Malignant Hypertension:A Systemic Cardiovascular Disease: JACC Review Topic of the Week.

Malignant hypertension (MHT) is a hypertensive emergency with excessive blood pressure (BP) elevation and accelerated disease progression. MHT is characterized by acute microvascular damage and autoregulation failure affecting the retina, brain, heart, kidney, and vascular tree. BP must be lowered within hours to mitigate patient risk. Both absolute BP levels and the pace of BP rise determine risk of target-organ damage. Nonadherence to the antihypertensive regimen remains the most common cause for MHT, although antiangiogenic and immunosuppressant therapy can also trigger hypertensive emergencies. Depending on the clinical presentation, parenteral or oral therapy can be used to initiate BP lowering. Evidence-based outcome data are spotty or lacking in MHT. With effective treatment, the prognosis for MHT has improved; however, patients remain at high risk of adverse cardiovascular and kidney outcomes. In this review, we summarize current viewpoints on the epidemiology, pathogenesis, and management of MHT; highlight research gaps; and propose strategies to improve outcomes.

Resveratrol Protects Cardiac Tissue in Experimental Malignant Hypertension Due to Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Properties.

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-ß and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

Subretinal Deposits in Pre-eclampsia and Malignant Hypertension: Implications for Age-Related Macular Degeneration.

PURPOSE: To describe the incidence of subretinal deposits that are similar in structure and stage on OCT imaging to subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) in patients with hypertensive choroidopathy secondary to severe pre-eclampsia and malignant hypertension (MHT) and the implications of this ischemic choroidopathy for the pathophysiologic characteristics of SDDs in AMD. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Thirty-three pre-eclampsia patients and 25 MHT patients with serous retinal detachment (SRD) in at least 1 eye were included. METHODS: Serial multimodal images, including enhanced depth imaging spectral-domain OCT of eyes with hypertensive choroidopathy secondary to pre-eclampsia and MHT, were reviewed at 2 time points, the acute phase (within 4 weeks of initial hypertensive insult) and the recovery phase (beyond 4 weeks). MAIN OUTCOME MEASURES: Incidence of SDD-like lesions in patients with hypertensive choroidopathy secondary to pre-eclampsia and MHT. RESULTS: Subretinal drusenoid deposit-like lesions were observed exclusively in eyes with SRD. Serous retinal detachment occurred in 87.87% of eyes of pre-eclampsia patients and in 94% of eyes of MHT patients. Subretinal drusenoid deposit-like lesions occurred in 28.57% of all eyes with SRD, in 32.76% of eyes with SRD from the pre-eclampsia group, and in 23.40% of eyes with SRD from the MHT group. Vascular imaging suggested underlying choroidal ischemia in all patients (12 eyes) in which it was performed. CONCLUSIONS: Choroidal ischemia may be the underlying mechanism of SDD-like lesions in patients with pre-eclampsia and MHT choroidopathy. These findings potentially are of utmost importance in understanding the mechanism of the reticular macular disease subtype of AMD. Reticular macular disease is characterized by the known association of choroidal insufficiency and SDD, with choroidal insufficiency postulated, but not proven, to be causative. Pre-eclampsia and MHT choroidopathy seems to be a model for lesions similar to SDD in AMD developing based on choroidal insufficiency and, as such, may offer further insights into the pathoetiologic features of SDD in AMD.

Retinal Arteriolar Occlusions and Exudative Retinal Detachments in Malignant Hypertension: More Than Meets the Eye.

BACKGROUND: Malignant hypertension is macrovascular and microvascular endothelial injury responsible for multiple organ damage. Considering the anatomical and functional homologies between the posterior pole of the eye and the kidney, ophthalmological explorations may inform clinicians on the mechanisms underpinning concurrent kidney injury in this condition. More specifically, we investigated whether the wall-to-lumen ratio (WLR) of retinal arterioles measured by adaptive optics ophthalmoscopy could be correlated to WLR of kidney arterioles as determined by pathology. We sought to estimate the incidence of retinal arteriole occlusion a supposedly uncommon complication of malignant hypertension. METHODS: All patients hospitalized in our renal Intensive Care Unit for malignant hypertension between 2016 and 2019 were referred to ophthalmological examinations. RESULTS: Twenty-seven patients were included. Median retinal WLR was 0.39 [0.31-0.47] and was correlated with initial systolic (r = 0.56, P = 0.003) and mean blood pressure (r = 0.46, P = 0.02) upon admission. The retinal WLR was not correlated to renal pathological findings, as assessed by juxtaglomerular WLR (r = 0.38, P = 0.2), ratio of glomerulosclerosis (r = -0.39, P = 0.2), or tubulointerstitial fibrosis (r = -0.45, P = 0.08). Retinal WLR was not associated with neurological or cardiovascular end-organ damage. Branch retinal artery occlusion was detected in 18.5% of patients and exudative retinal detachment (ERD) in 29.6% of patients, without any significant correlation with canonical signs of retinal hypertension including optic disc swelling. CONCLUSIONS: In the setting of malignant hypertension, we failed to demonstrate a significant relationship between WLR and other meaningful end-organ injuries. However, branch retinal artery occlusion and ERD may have been hitherto underestimated.

The pharmacological management of malignant hypertension.

: Malignant hypertension (MHT) still remains a severe condition that requires early recognition and treatment. Over the years, the prevention and treatment of MHT have significantly advanced through the introduction of modern antihypertensive agents. However, in the absence of robust clinical trials, there remain no formal guidelines on the treatment of MHT. This review summarizes the historical background and pathophysiological evidence of MHT, which has led to common practices in its pharmacological management but can also introduce challenges. The current consensus for treatment involves early intravenous infusion of antihypertensive agents, but oral blockers of the renin-angiotensin system may improve the management of MHT, and it offers a suitable treatment option in low-income countries where the condition remains relatively prevalent.

Recovery of Renal Function in a Kidney Transplant Patient After Receiving Hemodialysis for 4 Months.

Renal transplant is the preferred choice of treatment for end-stage renal diseases. To avoid rejection, increasingly potent immunosuppressants are administered to recipients of kidney transplants. Complications, when there is excess immunosuppression, include possible lethal infections, which reduce allograft survival and compromise patient survival. When there is insufficient immunosuppression, rejections could impair allograft outcomes. Moreover, recurrent primary diseases could also threaten allograft outcomes. Here, we report a case of a patient who underwent ABO-incompatible and living-related renal transplant in which the patient experienced 7 acute kidney injury episodes, including recurrent malignant hypertension, rejection, and infections. After the patient underwent 4 months of hemodialysis (with serum creatinine level of 17 mg/dL), which was later terminated, no adverse effects were found for 1 year (serum creatinine level of 3.7 mg/dL). Therefore, renal function recovery may be longer in patients with renovascular diseases with hypertension. For recipients undergoing hemodialysis with allograft failure, we suggest that the treatment should be not completely withdrawn of immunosuppressants so that acute kidney injuries are minimized. Even after prolonged hemodialysis (eg, for 4 months), recipients may still be able to recover renal function.

Correlations Between Interleukin-11 Expression and Hypertensive Kidney Injury in a Rat Model of Renovascular Hypertension.

BACKGROUND: Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS: Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-ß1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS: Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.

[Malignant arterial hypertension (HTAM) with severe systolic dysfunction of the reversible left ventricle]. / Hipertensión arterial maligna (HTAM) con disfunción sistólica grave del ventrículo izquierdo reversible.

Malignant arterial hypertension is still present in current clinical care despite the fact that for more than three decades we have had a wide range of antihypertensive drugs to control high blood pressure. It is essential to know how to detect it in time due to its high risk to life, with poor short-term prognosis if not treated properly. It may present with nonspecific, but potentially serious, clinical symptoms or manifest clinically as a hypertensive emergency accompanied by hypertensive encephalopathy and multi-organ failure. We present a case of a 49-year-old woman, attended in our hospital who had an initial hypertension of 223/170mmHg accompanied by multi-organ failure, who progressed satisfactorily with antihypertensive treatment.

Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome.

Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model.

BACKGROUND/AIMS: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. METHODS: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinß1 in addition to Angiotensin-II and TGF-ß1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-ß1 or receptor blockers. RESULTS: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinß1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-ß1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. CONCLUSIONS: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-ß1, culminating in apoptosis and detachment of non-viable podocytes.

Malignant Hypertension Revisited-Does This Still Exist?

Malignant or accelerated hypertension is the most severe form of hypertension, defined clinically by very high blood pressure (diastolic above 130 mm Hg) accompanied by bilateral retinal hemorrhages and/or exudates, with or without papilledema. The aim of this review is to discuss if malignant hypertension still poses a clinically relevant entity and to highlight the diagnostic challenges of this form of hypertension. The substantial improvement in prognosis in patients with malignant hypertension over the last decades is well documented, but there is no strong evidence to suggest a significant change in its incidence. In fact, with the growing population and improving life expectancy, malignant hypertension is likely to become even more prevalent worldwide, especially in the developing countries with less advanced health care services. Despite simple diagnostic criteria of malignant hypertension, the diagnoses may be difficult in many patients. Malignant hypertension patients often have the diagnosis established only when the target organ damage occur. Furthermore, retrospective diagnosis is problematic, as malignant hypertensive retinopathy gradually resolves over a relatively short period of time, while persistent target organ damage will, however, lead to the development of complications and much poorer prognosis than in nonmalignant hypertension patients. Certainly, malignant hypertension still poses a clinically relevant and challenging form of hypertension and its possibility should be always considered during the assessment of patients with poorly controlled hypertension.

Use of Aldosterone Antagonists for Treatment of Uncontrolled Resistant Hypertension.

BACKGROUND: Multiple studies indicate that primary aldosteronism (PA) is common in patients with resistant hypertension, with an estimated prevalence of approximately 20%. Additional studies suggest that beyond this 20% of patients with classical PA, there is a larger proportion of patients with lesser degrees of hyperaldosteronism which contributes even more broadly to antihypertensive treatment resistance. Given these observations, it is intuitive that use of aldosterone antagonists will provide antihypertensive benefit in patients with resistant hypertension and evidence of aldosterone excess. Intriguingly, however, are clinical findings demonstrating substantive benefit of aldosterone antagonists in patients with resistant hypertension, but without demonstrative evidence of hyperaldosteronism, that is, with seemingly normal or even low aldosterone levels. CONCLUSION: Spironolactone is clearly established as the most effective fourth agent for treatment of uncontrolled resistant hypertension. Emerging observations suggest a further role of spironolactone for counteracting the effects of diet high in sodium, particularly in obese, hypertensive patients.

Epoxyeicosatrienoic acid analog attenuates the development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats.

OBJECTIVE: We evaluated the therapeutic effectiveness of a new, orally active epoxyeicosatrienoic acid analog (EET-A) in rats with angiotensin II (ANG II)-dependent malignant hypertension. METHODS: Malignant hypertension was induced in Cyp1a1-Ren-2 transgenic rats by activation of the renin gene using indole-3-carbinol (I3C), a natural xenobiotic. EET-A treatment was started either simultaneously with I3C induction process (early treatment) or 10 days later during established hypertension (late treatment). Blood pressure (BP) (radiotelemetry), indices of renal and cardiac injury, and plasma and kidney levels of the components of the renin-angiotensin system (RAS) were determined. RESULTS: In I3C-induced hypertensive rats, early EET-A treatment attenuated BP increase (to 175 ±â€Š3 versus 193 ±â€Š4 mmHg, P < 0.05, on day 13), reduced albuminuria (15 ±â€Š1 versus 28 ±â€Š2 mg/24 h, P < 0.05), and cardiac hypertrophy as compared with untreated I3C-induced rats. This was associated with suppression of plasma and kidney ANG II levels (48 ±â€Š6 versus 106 ±â€Š9 and 122 ±â€Š19 versus 346 ±â€Š11 fmol ml or g, respectively, P < 0.05) and increases in plasma and kidney angiotensin (1-7) concentrations (84 ±â€Š9 versus 37 ±â€Š6 and 199 ±â€Š12 versus 68 ±â€Š9 fmol/ml or g, respectively, P < 0.05). Remarkably, late EET-A treatment did not lower BP or improve renal and cardiac injury; indices of RAS activity were not affected. CONCLUSION: The new, orally active EET-A attenuated the development of experimental ANG II-dependent malignant hypertension, likely via suppression of the hypertensiogenic axis and augmentation of the vasodilatory/natriuretic axis of RAS.

[HYPERTENSIVE CRISIS: MODERN VIEW OF THE PROBLEM AND OPTIMIZATION OF DIAGNOSTIC AND THERAPEUTIC MODALITIES].

The data collected by Burdenko Military Hospital indicate that in the 1980s hypertensive crisis (HC) occurred in roughly 30% of the patients with AH. This value fell down to 16% by 2012, with a rise in the number of uncomplicated crises from 46 to 62%. Analysis of the causes behind these changes showed that half of the patients simply experienced an elevated arterial pressure with minimal clinical symptoms. The decrease in the number of complicated cases from 54 to 39% is doubtful bearing in mind that ICD-10 gives the status of nosological entities to complications of hypertensive crisis (stroke, myocardial infarction, etc.) but not to the HC syndrome proper requiring urgent hospitalization; due to this hypertensive crisis itself tends to be disregarded and not included in statistics. HC with acute clinically significant lesions of target organs requires intensive care or resuscitation using infusion of vasodilators and loop diuretics to stabilize arterial pressure. In case of uncomplicted HC and aggravation of hypertensive disease, the medications of choice are oral short-acting ACE inhibitors and imidazoline receptor agonists.