Giuseppe Maiolino

Long-Term Control of Arterial Hypertension and Regression of Left Ventricular Hypertrophy With Treatment of Primary Aldosteronism

Primary aldosteronism (PA), a common cause of high blood pressure (BP), induces left ventricular (LV) hypertrophy and an excess rate of cardiovascular events. Whether its treatment provides long-term cure of hypertension and regression of cardiovascular damage remains uncertain. To the aim of assessing the effect of treatment of PA on BP and LV changes, we prospectively recruited 323 patients in a long-term follow-up study entailing serial echocardiography evaluations. Of them, 180 had PA and were assigned to either adrenalectomy (n=110) or medical therapy (n=70) on the basis of the adrenal vein sampling. The remaining 143 were consecutive optimally treated primary hypertensive patients. At baseline, the PA patients had more inappropriate LV mass than PH patients (27.1% versus 16.2%; P=0.020), despite similar BP values. At a median follow-up of 36 months (range, 6–225), BP was lowered (P<0.0001 versus baseline) to similar values in adrenalectomized (135±15/83±9 mm Hg), medically treated PA (133±11/83±7 mm Hg), and PH (139±15/86±9 mm Hg) patients. To this end, the adrenalectomized patients required significantly less drugs than the other groups. In PA patients, the LV mass index and the rate of LV hypertrophy fell through LV inward remodeling to the level of optimally treated PH patients, indicating that the LV work markedly decreased. Findings were similar when long-term (≥5 and ≥10 years) data were examined. Thus, an early diagnosis and a specific treatment of PA warrant normalization of BP and reversal of detrimental LV changes at long term.

The Role of Oxidized Low-Density Lipoproteins in Atherosclerosis: The Myths and the Facts

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.

Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients.

Background—Low-density lipoprotein (LDL) can be oxidatively modified by reactive oxygen species, thus generating oxLDL. The latter induce formation of specific antibodies (oxLDLAb), which are detectable in patients with atherosclerosis, in which they might play a pathogenic or a protective role. Thus, we aimed to investigate the association of antibodies with oxidized LDLs (oxLDL) (oxLDLAbs) with coronary artery disease (CAD) and acute coronary syndromes. Methods and Results—In a cross-sectional study of 529 consecutive patients undergoing quantitative coronary angiography for suspected CAD, we measured the titer of IgG oxLDLAbs by ELISA. With regression analysis techniques, we also investigated the determinants of oxLDLAb titer and the association of oxLDLAbs with CAD severity. We found no significant differences of oxLDLAb titer between groups of patients without and with different CAD severity. The oxLDLAb titer was 18.6 enzyme units (EU) (11.5 to 25.7 EU/mL) (mean, 95% CI) in patients without CAD; 16.8 EU (9.6 to 24.2 EU) in patients with stenosis <50%; and 19.9 EU (15 to 24.8 EU), 17.2 (13.8 to 20.6 EU), and 14.7 EU (12.1 to 17.3 EU) in those with in 1-, 2-, or 3-vessel ≥50% stenosis, respectively. Similarly, no differences of oxLDLAb titer between patients without and with acute coronary syndrome were found. The oxLDLAb titer correlated weakly with aging and with serum total, LDL, and HDL cholesterol and plasma homocysteine levels; however, only age and HDL cholesterol remained significant predictors of the oxLDLAb titer at a stepwise regression analysis. Conclusions—The results of this study, which was adequately powered from the statistical standpoint, provided no evidence for an association of IgG oxLDLAb titer with angiographically assessed CAD in whites.

A Meta-Analysis of Somatic KCNJ5 K+ Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma

CONTEXT Due to selection biases and inadequate statistical power, individual studies may fail to identify the clinical features of patients with an aldosterone-producing adenoma (APA) harboring KCNJ5 mutations. When this failure occurs, meta-analysis can provide significant outcome data. OBJECTIVE The objective was to determine the clinical features of these APA patients. DESIGN We systematically searched the PubMed, Scopus, Web of Science, and Cochrane databases library in January 2015 applying the Population, Intervention, Comparison, and Outcome (PICO) strategy. The standardized differences in mean and corresponding 95% confidence interval of continuous variables were computed by random-effects modeling. SETTING We performed a meta-analysis of all available studies on somatic KCNJ5 mutations in APA. PATIENTS We could identify 13 studies that recruited 1636 patients (age 49 ± 4 years; 55% females). MAIN OUTCOMES AND MEASURES Differences between APA with and without KCNJ5 mutations in gender, plasma renin activity, plasma aldosterone, tumor size, serum potassium, and blood pressure were investigated. RESULTS The overall prevalence of KCNJ5 mutations was 43% (range = 12-80%). Their rate was lower (P < .003) in the studies done in Europe, the United States, and Australia (35%) than in Japan and China (63%); it correlated (r = 0.60, P = .029) with the mean daily urinary sodium excretion. Compared with the wild-type, the mutated APA patients were younger (45 ± 3 vs 52 ± 5 yrs), had higher plasma aldosterone (42 ± 8 vs 33 ± 8 ng/dl), larger tumors (16.1 ± 6.4 versus 14.9 ± 7.4 mm), and were more often females (67% vs 44%) (all P < .05). CONCLUSIONS 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.

Plasma Adiponectin for Prediction of Cardiovascular Events and Mortality in High-Risk Patients

CONTEXT The prognostic value of plasma levels of adiponectin, an adipocytokine with antiatherogenic, antiinflammatory, and insulin-sensitizing effects, is contentious. OBJECTIVE The objective of the study was to investigate whether plasma adiponectin levels predict cardiovascular (CV) events and mortality in high-risk coronary artery disease (CAD) patients. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: We measured plasma adiponectin and examined its impact on the incidence of CV deaths and events at follow-up in the context of all potentially relevant background covariates in 712 high-risk patients of the Genetic and ENvironmental factors in Coronary Atherosclerosis study who underwent coronary angiography for suspected CAD. Based on the population plasma adiponectin median (6.38 microg/ml, interquartile range 4.2-10.2), we split the patients in a high- and a low-plasma adiponectin subgroup. After a median follow-up of 3.8 years (interquartile range 3.3-4.3 yr), outcome data were obtained in 100% of the patients and 45 CV deaths (6.4%) were recorded. Kaplan-Meier analysis unexpectedly showed a higher CV death rate in high-plasma adiponectin than low-plasma adiponectin patients. By contrast, multivariate Cox regression analysis, in which potential confounders, including ongoing medical treatment, were considered, showed no impact of plasma adiponectin on CV death. Similar negative results were obtained using the propensity score that considered all relevant covariables and medical treatment rate, which differed between the high- and low-plasma adiponectin group. CONCLUSIONS In high-risk CAD patients, plasma adiponectin above the median (6.38 microg/ml) implies a paradoxical higher risk of CV death. However, when relevant covariates that differ between high- and low-plasma adiponectin groups are considered, this association wanes, indicating that the clustering of plasma adiponectin with other covariates can abolish its impact on CV prognosis.

Galectin-3 Predicts Long-Term Cardiovascular Death in High-Risk Patients With Coronary Artery Disease

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.

Low plasma adiponectin is associated with coronary artery disease but not with hypertension in high-risk nondiabetic patients

Objective.  To investigate the association of plasma adiponectin levels with coronary artery disease (CAD), arterial hypertension (HT), and insulin resistance (IR) in nondiabetic Caucasian patients.

Hyperhomocysteinemia Is Inversely Related With Left Ventricular Ejection Fraction and Predicts Cardiovascular Mortality in High-Risk Coronary Artery Disease Hypertensives

Objective— The purpose of this study was to investigate the relationship of plasma homocysteine (tHcy) levels with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) in high-risk patients undergoing coronary angiography for suspected CAD. Methods and Results— In 936 consecutive patients, we measured LVEF, tHcy, folate levels, and quantified CAD with a modified Duke Index score. We also genotyped patients at the methylen-tetrahydrofolate-reductase 677C→T polymorphism. Hyperhomocysteinemia (HHcy) was defined as tHcy levels ≥15.46 &mgr;mol/L; total and cardiovascular mortality was assessed at follow-up that lasted 43 months (median). CAD was confirmed in 75% of patients and ruled out in the rest (non-CAD group). No relationship of HHcy with either arterial hypertension or the CAD score was found. In contrast, there was a significant inverse relationship of tHcy with LVEF in arterial hypertensive but not in normotensive patients, regardless of previous myocardial infarction. At logistic regression, HHcy was the strongest predictor (P=0.001) of a low (<40%) LVEF, followed by type 2 diabetes mellitus and cigarette smoking. At follow-up, HHcy significantly predicted cardiovascular mortality but only in the arterial hypertension subgroup. Conclusions— In arterial hypertensive but not in normotensive patients, HHcy predicts cardiovascular mortality and a low LVEF, independent of CAD and history of myocardial infarction.

Treatment of atherosclerotic renovascular hypertension: review of observational studies and a meta-analysis of randomized clinical trials

Atherosclerotic renal artery stenosis can cause ischaemic nephropathy and arterial hypertension. We herein review the observational and randomized clinical trials (RCTs) comparing medical and endovascular treatment for control of hypertension and renal function preservation. Using the Population Intervention Comparison Outcome (PICO) strategy, we identified the relevant studies and performed a novel meta-analysis of all RCTs to determine the efficacy and safety of endovascular treatment when compared with medical therapy. The following outcomes were examined: baseline follow-up difference in mean systolic and diastolic blood pressure (BP), serum creatinine, number of drugs at follow-up, incident events (heart failure, stroke, and worsening renal function), mortality, cumulative relative risk of heart failure, stroke, and worsening renal function. Seven studies comprising a total of 2155 patients (1741 available at follow-up) were considered, including the recently reported CORAL Study. Compared with baseline, diastolic BP fell more at follow-up in patients in the endovascular than in the medical treatment arm (standard difference in means -0.21, 95% confidence interval (CI): -0.342 to -0.078, P = 0.002) despite a greater reduction in the mean number of antihypertensive drugs (standard difference in means -0.201, 95% CI: -0.302 to -0.1, P < 0.001). At variance, follow-up changes (from baseline) of systolic BP, serum creatinine, and incident cardiovascular event rates did not differ between treatment arms. Thus, patients with atherosclerotic renal artery stenosis receiving endovascular treatment required less anti-antihypertensive drugs at follow-up than those medically treated. Notwithstanding this, they evidenced a better control of diastolic BP.

Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications

Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro-atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the Lp-PLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed.