Therapeutic Advances in Cardiovascular Disease

Objective The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study was a double-blind trial in patients with hypertension at increased cardiovascular risk with carotid wall thickening and a defined atherosclerotic plaque that used non-invasive 2- and 3-dimensionaL (D) ultrasound (US), to compare the effects of a 2-year treatment based on either olmesartan medoxomil or atenolol on common carotid (CC) intima-media thickness (IMT) and plaque volume (PV).

Methods A total of 165 patients (with systolic/diastolic blood pressure 140—180/ 90—105 mmHg) were randomized to receive either olmesartan (20—40 mg/day) or atenolol (50—100 mg/day). US was performed at baseline and 28, 52 and 104 weeks. The primary efficacy outcome was the change from baseline ( Δ) in CC-IMT assessed by 2D US. Secondary outcomes included Δ PV assessed by 3D US and blood pressure (BP).

Results Olmesartan and atenolo produced comparable significant reductions in CC-IMT; mean Δ IMT (SEM) was -0.090 (0.015) mm for oLmesartan and -0.082 (0.014) mm for atenolol. Mean Δ PV was -4.4 (2.3) µl and 0.1 (1.5) µl in the olmesartan and atenolol treated subjects, respectively, without significant between-treatment differences. In the subgroup of patients with baseLine PV ≥ median (33.7 µl), significant between-treatment differences existed in Δ PV (p = 0.023), because PV regressed significantly with olmesartan (Δ PV: -11.5 (4.4) µl) but not with atenolol ( Δ PV: 0.6 (2.5) µl). In these patients BP reductions were comparabLe.

Conclusions Carotid IMT and BP decreased similarly with olmesartan and atenolol, but only olmesartan reduced the volume of larger atherosclerotic plaques.

The development of chronic kidney disease (CKD) is associated with poor outcomes largely due an increased likelihood of adverse cardiovascular events. Many factors are playing a role in cardiovascular disease in CKD including the development of vascular calcification (VC). Studies have indeed shown that the presence of VC is associated with decreased survival among patients with CKD. The pathogenesis of VC is itself multi-factorial. LikeLy playing a significant role is the altered mineral metabolism of CKD. Management of the altered mineral metabolism in CKD is quite difficult and may also play a role in the pathogenesis of VC. In this manuscript, we will review the pathogenesis of the altered mineral metabolism of CKD, its management, and how both may play a role in the development of VC.

Advances in the understanding of the mechanisms accounting for the elevation of arterial pressure in essential hypertension suggest that there is value in assessing the relative contribution of hemodynamic factors in tailoring specific therapies to control arterial pressure. The non-invasive method of impedance cardiography (ICG) to measure hemodynamic abnormalities in hypertensive patients has emerged as a valuable adjuvant in the decision-making process of selecting antihypertensive agents. The technique is both accurate and reproducible in delineating the hemodynamic mechanisms of hypertension, comparing age-and gender-related changes in hemodynamics, detecting the presence of left ventricular dysfunction, and demonstrating clinically significant improvement in blood pressure control using ICG-guided therapy.

In hypertension, Left ventricular hypertrophy is initially a useful compensatory process that represents an adaptation to increased ventricular wall stress; however, it is also the first step toward the development of overt clinical disease. For this reason most international guidelines recommend the assessment of cardiac target organ damage in hypertensive patients for cardiovascular risk stratification. It is therefore of great importance to keep in mind the strengths and weakness of the different available methods for LVH assessment.

Several methods are currently available for the assessment of LVH; however the various techniques differ in cost, availability, sensitivity and specificity. Due to its wide availability and its low cost, eLectrocardiography should be part of all routine assessment of subjects with high blood pressure; however, despite its good specificity, the sensitivity for LVH detection is low. Several other methods have been proposed for LVH detection. Cardiac magnetic resonance imaging allows 3D reconstruction of the heart with high spatial resolution; however its main limitation is represented by the relatively low availability and by its costs. Echocardiography certainly represents a valuable method for the detection of LVH in hypertensive patients, due to its wide availability and its relatively low cost. The main limitations of the technique are represented by the lower spatial resolution and reproducibility in comparison with magnetic resonance. The development of new matrix-array transducers and new software for 3D reconstruction with echocardiography make this approach particularly promising for the future; in the meantime, standard echocardiography, widely available and with low cost, will probably remain the most used tool for the evaluation of left ventricular structure and function in hypertension.

At the level of the small artery, essential hypertension is associated with eutrophic inward remodeling. This involves reduction in lumen diameter by an increase in wall thickness. Previously thought to involve either hypertrophy or hyperplasia of the vascular smooth muscle cells in the media, it is now felt to be mediated by a functional property of the wall: myogenic tone. This is the ability of an artery to contract in response to an increase in intraluminal pressure. This autoregulatory function is also vital to ensure stabilisation of distal capillary pressures and so prevent, or limit, organ damage. Indeed in any animal model studied, when myogenic autoregulation is affected, target organ damage ensues. We have also observed, in two studies, that when myogenic autoregulation is damaged in the context of hypertension, eutrophic remodeling is replaced by an outward growth of the arterial wall with preservation of lumen diameter. This is called hypertrophic remodeling and, independently, has been observed by a number of groups in small arteries from patients with type 2 diabetes. We believe that this is a key reason for the unique propensity to hypertensive injury seen in patients with diabetes. We also discuss the significance of integrins, transmembrane proteins with wide ranging functions; from initiation of cell migration to intracellular signalling. Two particular integrins, α5β1 and ανβ3, have been found to be necessary for both normal myogenic autoregulation and eutrophic remodeling and the possibility that damage to these may occur in diabetes is examined.