >3.0 mmol/L and/or
High-density lipoprotein cholesterol: men <1.0 mmol/L, women <1.2 mmol/L, and/or
Triglycerides >1.7 mmol/L
Fasting plasma glucose 5.6–6.9 mmol/L
Abnormal glucose tolerance test
Obesity (body mass index ≥30 kg/m2 (height2))
Abdominal obesity (waist circumference: men ≥102 cm; women ≥88 cm) (in Caucasians)
Family history of premature cardiovascular disease (men <55 years; women <65 years)
Asymptomatic organ damage
Pulse pressure (in the elderly) ≥60 mmHg
Electrocardiographic left ventricular hypertrophy (Sokolow–Lyon index >3.8 mV and/or
Cornell voltage duration product >244 mV*ms)
Echocardiographic left ventricular hypertrophy (men >115 g/m2; women >95 g/m2 (body
surface area))#
Carotid wall thickening (intima media thickness >0.9 mm) or plaque
Carotid–femoral pulse wave velocity >10 m/s
Ankle/brachial index <0.9
Microalbuminuria (30–300 mg/24 h), or albumin–creatinine ratio (30–300 mg/g; 3.4-34
mg/mmol) (preferentially on morning spot urine)
Diabetes mellitus
Fasting plasma glucose ≥7.0 mmol/L on two repeated measurements, and/or
HbA1c >7%, and or

17
 Post-load plasma glucose >11.0 mmol/L
Established cardiovascular or renal disease
Cerebrovascular disease: ischaemic stroke; cerebral haemorrhage; transient ischemic attack
Coronary heart disease: myocardial infarction; angina; myocardial revascularization with
percutaneous coronary intervention or coronary artery bypass graft
Heart failure, including heart failure with preserved ejection fraction
Symptomatic lower extremities peripheral artery disease
Chronic kidney disease with estimated glomerular filtration rate <30 mL/min/1.73m2;
proteinuria (>300 mg/24 h)
Advanced retinopathy: haemorrhages or exudates, papilloedema

# Risk maximal for concentric left ventricular hypertrophy: increased left ventricular mass
index with a wall thickness/radius ratio of >0.42.

18
Figure 1
Stratification of total cardiovascular risk in categories of low, moderate, high and very high
risk according to systolic blood pressure and diastolic blood pressure and prevalence of risk
factors (RF), asymptomatic organ damage (OD), diabetes, chronic kidney disease (CKD)
stage or symptomatic cardiovascular disease (CVD). Subjects with a high normal office but a
raised out-of-office blood pressure (masked hypertension) have a cardiovascular risk in the
hypertension range. Persons with a high office BP but normal out-of-office BP (white-coat
hypertension), particularly if there is no diabetes, OD, CVD or CKD, have lower risk than
sustained hypertension for the same office BP.

19
20
21