Malignant hypertension (MHT) is a hypertensive emergency in which blood pressure is excessively elevated and disease progression accelerates. It is characterized by acute microvascular injury and autoregulatory failure, which can affect the retina, brain, heart, kidneys, and vascular tree, and blood pressure must be lowered within a few hours to reduce the patient's risk. The absolute level of blood pressure and the rate of increase determine the risk of target organ damage. Although antiangiogenic and immunosuppressive therapy can also cause hypertensive emergencies, poor adherence to antihypertensive regimens remains the most common cause of MHT. Depending on the patient's clinical presentation, antihypertensive may be initiated with parenteral or oral therapy. Currently, there are insufficient data on evidence-based outcomes for MHT. Effective treatment improves the prognosis of MHT patients; However, patients remain at high risk of adverse cardiovascular and renal outcomes. A recent review published in J Am Coll Cardiol provides a detailed account of MHT-related etiology, pathophysiology, testing, treatment, prognosis, and challenges. In this article, we will organize the main points for the benefit of readers.
Overview of malignant hypertension
MHT was initially defined as the co-presence of severe hypertension and bilateral retinopathy. Studies have shown limited survival in patients with severe hypertension and advanced retinopathy (retinal hemorrhage and cotton wool spots with or without papilledema) in the absence of medical therapy.
The advent of effective antihypertensive drugs and screening methods to monitor the risk of cardiovascular disease (CVD) has dramatically improved the prognosis of MHT. However, due to the progression of life-threatening target organ damage, MHT should still be considered an emergency.
MHT-associated retinopathy is an important indicator of other vascular injury, and there may be co-existing acute kidney injury and thrombotic microangiopathy (TMA). Since systemic microcirculatory impairment is a pathologic feature of MHT, and patients with acute kidney injury may not have retinopathy, the term "acute hypertensive microangiopathy" may be more informative.
1. Causes and triggers
√ there is no specific blood pressure threshold that can be used to define MHT. Most often, diastolic blood pressure is below 120 mmHg, and MHT rarely occurs. In principle, any trigger that causes a sharp increase in blood pressure can cause MHT, as long as the stimulation is strong and sustained enough. √ secondary hypertension (including renal artery stenosis, mineralocorticoid excess, and pheochromocytoma) is associated with MHT but is uncommon as a single cause. √ recent findings, cytotoxic and antiangiogenic drugs have also been associated with severe hypertension and TMA. Antiangiogenic drugs (vascular endothelial growth factor and tyrosine kinase inhibitors) and immunosuppressants, including calcineurin inhibitors, have been associated with the development of severe hypertension. Case reports and series have shown that these agents are associated with the development of MHT and reversible posterior encephalopathy syndrome (PRES). √ pathophysiology of MHT involves direct vasoconstrictive effects and endothelial damage, resulting in severe hypertension with or without TMA. √ MHT is associated with IgA nephropathy and other kidney diseases, including glomerulonephritis, but it is difficult to distinguish between MHT-associated renal failure in the acute phase because proteinuria and hematuria are often associated with it. ➤ Most patients with MHT have a history of poorly controlled blood pressure or untreated essential hypertension. Poor adherence to conventional oral medications and abrupt discontinuation of medications, especially antisympathetic drugs, can lead to severe hypertension. However, although blood pressure is not controlled in many patients with hypertension, progression to MHT is uncommon.
➤ Among the factors that directly raise blood pressure, genetic variations in the renin-angiotensin system (RAS) and complement system may contribute to vascular injury and promote progression to MHT.
2. Pathophysiology
➤ Experimental evidence suggests that MHT is mostly an angiotensin-mediated type of hypertension with significant RAS activation. The degree of RAS activation is highly variable and correlates with the severity of vascular injury and the presence of TMA. RAS activation has been shown to be a secondary event triggered by vascular damage due to ischemic nephropathy and hypertension (Figure 1).
Fig.1 Pathophysiology of MHT
➤ MHT is characterized by endomysial hyperplasia of arterioles and fibrinoid necrosis caused by fibrin (and other serum proteins) leaking through the necrotic vessel wall. In the kidneys, endomysial thickening of afferent arterioles leads to luminal stenosis and RAS activation, further elevating hypertension and worsening vascular damage (Figure 2).
Fig.2 Renal biopsy (47-year-old female) with MHT, renal insufficiency, and TMA
Note: Microscopically endomysial hyperplasia with fibrinoid necrosis, proximal arteriolar occlusion (arrow), and glomerular ischemic contraction with widening of the renal sac lumen (*).
➤ While RAS activation is often causally associated with MHT, angiotensin II-mediated aldosterone secretion and sympathetic activation further accelerate blood pressure increases. Experimental evidence suggests significant upregulation of adhesion molecules, followed by monocyte and macrophage infiltration. A key regulator in MHT-induced vascular injury is nuclear factor-kB (NF-kB). The authors found that either antihypertensive therapy or direct inhibition of NF-kB, a key regulator of adhesion molecules and pro-inflammatory cytokines, attenuated MHT-associated vascular alterations and inflammation.
➤ The extent to which influx of immune cells, including monocytes, lymphocytes, and their derived cytokines, contributes to the progression of MHT is unknown. Experimental studies suggest that lymphocytes and monocytes play a causal role in hypertension, vascular remodeling, and the development of endothelial function. In renal biopsies of patients with MHT, there is significant evidence of monocytic influx and increased complement activation, suggesting that anti-inflammatory therapy may reduce MHT-induced kidney injury.
Relevant checks
➤MHT is a hypertensive emergency that requires immediate lowering of blood pressure; However, its examination should not delay treatment in any way. History and physical examination should include careful examination of target organ damage and various identifiable aetiological features of hypertension.
Table 1 Related checks
注：BNP，B型利钠肽；eGFR，估算的肾小球滤过率；LDH，乳酸脱氢酶；TTE，经胸超声心动图。
1. Fundoscopy
➤ Fundoscopy is useful in all patients with suspected MHT. However, patients with MHT may be free of retinopathy and have other target organ damage, including the brain, heart, and kidneys. Fundoscopy can also be used to distinguish MHT-associated TMA from thrombotic thrombocytopenic purpura and TMA associated with hemolytic uremic syndrome.
2. Acute renal failure with oliguria
➤ Acute renal failure with oliguria may be the main presentation. Elevated creatinine occurs in 60% to 70% of cases, suggesting progressive renal dysfunction with RAS overactivation. In the acute phase, kidney injury due to MHT is often difficult to distinguish from other causes.
3. Hypocyromemia
➤ Hypokalemia is observed in approximately 50% of patients with MHT despite the presence of renal impairment. It is caused by activation of the renin-angiotensin-aldosterone cascade caused by renal ischemia. Hyponatremia is usually the result of excessive antidiuretic hormone (ADH) secretion stimulated by angiotensin II drugs and can be severe.
4. Relevant laboratory tests
➤ Laboratory tests should include a complete blood count and peripheral smear, LDH, haptoglobin, and fibrinogen to rule out TMA. TMA may include many acute syndromes with microangiopathy, hemolytic uremic, thrombocytopenia, and organ damage, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
5. Miscellaneous
➤ Hypertensive encephalopathy with or without PRES can be diagnosed by cranial magnetic resonance imaging (MRI). ➤ TTE can replace ECG as the primary MHT assessment tool. ➤Cardiac MR, N-terminal B-type natriuretic peptide precursor (NT-proBNP), and troponin may be helpful in assessing the degree of cardiac dysfunction and/or damage.
➤ Tests for secondary hypertension should be deferred until the patient is clinically stable.
Table 2 Five scenarios for MHT are considered
MHT management
➤ Management of MHT depends primarily on the presence or absence of significant target organ damage.
➤ Antihypertensive therapy should be prompt when patients have ischemic and hemorrhagic stroke, hypertensive encephalopathy, aortic dissection, acute heart failure, acute coronary syndrome and preeclampsia; Blood pressure should be controlled intravenously with strict haemodynamic monitoring, preferably in a coronary or intensive care unit.
➤ Because patients with MHT exhibit impaired cerebral autoregulation and are at risk of cerebral vascular hypoperfusion, treatment is challenged to lower blood pressure without impairing cerebral circulation.
Fig.3 Blood pressure control strategies for patients with MHT in various clinical settings
Table 3 Clinical management issues
➤ Recent hypertension guidelines advocate the use of intravenous antihypertensive therapy, with the goal of reducing average blood pressure by no more than 25% in the first few hours to avoid cerebral hypoperfusion. Based on availability, labetalol, nicardipine, nitroglycerin, enalaprila, fenoldopam, hydralazine, and urapidil are commonly used intravenous antihypertensive agents. In the absence of data on morbidity and mortality outcomes, there is no evidence that patients are more likely to use one of these agents. After 24 to 48 hours, oral antihypertensive drugs can be started slowly and the intravenous dose can be tapered. ➤ In 45% of cases, patients may present with severe hypertension and advanced retinopathy without signs of acute target organ damage (no symptomatic heart failure, TMA, and kidney damage - KDIGO stage 3 or higher). For these patients, initiation of rapid titration oral therapy without intravenous therapy may be considered. ➤ Early application of RAS inhibitors in MHT reduces organ damage and deterioration of renal function. Treatment should be started with a low dose and increased every 6 hours if tolerated. Alternatively, treatment with a long-acting calcium-channel blocker may be started. Patients should be monitored for 2 days ≥ after blood pressure elevation to prevent a sharp drop in blood pressure. Short-acting medications, such as nifedipine taken sublingually, are contraindicated because of their unpredictable effects. The so-called clonidine load should be avoided because the adverse effects of clonidine (e.g., lethargy, confusion, and drowsiness) may be misinterpreted as MHT encephalopathy. ➤ There are no specific data on the optimal blood pressure target for oral therapy in MHT. A <25% reduction in mean blood pressure is recommended in the first few hours, with subsequent adjustments considered in the subsequent 24 to 48 hours. ➤ Intra-arterial monitoring is often preferred when a patient is admitted to the hospital for intravenous therapy, as repetitive, oscillating blood pressure measurements triggered by excessively high blood pressure values can be uncomfortable for the patient and often result in false warnings. ➤ Regardless of the mode of treatment, there is consensus on reducing blood pressure to an acceptable but abnormal level during hospitalization. The risk of hypotension at discharge should be discussed with the patient and guidance should be provided accordingly.
prognosis
➤ Despite the effectiveness of antihypertensive drugs, patients with MHT are at increased risk of cardiovascular and renal complications. In the Bordeaux cohort, 18% had end-stage renal disease, major cardiovascular events, or died after 4 years. In the Amsterdam cohort, after a median follow-up of 67 months, 15% died and 24% required renal replacement therapy. The average age of both cohorts was 40-50 years.
➤ The degree of renal dysfunction at presentation and blood pressure levels during follow-up were the main predictors of renal failure, emphasizing the importance of good blood pressure control. In a subgroup of patients with MHT with oliguric renal failure, normal kidney size, and evidence of TMA, impaired renal function may recover with appropriate control of blood pressure. ➤ Mortality from MHT is particularly high in areas of low socioeconomic status; Hypertension screening, access to antihypertensive therapy, and adherence to hypertension are poor in these areas.
➤ Given the effectiveness of antihypertensive drugs in preventing MHT and its cardiovascular and renal complications, increasing awareness, treatment, and control of hypertension in the general population will reduce not only the burden of CVD, but also the burden of MHT. Ensuring adherence to treatment is essential to avoid deterioration of end-organ function and prevent recurrence of MHT.
Current perspectives and challenges
➤ MHT, as an angiotensin-mediated extreme phenotype of hypertension, is of great interest both from a patient and research perspective.
➤ Current treatment of MHT is mainly based on consensus and pathophysiological recommendations. Evidence for MHT-related outcomes is lacking. Through timely antihypertensive therapy in the intensive care unit, the short-term survival rate of patients was significantly improved. Clinical trials are evaluating whether oral therapy is safe and effective in milder cases.
➤ In addition, other therapeutic strategies to limit target organ damage, including anticoagulation, anti-inflammatory, or antifibrotic therapy, remain to be explored. There are still many questions after the acute phase, including thresholds for antihypertensive therapy, transition to oral therapy, and follow-up monitoring.
参考文献1. Boulestreau R, Śpiewak M, Januszewicz A, et al. Malignant Hypertension:A Systemic Cardiovascular Disease: JACC Review Topic of the Week. J Am Coll Cardiol. 2024 Apr 30; 83(17):1688-1701. doi: 10.1016/j.jacc.2024.02.037. PMID: 38658108.
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