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CVJAFRICA • Volume 26, No 2, H3Africa Supplement, March/April 2015
Endothelial dysfunction: a unifying hypothesis for the
burden of cardiovascular diseases in sub-Saharan Africa
Uchechukwu KA Sampson, Michael M Engelgau, Emmanuel K Peprah, George A Mensah
Abstract
It is well established that the leading causes of death and
disability worldwide are cardiovascular diseases (CVD), chief
among which is ischaemic heart disease. However, it is also
recognised that ischaemic heart disease frequently coexists
with other vascular conditions, such as cerebrovascular,
renovascular and peripheral vascular disease, thus raising the
notion of a common underlying pathobiology, albeit with
differing manifestations, dictated by the implicated vascular
bed.
The understanding that common metabolic and behav-
ioural risk factors as well as social determinants and drivers
are convergent in the development of CVD evokes the idea
that the dysfunction of a common bio-molecular platform
is central to the occurrence of these diseases. The state
of endothelial activation, otherwise known as endothelial
dysfunction, occurs when reactive oxygen signalling predomi-
nates due to an uncoupled state of endothelial nitric oxide
synthase (eNOS). This can be a physiological response to
stimulation of the innate immune system or a pathophysi-
ological response triggered by cardiovascular disease risk
factors.
The conventional wisdom is that the endothelium plays an
important role in the initiation, progression and development
of CVD and other non-communicable diseases. Consequent-
ly, the endothelium has remarkable relevance in clinical and
public health practice as well as in health education, health
promotion, and disease- and risk-factor prevention strategies.
It also presents a plausible unifying hypothesis for the burden
of CVD seen globally and in sub-Saharan Africa. Impor-
tantly, the heterogeneity in individual responses to metabolic,
behavioural, and social drivers of CVD may stem from a
complex interplay of these drivers with genomic, epigenetic
and environmental factors that underpin eNOS uncoupling.
Therefore, further biomedical research into the underlying
genetic and other mechanisms of eNOS uncoupling may
enlighten and shape strategies for addressing the burden of
CVD in sub-Saharan Africa and other regions of the world.
Keywords:
endothelium, risk factors, cardiovascular disease,
public health, outcomes
Cardiovasc J Afr
2015;
26
: S56–S60
www.cvja.co.zaDOI:
10.5830/CVJA-2015-043
The understanding that hypertension, dyslipidaemia and tobacco
use are powerful risk factors for the genesis of cardiovascular
disease (CVD) has led to heavy investments in basic, clinical
and population science research targeted at the prevention,
treatment and control of CVD risk factors. Cumulative evidence
from these research investments have informed clinical practice
guidelines for the management of CVD, and largely account
for the observed 60 to 80% decline in mortality from stroke and
coronary artery disease in most developed nations in the past 50
years.
1
In the United States, we have witnessed a 68% decrease
in age-adjusted death rates from heart disease (from 56 to 18
per 10 000 population) and a 79% decrease in stroke death rates
(from 18 to four per 10 000 population) between 1958 and 2010.
2
A more recent notion based on convergent lines of
experimental and pathological evidence is that inflammation may
be the unifying factor in the pathobiology of atherothrombosis
and its complications, as well as most vascular diseases.
3
Herein,
the aggregate of clinical trial evidence led to the coronation
of statins as the undisputed heavy-weight champions of
pharmacological strategies for modulating inflammation, over
and beyond cholesterol levels, for primary and secondary
prevention of CVD events.
4
The risk factor and inflammation
hypotheses were pivotal in helping us understand the decline in
CVD mortality rates in industrialised nations. However, despite
the remarkable progress in reducing CVD mortality rates, recent
evidence indicates that ischaemic heart disease and stroke remain
leading causes of mortality in the United States and worldwide.
5
Further significant reduction in CVD mortality rates may
require new transformative paradigms that can have broad
impact. In this context, there are clues that point to the
endothelium as the expansive entity that links various vascular-
related diseases. Most CVD is caused by atherosclerosis initiated
by the loss of functional integrity of the endothelium, which
can affect various vascular beds, resulting in disease conditions
such as coronary heart disease, peripheral arterial disease and
cerebrovascular disease.
Furthermore, the fact that common social determinants, and
behavioral and metabolic risk factors attend these diseases and
other major non-communicable diseases (NCDs) suggests the
presence of a common broad unifying entity that has wide spatial
distribution. In this light, we consider the endothelium as the
unifying feature/element for the burden of CVD in sub-Saharan
Africa (SSA), because its functional integrity, which comprises
the genotypic, phenotypic and environmental context of its
existence, can predispose individuals or populations to CVD.
In this regard, we discuss the public health relevance of the
endothelium and the challenges and opportunities regarding the
quest for transformative paradigms for reducing CVD burden.
6,7
Center for Translation Research and Implementation
Science, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD, USA
Uchechukwu KA Sampson, MD, MSc, MBA, MPH, MS, FACC,
uchechukwu.sampson@nih.govMichael M Engelgau, MD, MS, FACP
Emmanuel K Peprah, PhD
George A Mensah, MD, FACC