The oxidative modification hypothesis of atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucial role in atherosclerosis initiation and progression, is still debated. This review examines the role played by oxidized LDLs in atherogenesis taking into account data derived by studies based on molecular and clinical approaches. Experimental data carried out in cellular lines and animal models of atherosclerosis support the proatherogenic role of oxidized LDLs: (a) through chemotactic and proliferating actions on monocytes/macrophages, inciting their transformation into foam cells; (b) through stimulation of smooth muscle cells (SMCs) recruitment and proliferation in the tunica intima; (c) through eliciting endothelial cells, SMCs, and macrophages apoptosis with ensuing necrotic core development. Moreover, most of the experimental data on atherosclerosis-prone animals benefiting from antioxidant treatment points towards a link between oxidative stress and atherosclerosis. The evidence coming from cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstanding some discrepancies, seems to point towards a role of oxidized LDLs in atherosclerotic plaque development and destabilization. Finally, the results of randomized clinical trials employing antioxidants completed up to date, despite demonstrating no benefits in healthy populations, suggest a benefit in high-risk patients. In conclusion, available data seem to validate the oxidative modification hypothesis of atherosclerosis, although additional proofs are still needed.

Meta-analysis showed that more pronounced hyperaldosteronism, young age, female gender, and larger tumors are the phenotypic features of APA patients with KCNJ5 mutations. No significant differences in blood pressure and serum K(+) was found, which suggests that these clinical features do not help in identifying mutated APA patients.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men ( P <0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P =0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications ( P <0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P <0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01234220.

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Context Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. Objectives To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. Design and settings In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. Results AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as &lt;25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P &lt; 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. Conclusion Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)

Objective— Galectin-3 (Gal-3) can affect atherogenesis by multiple mechanisms, but it remains scarcely known whether plasma Gal-3 levels predict cardiovascular events in patients with coronary artery disease. Therefore, we investigated if Gal-3 predicts cardiovascular death in patients with coronary artery disease of the Genetic and ENvironmental factors In Coronary Artery disease study. Approach and Results— In a prospective cohort study, we measured the plasma levels of Gal-3 in 1013 randomly selected patients who underwent coronary angiography and long-term follow-up to assess incident cardiovascular events. The primary end points were (1) cardiovascular death and (2) a composite of cardiovascular death, acute coronary syndrome, and stroke. Secondary end points entailed (1) acute myocardial infarction, (2) stroke, and (3) a composite fatal ischemic event including fatal myocardial infarction and stroke. The effect of Gal-3 on prognosis was assessed using Kaplan–Meier analysis and multivariate Cox’s regression. During long-term follow-up (median, 7.2 years), 115 cardiovascular deaths occurred (15.2%), more commonly in the high Gal-3 tertile (25.2%) than in the intermediate and the low tertiles (13.6% versus 7.5%, respectively; P <0.001). The adverse prognostic effect of high Gal-3 was confirmed in subgroup analysis of the patients with angiographically documented coronary artery disease and also of those with a normal left ventricular ejection fraction. At multivariate analysis, Gal-3 was a predictor of cardiovascular mortality (hazard ratio, 1.79; 95% confidence interval, 1.10–2.93; P =0.020) along with age, left ventricular ejection fraction, and coronary atherosclerotic burden. Conclusions— In high cardiovascular risk patients referred for coronary angiography Gal-3 is a strong independent predictor of cardiovascular death.

Our understanding of Na + homeostasis has recently been reshaped by the notion of skin as a depot for Na + accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na + could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na + excess upon high Na + intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na + in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na + excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na + excess, are both mechanistic and clinical.

A large prospective study showed that primary aldosteronism (PA) is the most prevalent form of endocrine hypertension among hypertensive patients referred to specialized hypertension centers. 1 The discrimination between its main subtypesaldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH, also referred to as idiopathic hyperaldosteronism, IHA)-is crucial, as the former is surgically curable, whereas the latter requires lifelong medical treatment.2,3 This distinction is, however, challenging because of the biochemical and pathological overlapping of APA and BAH, and the lack of well-defined functional and morphological criteria. The tissue surrounding the APA often contains multiple nodules and shows paradoxical hyperplastic changes. Furthermore, cases of multinodular adrenal hyperplasia have been reported, 4 even though their distinctive criteria from APA remain vague.Thus, a pathological continuum between APA and BAH featuring a transition from hyperplasia to a nodular phase has been proposed, 5 which suggests that pathogenic mechanisms common to these conditions exist. However, the stimuli driving this transition eluded identification thus far notwithstanding a long quest. For example, even though angiotensin-II type-1 (AT1) receptors were detected in both the normal adrenocortical zona glomerulosa and in APA, 6-8 angiotensin-II (Ang-II), one of the known secretagogues of aldosterone, is barely detectable in PA patients.Of interest, circulating autoantibodies against a specific epitope of the AT1 receptor (AT1AA) with specific agonistic activity have been suggested to play a pathogenic role in diseases characterized by vascular and renal damage, such as preeclampsia and malignant hypertension. 9-16These agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) could stimulate aldosterone secretion and trigger the development of hyperplastic changes in the zona glomerulosa in PA patients. We therefore sought for AT1AA in serum of patients with PA and investigated whether their titer was higher Abstract-The mechanisms of excess aldosterone secretion in primary aldosteronism (PA) remain poorly understood, although a role for circulating factors has been hypothesized for decades. Agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) are detectable in malignant hypertension and preeclampsia and might play a role in PA. Moreover, if they were elevated in aldosterone-producing adenoma (APA) and not in idiopathic hyperaldosteronism (IHA), they might be useful for discriminating between these conditions. To test these hypotheses, we measured the titer of AT1AA in serum of 46 patients with PA (26 with APA, 20 with IHA), 62 with primary hypertension (PH), 13 preeclamptic women, and 45 healthy normotensive blood donors.We found that the AT1AA titer was higher (P<0.