Lorenzo Castello

Left ventricular mass increase is associated with cognitive decline and dementia in the elderly independently of blood pressure

AIMS Left ventricular (LV) mass increase is considered part of composite target organ damage in hypertension and an independent risk factor for cardiovascular (CV) events. This study was designed to explore whether left ventricular mass index (LVMI) is associated with cognitive decline and dementia in elderly subjects, independently of blood pressure (BP) levels. METHODS AND RESULTS Four hundred subjects (mean age 79 +/- 6 years) were studied. Left ventricular mass was measured echocardiographically in accordance with American Society of Echocardiography and normalized for body height to the 2.7 (LVMI). Global cognitive function was evaluated with the mini-mental state examination (MMSE) (maximum score 30). Dementia was defined as an MMSE score <21. Arterial stiffness was evaluated as carotid-femoral pulse wave velocity by Complior. Prevalence of hypertension was 70% and diabetes mellitus was diagnosed in 25%. No significant differences in traditional CV risk factors were observed across LVMI quartiles. Mini-mental state examination showed an inverse trend across LVMI quartiles (the higher the LVMI, the lower the MMSE, P for trend <0.05); systolic and diastolic BP levels were not different across LVMI quartiles. In multivariable logistic regression models, including age, sex, BP levels, and use of antihypertensive drugs as covariates, the highest LVMI was found to be independently associated with a two-fold higher likelihood of having dementia. The association persisted significant even after adjustment for arterial stiffness. CONCLUSION In elderly subjects, LVMI is associated with a progressive cognitive decline. This association is independent of BP levels and/or large artery stiffness.

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes

AIM Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. METHODS AND RESULTS In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-κB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2α and plasma levels of adhesion molecules. CONCLUSIONS Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.

Alzheimer’s disease and endothelial dysfunction

Recent studies suggest strong interactions between cerebrovascular and Alzheimer’s disease (AD) pathology. These conditions share common risk factors and individuals having both frequently show greater cognitive impairment than those affected by only one disease. Many studies point to early vascular dysregulations in AD. The exchange between vascular and neural cells occurs through mechanisms not completely understood, involving interactions among endothelial, glial, neuronal and smooth muscle cells within the neurovascular unit. Studies suggest that the dysregulation of the unit is likely associated with hypertension and other systemic diseases. Associations between hypertension and cognitive decline are not established, but other variables associated with hypertension could create a causal link. Many studies have lacked a consistent, quantitative neuropsychological approach for assessing cognitive functions. This approach is reductive, as the need for a formal neuropsychological assessment has gained broad recognition, and the definition of dementia has gone through revision processes, which are in progress.

C2238 Atrial Natriuretic Peptide Molecular Variant Is Associated With Endothelial Damage and Dysfunction Through Natriuretic Peptide Receptor C Signaling

Rationale: C2238 atrial natriuretic peptide (ANP) minor allele (substitution of thymidine with cytosine in position 2238) associates with increased risk of cardiovascular events. Objective: We investigated the mechanisms underlying the vascular effects of C2238-&agr;ANP. Methods and Results: In vitro, human umbilical vein endothelial cell were exposed to either wild-type (T2238)- or mutant (C2238)-&agr;ANP. Cell survival and apoptosis were tested by Trypan blue, annexin V, and cleaved caspase-3 assays. C2238-&agr;ANP significantly reduced human umbilical vein endothelial cell survival and increased apoptosis. In addition, C2238-&agr;ANP reduced endothelial tube formation, as assessed by matrigel. C2238-&agr;ANP did not differentially modulate natriuretic peptide receptor (NPR)-A/B activity with respect to T2238-&agr;ANP, as evaluated by intracellular cGMP levels. In contrast, C2238-&agr;ANP, but not T2238-&agr;ANP, markedly reduced intracellular cAMP levels in an NPR-C–dependent manner. Accordingly, C2238-&agr;ANP showed higher affinity binding to NPR-C, than T2238-&agr;ANP. Either NPR-C inhibition by antisense oligonucleotide or NPR-C gene silencing by small interfering RNA rescued survival and tube formation of human umbilical vein endothelial cell exposed to C2238-&agr;ANP. Similar data were obtained in human aortic endothelial cell with NPR-C knockdown. NPR-C activation by C2238-&agr;ANP inhibited the protein kinase A/Akt1 pathway and increased reactive oxygen species. Adenovirus-mediated Akt1 reactivation rescued the detrimental effects of C2238-&agr;ANP. Overall, these data indicate that C2238-&agr;ANP affects endothelial cell integrity through NPR-C–dependent inhibition of the cAMP/protein kinase A/Akt1 pathway and increased reactive oxygen species production. Accordingly, C2238-&agr;ANP caused impairment of acetylcholine-dependent vasorelaxation ex vivo, which was rescued by NPR-C pharmacological inhibition. Finally, subjects carrying C2238 minor allele showed early endothelial dysfunction, which highlights the clinical relevance of our results. Conclusions: C2238-&agr;ANP reduces endothelial cell survival and impairs endothelial function through NPR-C signaling. NPR-C targeting represents a potential strategy to reduce cardiovascular risk in C2238 minor-allele carriers.

Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbA1c levels

Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α (8-isoPGF2α), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF2α, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2α, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shc promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels.

Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress and Endothelial Dysfunction in Type 2 Diabetic Patients with Target HbA 1c Levels

Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α (8-isoPGF2α), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF2α, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2α, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shc promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels.

Relation between right and left ventricular function in patients undergoing chronic dialysis

Aims Occurrence of heart failure during dialysis treatment is associated with high mortality. However, mechanisms underlying left ventricular dysfunction (LVD) in these patients are still elusive. In patients undergoing haemodialysis, arteriovenous fistula (AVF) is associated with right ventricular dysfunction (RVD) and a further impairment is observed when AVF is brachial rather than radial. However, it is not known whether AVF-induced RVD is associated with an impaired left ventricular function. We studied the relation between right and left ventricular function in 120 patients undergoing either haemodialysis or peritoneal dialysis and 100 healthy age-matched controls. Methods Echocardiography including tissue Doppler imaging (TDI) was performed for both ventricles. Average myocardial performance index (MPI) of the right ventricle (RV MPI) was obtained with a multisegmental approach by using TDI. Results RVD was higher in haemodialysis than peritoneal dialysis patients and a further increase was observed in haemodialysis patients with brachial access. Interestingly, RV MPI inversely correlated with indices of both left ventricular contraction and relaxation and the association was even stronger in haemodialysis patients, particularly in those with brachial AVF. Of note, dialysis patients in the upper tertile of RV MPI showed the larger impairment of left ventricular function. Regression analyses showed that RV MPI was independently associated with reduced left ventricular function. By contrast, LVD did not significantly affect right ventricular performance in this setting. Conclusion AVF-induced RVD may contribute to LVD in dialysis patients. AVF plays a pivotal role in triggering LVD via right-to-left ventricular interdependence.

Depression is associated with increased occurrence of left ventricle concentric geometry in older subjects independently of blood pressure levels

BACKGROUND AND AIM Depression is emerging as an independent risk factor for CV events, though mechanisms underlying this association are unknown. We investigated the relation between depression and LV hypertrophy (LVH) and LV structure in a group of elderly subjects. METHODS AND RESULTS Three hundred seventy patients (mean age 79 ± 6 years) were enrolled. CV risk factors were assessed. Depression was defined as a score ≥ 6 on the 15-item Geriatric Depression Scale. On the basis of the presence of LVH and of LV relative wall thickness (RWT) 4 echocardiographic patterns of LV adaptation were defined: concentric LVH (LVH with increased RWT); eccentric LVH (LVH with normal RWT); concentric LV remodeling (no LVH with increased RWT); normal LV (no LVH with normal RWT). Prevalence of hypertension was approximately 86% and 24.7% had diabetes (n.s. depressed vs not depressed subjects). BP was comparable in these two groups (134.7 ± 1.4 vs 135.3 ± 1.8 mmHg, 77.1 ± 0.8 vs 76.3 ± 1.0 mmHg for SBP and DBP respectively). Depressed subjects (n = 165) showed a significantly higher occurrence of concentric LVH than not depressed, after adjustment for age, sex, and hypertension. Depression was associated with a 2.1 fold higher risk of showing a LV concentric, either remodeling or LVH, pattern after adjustment for age, sex, and traditional CV risk factors. CONCLUSIONS Depression is accompanied by a higher occurrence of concentric LVH in elderly subjects, independently of BP levels.

Effects of Olmesartan on Endothelial Function

It is well established that a functional endothelium contributes to maintain cardiovascular homeostasis mainly through the activity of endothelium-derived nitric oxide (NO). However, in the presence of proatherogenic risk factors including hypertension, diabetes mellitus and hypercholesterolaemia, the bioavailability of NO is reduced. This condition is defined as endothelial dysfunction and characterised by vasoconstriction, platelet aggregation, leucocyte adhesion and smooth muscle cell proliferation. A reduced availability of NO is mainly due to an increase in reactive oxygen species (ROS) production, which is responsible for NO breakdown. A large body of evidence indicates that, especially under pathological conditions, the activity of the renin-angiotensin system (RAS) is associated with angiotensin II (Ang II)-mediated ROS production, thus unbalancing endothelial function and leading to progressive vascular disease. The action of RAS is mostly linked to the downstream effects of the binding with the Ang II subtype 1 receptors (AT1). Therefore, selective RAS blockade with angiotensin receptor blockers (ARBs) is able to restore endothelial function in patients with cardiovascular risk factors. Olmesartan, an effective ARB, beyond its blood-pressure lowering effect, has been reported to affect the redox state of the vessel wall by restoring NO availability under different pathological conditions. Furthermore, it has been described that olmesartan exerts anti-inflammatory effects and increases endothelial progenitor cells. This article reviews the evidence linking olmesartan to vascular endothelial protection and examines the possibility that this effect translates to beneficial clinical properties of this ARB.

Upcoming Challenges for Training in Cardiology

The prevalence of cardiovascular disease (CVD) is increasing in industrialised societies and is dramatically progressing in developing countries. The overall burden of CVD results in reduced availability of suitable healthcare facilities. Among the multiple emergencies generated by CVD, there is certainly the threat of a significant shortage of cardiologists. Furthermore, the field of cardiology is adapting to such changes by attempting to provide more specialists and more ‘hyper-specialised’ physicians to face the growing complexity of the clinical management of CVD. Two separate educational plans for specialty schools of cardiology are proposed. The first plan is for trainees who wish to undertake general clinical cardiology, which includes specific educational pathways for clinical, intensivist and preventive cardiology. The second plan is devoted to those willing to specialise in a specific area of the field, including diagnostic and interventional cardiology, or areas that require specific skills. It is fundamental to focus on new training programmes for people willing to get involved in cardiology, paying constant attention to the evolving needs of society in terms of high-quality and cost-effective cardiovascular care. In the future, the challenge for cardiologists will be to assign more patients to a specific and integrated plan of medical care including general management and high-level diagnostics and therapy. This could result in a better and more effective management of the overall burden of CVD, especially through the formation of more skilled healthcare providers.