Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids.
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ABSTRACT:
SUBMITTER: Luther JM
PROVIDER: S-EPMC8320355 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
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Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids.
Luther James M JM Wei Dawei S DS Ghoshal Kakali K Peng Dungeng D Adler Gail K GK Turcu Adina F AF Nian Hui H Yu Chang C Solorzano Carmen C CC Pozzi Ambra A Brown Nancy J NJ
Hypertension (Dallas, Tex. : 1979) 20210215 4
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Project description:BackgroundEpoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that may impact atherosclerosis, and animal experimental studies suggest EETs protect cardiac function. Plasma EETs are mostly esterified to phospholipids and part of an active pool. To address the limited information about EETs and CVD in humans, we conducted a prospective study of total plasma EETs (free + esterified) and diabetes-related CVD in the Cardiovascular Health Study (CHS).MethodsWe measured 4 EET species and their metabolites, dihydroxyepoxyeicosatrienoic acids (DHETs), in plasma samples from 892 CHS participants with type 2 diabetes. We determined the association of EETs and DHETs with incident myocardial infarction (MI) and ischemic stroke using Cox regression.FindingsDuring follow-up (median 7.5 years), we identified 150 MI and 134 ischemic strokes. In primary, multivariable analyses, elevated levels of each EET species were associated with non-significant lower risk of incident MI (for example, hazard ratio for 1 SD higher 14,15-EET: 0.86, 95% CI: 0.72-1.02; p=0.08). The EETs-MI associations became significant in analyses further adjusted for DHETs (hazard ratio for 1 SD higher 14,15-EET adjusted for 14,15-DHET: 0.76, 95% CI: 0.63-0.91; p=0.004). Elevated EET levels were associated with higher risk of ischemic stroke in primary but not secondary analyses. Three DHET species were associated with higher risk of ischemic stroke in all analyses.InterpretationFindings from this prospective study complement the extensive studies in animal models showing EETs protect cardiac function and provide new information in humans. Replication is needed to confirm the associations.FundingUS National Institutes of Health.
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Project description:BackgroundEpoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians.MethodsWe measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts.FindingsWe observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose.InterpretationIn this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms.FundingUS National Institutes of Health.
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Project description:Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase-deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90-120 minutes +530.5±384.1 pmol/L, P=0.004; Δinsulin 90-120 minutes +183.0±122.6, P=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg-1·min-1·pmol-1·L; P=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism.
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Project description:Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid through cytochrome P450 (CYP) epoxygenases have many biological functions. Importantly, CYP epoxygenase-derived EETs are involved in the maintenance of cardiovascular homeostasis. In fact, in addition to their potent vasodilating effect, EETs have potent anti-inflammatory properties, inhibit platelet aggregation, promote fibrinolysis, and reduce vascular smooth muscle cell proliferation. All EETs are metabolized to the less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Numerous evidences support the role of altered EET biosynthesis in the pathophysiology of hypertension and suggest the utility of antihypertensive strategies that increase CYP-derived EET or EET analogs. Indeed, a number of studies have demonstrated that EET analogs and sEH inhibitors induce vasodilation, lower blood pressure and decrease inflammation. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. However, the role of CYP epoxygenases and of the metabolites generated in cancer progression may limit the use of these drugs in humans.
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Project description:Primary aldosteronism (PA) is a common cause of secondary hypertension caused by excessive and inappropriate secretion of the hormone aldosterone from one or both adrenal glands. The prevalence of PA ranges from 10% in the general hypertensive population to 20% in resistant hypertension, yet only a small fraction of patients is diagnosed. Disease and symptom recognition, screening in indicated populations, multidisciplinary communication, and appropriate imaging and biochemical workup can identify patients who might benefit from effective and targeted treatment modalities. Effective treatments available include both surgical and medical approaches, usually dependent on the subtype of PA present. Our collective understanding of the pathophysiology of PA is expanded by recent developments in molecular biology and genetics, including understanding the specific somatic and germline mutations involved in pathogenesis. We review the pathophysiology, diagnostic workup, and treatment considerations for this disease process.
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Project description:Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.
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Project description:IntroductionGreater reduction in estimated glomerular filtration rate (eGFR) after specific treatment for primary aldosteronism (PA) reflects improvement in glomerular hyperfiltration associated with PA and leads to better patient outcomes. However, little is known regarding the mechanisms underlying eGFR reduction after treatment for PA.MethodsWe analyzed data from the nationwide PA registry in Japan. Patients were assigned to adrenalectomy (n = 438) and mineralocorticoid receptor (MR) antagonist (n = 746) groups. We assessed associations between changes in blood pressure (BP), plasma renin activity (PRA) and plasma aldosterone concentrations (PAC), and eGFR before and 6 months after treatment for both groups.ResultsIn a multivariable linear regression, the adjusted β values (95% confidence interval [CI]) for change in eGFR after treatment were -2.76 (-4.29, -1.22) ml/min per 1.73 m2 for PRA (per 3.2 ng/ml per hour), and 1.97 (1.08, 2.85) ml/min per 1.73 m2 for PAC (per 236.1 pg/ml) in the adrenalectomy group; and -0.45 (-0.89, -0.01) ml/min per 1.73 m2 for PRA and -0.72 (-1.62, 0.18) ml/min per 1.73 m2 for PAC in the MR antagonist group. Change in mean arterial pressure after treatment was not significantly associated with change in eGFR in either group. Changes in PRA and PAC but not BP before and 6 months after treatment for PA were associated with greater reductions in eGFR.ConclusionPost-treatment improvements in glomerular hyperfiltration may be attributable to decreased MR activity in the kidneys, but not to reductions in systemic BP.
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Project description: Not available
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Project description:Determination of plasma aldosterone concentrations (PAC) and plasma active renin concentrations (ARC) is essential for the diagnosis of primary aldosteronism (PA). In Japan, although PAC and ARC are measured by radioimmunoassay and immunoradiometric assay, respectively, non-radioisotopic methods with better detection sensitivity, measurement accuracy, and technical simplicity are needed. We developed two-site sandwich chemiluminescent enzyme immunoassays (CLEIAs) to measure both PAC and ARC using monoclonal antibodies immobilized onto ferrite particles. The results of both assays are obtained simultaneously from a single plasma sample within 30 min using a fully automated system. The novel CLEIAs were validated using plasma samples from patients with PA (n = 52) and essential hypertension (n = 23). The PAC determined by the CLEIA was significantly correlated with that measured by liquid chromatography/mass spectrometry or conventional radioimmunoassay. The ARC determined by the CLEIA was significantly correlated with that measured by immunoradiometric assay. The limits of detection of the CLEIAs for PAC and ARC were 0.1 ng/dl and 0.04 pg/ml, respectively, which were better than those of conventional methods (PAC: 2.5 ng/dl; ARC: 5 pg/ml). The PAC and PAC/ARC ratio (ARR) were significantly higher, and the ARC significantly lower, in patients with PA than in those with essential hypertension. An ARR cut-off of 1.31 ng/dl per pg/ml showed a sensitivity of 96.2% and specificity of 78.3% for PA screening. The newly developed CLEIAs for measuring PAC and ARC could provide a clinically powerful alternative to conventional methods used for hypertension screening in clinical practice.
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