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An evolutionary rebus

the complex link between malaria and hypertension

Volpe, Massimoa,b; Battistoni, Allegraa

doi: 10.1097/HJH.0000000000002090
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aDepartment of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Rome

bIRCCS Neuromed, Pozzilli, Italy

Correspondence to Professor Massimo Volpe, Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy. Tel: +39 0633775989; e-mail: massimo.volpe@uniroma1.it

Over the last 10 years, the idea of a possible association between malaria infection and arterial hypertension has attracted growing scientific interest. Indeed, the significant progress made during the last 20 years by healthcare systems in low-middle income countries, namely Africa and South Asia, has promoted the collection of epidemiological data showing an alarming high prevalence of arterial hypertension among patients aged less than 50 years in these countries, compared with matched population in high-income countries [1]. If, on the one hand, this evidence is partly justifiable with the importation of unhealthy western lifestyles in developing countries, this does not account for the increase in the prevalence of arterial hypertension in the most rural regions of Africa [2].

Different scientific approaches have been attempted to investigate the possible relationship between arterial hypertension and the endemic malaria. Each one retrieves only one specific piece of evidence, thus leading to the development of difficult, often conflicting, theories overtime. First, observational studies have highlighted the role of malarial infection as a causal risk factor for the development of preeclampsia and eclampsia during pregnancy [3]. Moreover, the infection may cause low birth weight, which is known to be a risk factor for the development of arterial hypertension in youth and later in adult life [4,5]. Similarly, young patients affected by malaria end up being malnourished and defeated, both these conditions being associated with the development of hypertension in older ages [6]. This last hypothesis would fall in the paradigm that recurrent infections during lifetime, may favour the perpetuation of a pro-inflammatory state that would increase the risk of developing arterial hypertension [7].

On the other hand, epidemiological data indicate that individuals with African and South Asian genetic background have a higher prevalence of hypertension when living in malaria-free areas, compared with Caucasians [8,9]. This suggests an evolutionary role for the coexistence of malaria and arterial hypertension, as high blood pressure is maintained in these populations after living in malaria-free areas for generations. This hypothesis is supported by data showing that some polymorphisms of the angiotensin I-converting enzyme (ACE) associated with an increase in angiotensin II levels are widespread among hypertensive patients belonging to the genetic background of areas with endemic malaria [10–12]. It seems that such polymorphisms, because of the accumulation of angiotensin II, on one side promote the development of hypertension, but on another side lead to a less severe presentation of malarial infection [13]. In particular, in the presence of these polymorphisms, cerebral malaria, which is usually burdened by high mortality, seems to be uncommon. Therefore, these polymorphisms even though carrying the risk of developing hypertension, may protect from dying from malaria infection. An underlying pathophysiological explanation has found roots through in-vivo and in-vitro studies showing that angiotensin II can reduce the multiplication of the pathogen in erythrocytes and is able to reinforce the blood–brain barrier [14,15].

The study ‘Epidemiological links between malaria parasitemia and hypertension: Findings from a population-based survey in rural Côte d’Ivoire’ by Eze et al.[16] published in this issue of the Journal represents a new point of view on this intriguing and complex issue. In fact, this analysis not only shows for the first-time data from a population-based survey, but also introduces two new elements, namely the method to diagnose malaria, by rapid diagnostic test (RDT) or by thick and thin blood film microscopy, and the presence or absence of fever. These last two variables introduced in the analysis of a possible association between malaria and hypertension are both indicative of the multiple clinical manifestations of this infection, which make it difficult not only to conduct clinical studies, but even more hard to identify correct pathophysiological links.

On the basis of Eze's findings, it is hypothesized that malaria in its milder forms (only RDT positive) is negatively associated with hypertension in participants with lower body temperature. Whereas, microscopic malaria infection is positively associated with hypertension in participants with elevated body temperature. Therefore, it seems that individuals with more latent/asymptomatic malaria have a lower risk of hypertension and those with more acute/symptomatic malaria have a tendency toward higher blood pressure. Moreover, individuals having microscopic malaria with elevated body temperature have three-fold higher odds of hypertension than malaria-negatives with lower temperature. The authors of the current report suggest that people with asymptomatic malaria might have a higher likelihood of efficiently fighting infections so that the risk of developing hypertension, which may be enhanced by lifetime recurrent infections, is decreased. Moreover, they claim that the observed association of latent malaria with lower hypertension risk may suggest that in countries with endemic malaria, genetic variants have been selected, which protect humans against severe malaria and at the same time protect against high blood pressure. On the contrary, symptomatic forms of malaria may be associated with high blood pressure levels because of an individual predisposition to recurrent infections, leading to increased vascular resistance and hypertension. Alternatively, this status may reflect the manifestation of an unknown genomic association between the two diseases simply reflect a temporary clinical condition of malaria disease characterized by an increase in blood pressure.

Indeed, as stated by the Authors, such kind of population-based survey are unpowered to detect associations and even less cause–effect relationships. In fact, the cross-sectional nature of these studies, precludes any conclusion about a causal inference, therefore, making not possible to discriminate between malaria's temporary effects on blood pressure elevation from malaria's effects on the risk of developing arterial hypertension. Even though case–control studies could provide an efficient way to test hypothesis, when involving malaria, they are limited by the variability of immunologic markers to detect previous exposure to malaria [17–19]. Likewise, a life-course epidemiological approach with a longitudinal collection of events from the antenatal period or birth would allow to test hypothesis about how malaria could lead to hypertension. Unfortunately, demographic surveillance systems in low–middle-income countries were only set up in the last 15 years, and therefore may not have accumulated enough follow-up time to draw conclusions [7]. Finally, Mendelian randomization studies, where genetic polymorphisms are used as instrumental variables representing malaria exposure, would be particularly attractive for answering the question as they overcome many of the limitations of observational. An important prerequisite for using Mendelian randomization to make causal inferences about the effects of environmental exposures, is that the candidate polymorphisms should not influence the outcome through different pathways independent of the index environmental exposure [7,20].

Therefore, it seems reasonable that, to get the right relationships between malaria and hypertension, different approaches should be merged to lead to a unifying interpretation. These efforts would be justified by the widespread relevance of hypertension in low–middle-income countries and the heavy constant burden of malaria. Indeed, finding a link between them could help in the management of both, as it has been already suggested recommending the use of angiotensin II receptor antagonist to treat malaria [14].

Last, but not least, consideration is the potential meaning that the discovery of the link between malaria and hypertension could have on the understanding of the evolution of species and the pathophysiology of diseases.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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