Journal of the American Heart Association

EARLY CAREER PERSPECTIVE

Malignant Hypertension: Current

Perspectives and Challenges
Romain Boulestreau , MD; Bert-­Jan H. van den Born , MD, PhD; Gregory Y. H. Lip , MD, PhD;
Ajay Gupta , MD, PhD

M
alignant hypertension is a hypertensive emer- MHT have been 2 new cases per 100 000 individuals
gency, with rapid disease progression and poor per year, with up to 4-­fold higher rates (7.3 per 100 000
prognosis. Although recognized as a separate per year) reported for self-­reported Black-­African/Afro-­
entity more than a century ago, significant knowledge Caribbean ethnicity.8 While survival after MHT has
gaps remain about its pathogenesis and treatment. considerably improved, it is still associated with signifi-
This narrative review summarizes current viewpoints, cant morbidity and mortality. Amraoui et al reported an
research gaps, and challenges with a view to pooling all-­cause mortality of 10% at 5 years in patients with
future efforts at improving treatment and prognosis. a mean age of 44 years,9 while 20% needed a kidney
About 0.5% to 3% of all emergency department replacement. Yet MHT has received little attention from
visits concern individuals who present with a sus- the medical and scientific community, and diagnostic
pected hypertensive emergency. One quarter of them and therapeutic guidelines are mainly based on con-
have a hypertensive emergency that requires urgent sensus rather than robust data, while definitions are
treatment to lower blood pressure (BP) to safe lev- not uniform (Table).2
els.1 Hypertensive emergencies are potentially life-­ In this review, we summarize current viewpoints on
threatening manifestations of hypertension, associated MHT, highlight ongoing challenges in its management,
with acute impairment of ≥1 organs including the large and propose future investigations to improve patient
arteries, heart, kidney, and brain.2 The Studying the care.
Treatment of Acute Hypertension registry reported
6.9% hospital mortality and a 37% readmission rate
90 days after discharge for a hypertensive emergency EPIDEMIOLOGICAL CHALLENGES
in 25 US institutions, between January 2007 and April While progress in the treatment and control of hyper-
2008.3 Of the different types of hypertensive emergen- tension in the population at large has resulted in a de-
cies, malignant hypertension (MHT) is characterized cline in the number of MHT cases, it still exists. Recent
by extreme BP elevations and acute microvascular evidence from the Birmingham, Bordeaux10 and
damage affecting various organs, in particular the ret- Amsterdam MHT registries suggests that the number
ina, brain, and kidney (Table).2,4–­7 Data on prevalence of cases is rising,2,8 in particular among ethnic minor-
and incidence of MHT are sparse. In large multi-­ethnic ity groups. In the Bordeaux cohort, mean inclusions
urban communities in Birmingham (United Kingdom) increased from 3 to 5 patients per year between 2001
and Amsterdam (Netherlands), overall incident rates of and 2006 to >15 after 2016. In line with this observation,
Key Words: basic science ■ clinical research ■ hypertensive emergency ■ malignant hypertension

Correspondence to: Romain Boulestreau, MD, Service de Cardiologie, Hypertension Excellence Center, Hopital Saint André, CHU de Bordeaux, 1 rue Jean
Burguet, 33000 Bordeaux, France. E-­mail: [email protected]
This manuscript was sent to Alexandros Briasoulis, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 4.
© 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative
Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use
is non-­commercial and no modifications or adaptations are made.
JAHA is available at: www.ahajournals.org/journal/jaha

J Am Heart Assoc. 2022;11:e023397. DOI: 10.1161/JAHA.121.0233971

Boulestreau et al Challenges in Malignant Hypertension Research

Table 1. Agreement and Disagreement About Malignant Hypertension Definition in Latest Hypertension Guidelines/
Consensus

Guidelines/DOI Definition Agreement and disagreement

4
ISH 2020 Severe blood pressure elevation (commonly Need for severe rise in blood pressure is commonly
>200/120 mm Hg) associated with advanced accepted, but no specific threshold has been validated
bilateral retinopathy (hemorrhages, cotton wool to date. In this context, presence of severe hypertensive
spots, papilledema) retinopathy triggers diagnosis of malignant hypertension.
This is a consensus. Whether it is mandatory in presence
of heart, kidney, brain damage, and/or thrombotic
microangiopathy is debated, as is need for bilateral retinal
involvement or presence of papilledema. Isolated dry
exudates, cotton wool spots, and hemorrhages may also
evoke severe hypertensive retinopathy
NICE 20195 Severe increase in blood pressure to Committee agreed that further research is needed in this
180/120 mm Hg or higher (and often area. No relevant clinical studies or published evidence
>220/120 mm Hg) with signs of retinal hemorrhage were identified during review process
and/or papilledema (swelling of optic nerve). Usually
associated with new or progressive target organ
damage
ESC/ESH 20186 Malignant hypertension is a hypertensive Authors stated that rate and magnitude of BP increase may
emergency characterized by presence of severe BP be at least as important as absolute BP level in determining
elevation (usually >200/120 mm Hg) and advanced magnitude of organ injury
retinopathy, defined as bilateral presence of
flame-­shaped hemorrhages, cotton wool spots, or
papilledema
European Consensus 20182 Coexistence of high BP values (often Plea for broader definition, considering gaps in evidence
>200/120 mm Hg) with advanced retinopathy and pathophysiology of disease, because retinal lesions
(defined as bilateral presence of flame-­ may be absent in patients with acute microvascular
shaped hemorrhages, cotton wool spots, damage to kidney, heart, and brain
or papilledema), acute renal failure, and/or
thrombotic microangiopathy. Because systemic
microcirculatory damage is a pathological hallmark
of malignant hypertension, and retinal lesions can
be absent in patients with acute microvascular
damage to kidney and brain, acute hypertensive
microangiopathy could be an alternative term
AHA 20177 Not mentioned Malignant hypertension not mentioned in section on
hypertensive emergencies, reflecting oversight of this form
by medical community

BP indicates blood pressure.

the number of patients on hemodialysis owing to MHT international registry should be set up to answer these
has also increased in hemodialysis registries in the questions.
Netherlands and elsewhere in Europe. MHT is prob-
ably underdiagnosed, being classified as hypertensive
emergency or being missed for several reasons: (1) CLINICAL RESEARCH CHALLENGES
BP may not be taken initially because patients often
To improve the management of patients with MHT,
present with atypical symptoms, including headache,
clinical research must be strengthened. Currently, di-
visual disturbances, or gastrointestinal complaints; (2)
agnostic criteria and treatment proposals can only be
differentiating between severe uncontrolled hyperten-
based on consensus, as no solid scientific evidence is
sion and malignant hypertension maybe challenging
available in this area.
if target organs are not systematically screened11; (3)
the clinical presentation is heterogeneous with cardiac,
renal, or neurological forms sometimes predominating Clinical Diagnosis
and involving several disciplines.10 There is debate whether the traditional definition fully
In summary, the main challenge from the clinical captures the extent of the microvascular damage as-
epidemiology point of view is to define the current inci- sociated with MHT and whether a more extensive defi-
dence and prevalence of malignant hypertension in de- nition should be used to better identify patients with
veloping countries and to specify the characteristics of acute microvascular damage. This is also reflected
patients and different care pathways involved (Figure). in current definitions which, to various degrees, tend
This may help increase awareness about the disease to go beyond the original definition (see Table). A re-
among physicians managing MHT. A prospective cent proposal is based on the presence of multiorgan

J Am Heart Assoc. 2022;11:e023397. DOI: 10.1161/JAHA.121.0233972

Boulestreau et al Challenges in Malignant Hypertension Research

EPIDEMIOLOGY
Improve disease awareness and screening

Investigate and document Describe and document Develop understanding

incidence of disease more patient characteristics of optimal care
accurately. in current context. pathways

Delineate different phenotypic Identify genetic,

traits and comorbidities environmental, and
in patients. other predisposing
Malignant factors.
Hypertension
Challenges

Revise definition and Develop risk prediction

diagnostic criteria algorithms, and
diagnostic biomarkers

Define novel therapeutic

Harmonize therapeutic targets based on
approaches new pathophysiological
insights

CLINICAL RESEARCH BASIC RESEARCH

Improve patient management Prepare for the future

Figure. Challenges in malignant hypertension research and management.

damage to define MHT, even if the fundus is normal Challenges With Heterogeneous
or data are not available.12 This definition assumes the Presentations and Associated Factors
availability of modern diagnostic methods to explore
target organ damage resulting from microcirculatory It is widely considered that any condition that results
damage, including blood and urine samples for the in a significant BP increase (such as associated kid-
evaluation of thrombotic microangiopathy and acute ney disease or renal artery stenosis, use of pressor
kidney injury, respectively, and cerebral and cardiac or toxic agent, poor adherence) may further worsen
magnetic resonance imaging.12 Future research is BP control in those who are untreated or uncontrolled
needed to establish whether patients with the classical despite medication and present them with signs and
or the new definition share the same prognosis and symptoms consistent with MHT.2 Pregnancy is another
clinical and paraclinical features. known precipitating factors.

J Am Heart Assoc. 2022;11:e023397. DOI: 10.1161/JAHA.121.0233973

Boulestreau et al Challenges in Malignant Hypertension Research

To what extent genotype and pathophysiological In summary, the basic science challenges are to
background differ between such patients remains elu- identify new pathophysiological pathways that could
sive, and whether understanding of these differences help define specific biomarkers for the risk assess-
would improve their management or lead to new ther- ment, diagnosis, and monitoring of MHT. This could
apeutic pathways is still a matter of conjecture. In the lead to targeted prevention strategies involving per-
Bordeaux cohort, most common reasons for hospital sonalized medicine and new therapeutic approaches
admission were visual impairment (25%), stroke (21%), based on specific pathophysiological data (Figure).
and heart failure (10%), while the remaining patients
were admitted for high BP (20%) and less specific
symptoms including headaches, dizziness, anorexia, CONCLUSIONS
and asthenia (17%).10 Although the original article in The management of MHT is mainly based on con-
1928 described the cardiac, neurological, and renal sensus gleaned from clinical expertise and evidence
forms of the disease,13 it is still unclear why these or- of inadequate quality. Accumulating good-­quality data
gans are particularly affected, even though autopsy through multicenter registries, comparative trials, and
studies reported generalized microvascular damage.14 centralized biobanks could help improve the assess-
ment and management of these patients. In this per-
Limited Therapeutic Options spective, the Hypertension Arterielle MAligne (HAMA)
The optimal treatment for MHT remains to be estab- project (NCT03755726) aims to become an interna-
lished. Traditional intravenous therapy reducing mean tional prospective database that would create a pow-
BP of 25% in the first hours is being challenged in un- erful platform for collaborative research on MHT.
complicated MHT. Inappropriate management may
cause microvascular damage and result in irreversible
ARTICLE INFORMATION
tissue injury, while vigorous BP-­lowering treatment has
Received July 26, 2021; accepted February 16, 2022.
resulted in ischemic stroke and death. Research has
shown that cerebral autoregulation is impaired in pa- Affiliations
tients with MHT, making them prone to cerebral hy- Cardiology Department, European Excellence Hypertension Center,
Bordeaux University Hospital, Bordeaux, France (R.B.); Pau Hospital,
poperfusion when BP is lowered. Whether intravenous Pau, France (R.B.); INSERM Unit 1034, Pessac, France (R.B.); INI-­CRCT
therapy is always necessary is a matter of debate given Network, Nancy, France (R.B.); Departments of Internal Medicine and
recent reports that oral medication can also result in Public Health, Amsterdam Cardiovascular Sciences, Amsterdam UMC,
Location AMC, Amsterdam, the Netherlands (B.H.v.d.B.); Liverpool Centre
the controlled reduction of BP.2,15 To date, no specific for Cardiovascular Science, University of Liverpool and Liverpool Heart &
study has been conducted to answer these questions. Chest Hospital, Liverpool, United Kingdom (G.Y.L.); Department of Clinical
In summary, the main clinical challenges are as Medicine, Aalborg University, Aalborg, Denmark (G.Y.L.); William Harvey
Research Institute, Queen Mary University of London, United Kingdom
follows: (1) to better understand the different pheno- (A.G.); and St Bartholomew’s & Royal London Hospital, Barts Health NHS
typic presentations of MHT, and how their identification Trust, London, United Kingdom (A.G.).
could improve patient management; (2) to update the
definition and diagnostic criteria of MHT and to improve Sources of Funding
None.
our therapeutic knowledge of it; and (3) to standardize
and simplify the guidelines in terms of administration Disclosures
route, drug type, and BP targets (Figure). None.

BASIC SCIENCE CHALLENGES REFERENCES

The reason why some patients progress to MHT and 1. Paini A, Aggiusti C, Bertacchini F, Rosei CA, Maruelli G, Arnoldi C,
others do not remains an enigma. In historical cohorts Cappellini S, Muiesan ML, Salvetti M. Definitions and epidemiological
aspects of hypertensive urgencies and emergencies. High Blood Press
of patients with untreated hypertension, only 6% to 8% Cardiovasc Prev. 2018;25:241–­244. doi: 10.1007/s4029​2-­018-­0263-­2
progress to MHT.16 Progression to MHT likely results 2. Van den Born B-­ J, Lip GYH, Brguljan-­ Hitij J, Cremer A, Segura J,
from a complex interaction of genetic and environ- Morales E, Mahfoud F, Amraoui F, Persu A, Kahan T, et al. ESC Council
on hypertension position document on the management of hyperten-
mental factors. Past evidence points to the key role of sive emergencies. Eur Heart J Cardiovasc Pharmacother. 2019;5:37–­
the renal and renin-­angiotensin system in both animal 46. doi: 10.1093/ehjcv​p/pvy032
models and in humans.17,18 However, polymorphisms 3. Katz JN, Gore JM, Amin A, Anderson FA, Dasta JF, Ferguson JJ,
Kleinschmidt K, Mayer SA, Multz AS, Peacock WF, et al. Practice pat-
in the complement system may also predispose pa- terns, outcomes, and end-­organ dysfunction for patients with acute
tients to thrombotic microangiopathy and MHT,19 while severe hypertension: the Studying the Treatment of Acute hyperTen-
the involvement of other relevant pathways involving sion (STAT) Registry. Am Heart J. 2009;158:599–­606. doi: 10.1016/j.
ahj.2009.07.020
the profibrotic and antiangiogenic systems remains 4. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran
unexplored. D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, et al. 2020

J Am Heart Assoc. 2022;11:e023397. DOI: 10.1161/JAHA.121.0233974

Boulestreau et al Challenges in Malignant Hypertension Research

International Society of Hypertension Global Hypertension practice in the emergency care setting; a retrospective cohort study. J Clin
guidelines. Hypertension. 2020;75:1334–­ 1357. doi: 10.1161/HYPER​ Hypertens. 2020;00:1–­6. doi: 10.1111/jch.14064
TENSI​ONAHA.120.15026 12. Cremer A, Amraoui F, Lip GYH, Morales E, Rubin S, Segura J, Van den
5. National Guideline Centre (UK). Hypertension in adults: diagnosis and Born BJ, Gosse P. From malignant hypertension to hypertension-­MOD:
management. In: NBK547161. 2019. a modern definition for an old but still dangerous emergency. J Hum
6. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Hypertens. 2016;30:463–­466. doi: 10.1038/jhh.2015.112
Clement DL, Coca A, de Simone G, Dominiczak A, et al. 2018 ESC/ESH 13. Kernohan JW, Keith NM, Wagener HP. The syndrome of malignant hy-
guidelines for the management of arterial hypertension. Eur Heart J. pertension. Arch Intern Med. 1928;230:141–­188.
2018;33:3021–­3104. doi: 10.1093/eurhe​artj/ehy339 14. Keith N. Classification of hypertension and clinical differentitation of
7. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Himmelfarb the malignant type. Am Heart J. 1927;11:597–­608. doi: 10.1016/S0002​-­
CD, Depalma SM, Gidding S, Jamerson KA, Jones D, et al. 2017 ACC/ 8703(27)90207​-­5
AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guide- 15. Gosse P, Boulestreau R, Brockers C, Puel C, Rubin S, Cremer A. The
line for the prevention, detection, evaluation, and management of high pharmacological management of malignant hypertension. J Hypertens.
blood pressure in adults: a report of the American College of Cardiology/ 2020;38:2325–­2330. doi: 10.1097/HJH.00000​0 0000​0 02547
American Heart Association Task Force on Clinical Practice guidelines. 16. Dranov J, Skyler JS, Gunnels JC. Malignant hypertension. Arch Intern
J Am Coll Cardio. 2018;71:127–­248. doi: 10.1016/j.jacc.2017.11.006. Med. 1974;133:791–­801. doi: 10.1001/archi​nte.1974.00320​17007​3006
8. Shantsila A, Lip GYH. Malignant hypertension revisited—­does this still 17. van den Born BJH, Koopmans RP, van Montfrans GA. The renin-­
exist? Am J Hypertens. 2017;30:543–­549. doi: 10.1093/ajh/hpx008 angiotensin system in malignant hypertension revisited: plasma renin activ-
9. Amraoui F, Van Der Hoeven NV, Van Valkengoed IGM, Vogt L, Van Den ity, microangiopathic hemolysis, and renal failure in malignant hypertension.
Born B-­J. Mortality and cardiovascular risk in patients with a history Am J Hypertens. 2007;20:900–­906. doi: 10.1016/j.amjhy​per.2007.02.018
of malignant hypertension: a case-­ control study. J Clin Hypertens 18. Lohmeier TE, Cowley AW. Hypertensive and renal effects of chronic low
(Greenwich). 2014;16:122–­126. doi: 10.1111/jch.12243 level intrarenal angiotensin infusion in the dog. Circ Res. 1979;44:154–­
10. Rubin S, Cremer A, Boulestreau R, Rigothier C, Kuntz S, Gosse P. 160. doi: 10.1161/01.RES.44.2.154
Malignant hypertension: diagnosis, treatment and prognosis with ex- 19. Timmermans SAMEG, Wérion A, Damoiseaux JGMC, Morelle J,
perience from the Bordeaux cohort. J Hypertens. 2018;36:1–­9. doi: Reutelingsperger CP, Paassen VP. Diagnostic and risk factors for com-
10.1097/HJH.00000​0 0000​0 01913 plement defects in hypertensive emergency and thrombotic microan-
11. Nijskens CM, Veldkamp SR, Van Der Werf DJ, Boonstra AH, Ten Wolde giopathy. Hypertension. 2020;75:422–­430. doi: 10.1161/HYPER​TENSI​
M. Funduscopy: yes or no? Hypertensive emergencies and retinopathy ONAHA.119.13714

J Am Heart Assoc. 2022;11:e023397. DOI: 10.1161/JAHA.121.0233975