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.

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension.

Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT. Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus. Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites. Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Laboratory Testing for Endocrine Hypertension: Current and Future Perspectives.

BACKGROUND: Secondary hypertension (SH) is a form of high blood pressure caused by an identifiable underlying condition. Although, it accounts for a small fraction of the overall hypertensive population, detection and management of SH is of utmost importance, because SH phenotypes carry a high cardiovascular risk and can possibly be cured by timely treatment. CONTENT: This review focuses on the endocrine causes of SH, such as primary aldosteronism, Cushing syndrome, thyroid disease, pheochromocytoma and paraganglioma, acromegaly, and rare monogenic forms. It discusses current biomarkers, analytical methods, and diagnostic strategies, highlighting advantages and limitations of each approach. It also explores the emerging -omics technologies that can provide a comprehensive and multidimensional assessment of SH and its underlying mechanisms. SUMMARY: Endocrine SH is a heterogeneous and complex condition that requires proper screening and confirmatory tests to avoid diagnostic delays and improve patient outcomes. Careful biomarker interpretation is essential due to potential interferences, variability, and method-dependent differences. Liquid chromatography-tandem mass spectrometry is a superior method for measuring low-concentration hormones and metabolites involved in SH, but it requires expertise. Omics approaches have great potential to identify novel biomarkers, pathways, and targets for SH diagnosis and treatment, especially considering its multifactorial nature.

A European Renal Association (ERA) synopsis for nephrology practice of the 2023 European Society of Hypertension (ESH) Guidelines for the Management of Arterial Hypertension.

In June 2023, the European Society of Hypertension (ESH) presented and published the new 2023 ESH Guidelines for the Management of Arterial Hypertension, a document that was endorsed by the European Renal Association (ERA). Following the evolution of evidence in recent years, several novel recommendations relevant to the management of hypertension in patients with chronic kidney disease (CKD) appeared in these Guidelines. These include recommendations for target office BP < 130/80 mmHg in most and against target office BP < 120/70 mmHg in all patients with CKD; recommendations for use of spironolactone or chlortalidone for patients with resistant hypertension with eGFR higher or lower than 30 ml/min/1.73 m2, respectively; use of an SGLT2-inhibitor for patients with CKD and eGFR ≥20 ml/min/1.73 m2; use of finerenone for patients with CKD, type 2 DM, albuminuria, eGFR ≥25 ml/min/1.73 m2 and serum potassium < 5.0 mmol/L; and revascularization in patients with atherosclerotic renovascular disease and secondary hypertension or high-risk phenotypes if stenosis ≥ 70% is present. The present report is a synopsis of sections of the ESH Guidelines that are relevant to the daily clinical practice of nephrologists, prepared by experts of ESH and ERA. The sections summarized are those referring to the role of CKD in hypertension staging and cardiovascular risk stratification, the evaluation of hypertension-mediated kidney damage and the overall management of hypertension in patients with CKD.

Risks and benefits of renal artery stenting in fibromuscular dysplasia: Lessons from the ARCADIA-POL study.

INTRODUCTION: Although renal stenting is the standard revascularization method for atherosclerotic renal artery stenosis (RAS) (FMD-RAS), stenting in fibromuscular dysplasia (FMD) RAS is usually limited to periprocedural complications of angioplasty and primary arterial dissection. The main aim of the study was to retrospectively analyze the immediate and long-term results of renal stenting versus angioplasty in patients with FMD. METHODS: Of 343 patients in the ARCADIA-POL registry, 58 patients underwent percutaneous treatment due to FMD-RAS (in 70 arteries). Percutaneous transluminal renal angioplasty (PTRA) was performed as an initial treatment in 61 arteries (PTRA-group), whereas primary stenting was undertaken in nine arteries (stent-group). Stent-related complications were defined as: in-stent restenosis > 50% (ISR); stent fracture; under-expansion; or migration. RESULTS: In the PTRA-group, the initial restenosis rate was 50.8%. A second procedure was then performed in 22 arteries: re-PTRA (12 arteries) or stenting (10 arteries). The incidence of recurrent restenosis after re-PTRA was 41.7%. Complications occurred in seven of 10 (70%) arteries secondarily treated by stenting: two with under-expansion and five with ISR. In the stent-group, stent under-expansion occurred in one case (11.1%) and ISR in three of nine stents (33.3%). In combined analysis of stented arteries, either primarily or secondarily, stent-related complications occurred in 11/19 stenting procedures (57.9%): three due to under-expansion and eight due to ISRs. Finally, despite several revascularization attempts, four of 19 (21%) stented arteries were totally occluded and one was significantly stenosed at follow-up imaging. CONCLUSION: Our study indicates that renal stenting in FMD-RAS may carry a high risk of late complications, including stent occlusion. Further observational data from large-scale registries are required.

Impact of public restrictive measures on hypertension during the COVID-19 pandemic: existing evidence and long-term implications.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first identified in December 2019 and emerged into an ongoing global pandemic. Both the pandemic itself and the associated public restrictive measures of social mobility established with different intensity over different periods in various countries have significantly affected the everyday activities and lifestyles of people all over the world. The impact of lockdown and quarantine measures on hypertension incidence and blood pressure (BP) control is an important topic that requires further investigation. The aim of this review is: a) to present the current evidence regarding the actual effects of public restrictive measures on BP levels and control, originating primarily from studies investigating the impact of public restrictive measures on BP control with the use of various BP phenotypes; b) to summarize the possible pandemic-related effects of factors known to affect BP levels, including both traditional (e.g. dietary habits including alcohol and sodium intake, body weight, smoking and physical activity) and non-traditional (e.g. sleep patterns, air pollution, environmental noise, delayed diagnosis and medication adherence) ones.

Short- and long-term survival of patients hospitalized for COVID-19 in relation to cardiovascular risk factors and established cardiovascular disease: the Cor-Cardio study.

INTRODUCTION: The clinical presentation of COVID­19 may range from asymptomatic infection to severe disease. Previous studies reported a relationship between the course of COVID­19 and a history of cardiovascular (CV) disease (CVD). OBJECTIVES: We aimed to analyze the influence of CV risk factors, established CVD, and treatment with CV drugs on short- and long­term survival in patients hospitalized for COVID­19. PATIENTS AND METHODS: We retrospectively analyzed data of patients hospitalized in 13 COVID­19 hospitals in Poland (between March and October 2020). Individual deaths during the follow­up were recorded until March 2021. RESULTS: Overall, 2346 patients with COVID­19 were included (mean age, 61 years; 50.2% women). A total of 341 patients (14.5%) died during the hospitalization, and 95 (4.7%) died during the follow­up. Independent predictors of in­hospital death were older age, a history of established CVD, heart failure, and chronic kidney disease (CKD), while treatment with renin­angiotensin­aldosterone system blockers or statins was associated with a lower risk of death during hospitalization. Factors that independently predicted death during the follow­up were older age, a history of established CVD, CKD, and a history of cancer. The presence of CV risk factors did not increase the odds of death either in the hospital or during the follow­up. Of note, higher systolic blood pressure and oxygen blood saturation on admission were associated with better short- and long­term prognosis. CONCLUSION: Established CVD and CKD were the main predictors of mortality during both the hospitalization and the follow­up in the patients hospitalized for COVID­19, while the use of CV drugs during the hospitalization was associated with better prognosis. The presence of CV risk factors did not increase the odds of in­hospital and postdischarge death.

Atherosclerotic renovascular disease and cardiovascular risk: new concepts.

Renal vascular hypertension (RVHT) is one of the most common secondary forms of hypertension. It is estimated that 1% to 5% of all cases of hypertension can be attributed to RVHT. RVHT is generally caused by progressive stenosis of the renal artery most often due to atherosclerosis, and less often caused by fibromuscular dysplasia. Atherosclerotic renal artery stenosis (ARAS) can lead to the development of resistant hypertension and can also cause progressive impairment of renal function. ARAS can also result in serious cardiac complications, such as flash pulmonary edema or congestive heart failure. Most patients with ARAS are characterized by the presence of left ventricular hypertrophy and diastolic dysfunction. The disease progression is associated with an increase in left ventricular mass index and cardiac dilatation. Atherosclerotic renovascular disease is recognized as a relevant risk factor for cardiovascular morbidity and mortality. Studies published so far documented ARAS as a predictor of higher cardiovascular risk and showed that mortality after incidental ARAS diagnosis is much higher than that observed in the general population. Proper recognition of the patients with ARAS who would benefit from interventional treatment is crucial, particularly for identification of patients with true resistant hypertension, flash pulmonary edema, and progressive impairment of renal function.

Whole blood methylome-derived features to discriminate endocrine hypertension.

BACKGROUND: Arterial hypertension represents a worldwide health burden and a major risk factor for cardiovascular morbidity and mortality. Hypertension can be primary (primary hypertension, PHT), or secondary to endocrine disorders (endocrine hypertension, EHT), such as Cushing's syndrome (CS), primary aldosteronism (PA), and pheochromocytoma/paraganglioma (PPGL). Diagnosis of EHT is currently based on hormone assays. Efficient detection remains challenging, but is crucial to properly orientate patients for diagnostic confirmation and specific treatment. More accurate biomarkers would help in the diagnostic pathway. We hypothesized that each type of endocrine hypertension could be associated with a specific blood DNA methylation signature, which could be used for disease discrimination. To identify such markers, we aimed at exploring the methylome profiles in a cohort of 255 patients with hypertension, either PHT (n = 42) or EHT (n = 213), and at identifying specific discriminating signatures using machine learning approaches. RESULTS: Unsupervised classification of samples showed discrimination of PHT from EHT. CS patients clustered separately from all other patients, whereas PA and PPGL showed an overall overlap. Global methylation was decreased in the CS group compared to PHT. Supervised comparison with PHT identified differentially methylated CpG sites for each type of endocrine hypertension, showing a diffuse genomic location. Among the most differentially methylated genes, FKBP5 was identified in the CS group. Using four different machine learning methods-Lasso (Least Absolute Shrinkage and Selection Operator), Logistic Regression, Random Forest, and Support Vector Machine-predictive models for each type of endocrine hypertension were built on training cohorts (80% of samples for each hypertension type) and estimated on validation cohorts (20% of samples for each hypertension type). Balanced accuracies ranged from 0.55 to 0.74 for predicting EHT, 0.85 to 0.95 for predicting CS, 0.66 to 0.88 for predicting PA, and 0.70 to 0.83 for predicting PPGL. CONCLUSIONS: The blood DNA methylome can discriminate endocrine hypertension, with methylation signatures for each type of endocrine disorder.

Preanalytical Pitfalls in Untargeted Plasma Nuclear Magnetic Resonance Metabolomics of Endocrine Hypertension.

Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.

Preanalytical Considerations and Outpatient Versus Inpatient Tests of Plasma Metanephrines to Diagnose Pheochromocytoma.

CONTEXT: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. OBJECTIVE: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. METHODS: Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. RESULTS: Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. CONCLUSION: Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.

Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) have a heterogeneous prognosis, the basis of which remains unclear. We, therefore, assessed disease-specific survival (DSS) and potential predictors of progressive disease in patients with PPGLs and head/neck paragangliomas (HNPGLs) according to the presence or absence of metastases. METHODS: This retrospective study included 582 patients with PPGLs and 57 with HNPGLs. DSS was assessed according to age, location and size of tumours, recurrent/metastatic disease, genetics, plasma metanephrines and methoxytyramine. RESULTS: Among all patients with PPGLs, multivariable analysis indicated that apart from older age (HR = 5.4, CI = 2.93-10.29, P < 0.0001) and presence of metastases (HR = 4.8, CI = 2.41-9.94, P < 0.0001), shorter DSS was also associated with extra-adrenal tumour location (HR = 2.6, CI = 1.32-5.23, P = 0.0007) and higher plasma methoxytyramine (HR = 1.8, CI = 1.11-2.85, P = 0.0170) and normetanephrine (HR = 1.8, CI = 1.12-2.91, P = 0.0160). Among patients with HNPGLs, those with metastases presented with longer DSS compared to patients with metastatic PPGLs (33.4 versus 20.2 years, P < 0.0001) and only plasma methoxytyramine (HR = 13, CI = 1.35-148, P = 0.0380) was an independent predictor of DSS. For patients with metastatic PPGLs, multivariable analysis revealed that apart from older age (HR = 6.2, CI = 3.20-12.20, P < 0.0001), shorter DSS was associated with the presence of synchronous metastases (HR = 4.9, CI = 2.78-8.80, P < 0.0001), higher plasma methoxytyramine (HR = 2.4, CI = 1.44-4.14, P = 0.0010) and extensive metastatic burden (HR = 2.1, CI = 1.07-3.79, P = 0.0290). CONCLUSIONS: DSS among patients with PPGLs/HNPGLs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PPGLs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients.

Atherosclerotic cardiovascular disease burden in patients with familial hypercholesterolemia: interpretation of data on involvement of different vascular beds.

Familial hypercholesterolemia (FH) is a monogenic, autosomal dominant disorder that results in a rise of low­density lipoprotein cholesterol (LDL­C) and markedly increased risk of premature atherosclerotic cardiovascular disease. FH is relatively common, treatable, and its clinical course can be improved through early detection and timely initiation of lipid­lowering medications. The clinical picture of FH is highly variable, with a heterogeneous phenotype even within a single family, ranging from patients with very early onset of major cardiovascular events to those who do not develop overt cardiovascular disease even at an old age. We summarized studies indicating that atherosclerotic involvement in the coronary arteries and lower extremities is higher in FH patients than in the general population. There is a paucity of data regarding the relationship between FH and the incidence of atherosclerosis in other vascular beds. There are no studies systematically evaluating several vascular beds in asymptomatic patients with FH. Providing a systematic characteristic of patients with FH with respect to the presence and extent of atherosclerotic lesions in different vascular beds may have implications for daily practice not only for patients with FH but also for a larger number of patients with very high plasma LDL­C concentrations.

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma.

PURPOSE: Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. DESIGN: A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. METHODS: Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. RESULTS: Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. CONCLUSIONS: Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.

Fibrin clot properties and fibrinolysis in patients with endocrine hypertension due to aldosterone or catecholamines excess.

OBJECTIVE: The aim of the study was to investigate a new possible background of increased risk of cardiovascular events in two forms of endocrine hypertension: in primary aldosteronism (PA) and pheochromocytoma/paraganglioma (PPGL) in comparison to essential hypertension (EHT). CONTEXT: Prothrombotic properties of the fibrin clot structure, impaired fibrinolysis and enhanced thrombin generation have been reported to be associated with increased cardiovascular risk. DESIGN: Patients with PA and PPGL were evaluated at baseline and re-evaluated 3 months after causative treatment. At baseline PA and PPGL patients were compared to matched EHT patients and to healthy controls. PATIENTS: The study included 35 patients with PA, 16 patients with PPGL and two reference groups of patients with EHT (32 and 22 patients) and healthy controls (35 and 23 subjects). MEASUREMENTS: All subjects underwent evaluation according to the study protocol that included plasma fibrin clot permeability (Ks), clot lysis time, endogenous thrombin potential. RESULTS: There were no differences in clot structure and fibrinolytic activity in PA and PPGL patients as compared to matched patients with EHT, whereas all hypertensive groups were characterized by more compact fibrin clot structure, faster clot formation and enhanced thrombin generation in comparison to healthy controls. Both in PA and PPGL patients, fibrin clot properties and fibrinolytic parameters remained stable after the causative treatment. CONCLUSIONS: Patients with PA and PPGL are at a prothrombic state comparable to patients with EHT. The results suggest the higher risk of cardiovascular events observed in hypertensive PA and PPGL as compared to EHT is not mediated through investigated prothrombic mechanisms.