Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly

Elderly patients (age ≥65 years) with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target) provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease) have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes

Valsartan in the Treatment of Heart Attack Survivors

Survivors of myocardial infarction (MI) are at high risk of disability and death. This is due to infarct-related complications such as heart failure, cardiac remodeling with progressive ventricular dilation, dysfunction, and hypertrophy, and arrhythmias including ventricular and atrial fibrillation. Angiotensin (Ang) II, the major effector molecule of the renin–angiotensin–aldosterone system (RAAS) is a major contributor to these complications. RAAS inhibition, with angiotensin-converting enzyme (ACE) inhibitors were first shown to reduce mortality and morbidity after MI. Subsequently, angiotensin receptor blockers (ARBs), that produce more complete blockade of the effects of Ang II at the Ang II type 1 (AT1) receptor, were introduced and the ARB valsartan was shown to be as effective as an ACE inhibitor in reducing mortality and morbidity in high-risk post-MI suvivors with left ventricular (LV) systolic dysfunction and and/or heart failure and in heart failure patients, respectively, in two major trials (VALIANT and Val-HeFT). Both these trials used an ACE inhibitor as comparator on top of background therapy. Evidence favoring the use of valsartan for secondary prevention in post-MI survivors is reviewed

Modification of left ventricular geometry and function during healing after acute myocardial infarction

Increased left ventricular (LV) size and deformation of LV geometry are associated with LV dysfunction. Regional shape distortion (RSD), detected on two-dimensional echocardiography (2D-Echo) after acute myocardial infarction (MI), is associated with poor outcome. Two hypotheses were tested: i) early RSD of the asynergic infarct zone after MI is followed by progressive global LV dilatation, remodelling towards a spheroidal shape, and more LV dysfunction; and ii) the progressive remodelling of LV geometry spans the phases of early infarction and healing and may be modified by early and prolonged therapies applied over the phases of infarction and healing. A bench to bedside approach was used, with concurrent studies in a dog model of healing over 6 weeks after MI and patients with first MI's. Computer- assisted analysis of the 2D-Echo images with 3D reconstruction was used to quantify LV asynergy (akinesis + dyskinesis), LV volumes, LV ejection fraction, RSD bulge and global LV shape. The animal studies showed that collagen deposition during healing after MI increases progressively, reaching a plateau around 2 weeks, and deposition of collagen in already dilated infarct zones is followed by late thinning and further RSD associated with LV aneurysms. Importantly, serial 2D-Echo tracked the in- vivo changes in LV geometry and function and showed greater RSD and LV dysfunction with anterior than inferior MI, and with transmural MI than nontransmural MI. Other studies showed: i) lower LV resistance to distension and rupture in infarcted hearts; ii) marked extracellular matrix (ECM) disruption and RSD in transmural MI; ill) delayed effects on LV remodelling after infarct-limiting therapies given during acute MI; iv) loss of beneficial effects of the vasodilator nitroglycerin (NTG) with hypotension induced by high doses during acute MI; v) decreased wall stress by prolonged LV unloading after MI, with nitrates (eccentric dosing) and angiotensin-converting enzyme (ACE) inhibitors, limited early RSD and progressive LV remodelling and dysfunction; this effect was greater with therapy over 6-weeks than just over the first 2 weeks; vi) late reperfusion limited early RSD and adverse LV remodelling, and preserved ECM in the epicardial rim; vii) the resistance of the healed left ventricle to distension and rupture was further reduced by prolonged anti-inflammatory therapy (ibuprofen); viii) prolonged ACE inhibitor therapy decreases infarct collagen, which may be harmful under certain conditions. The clinical studies with serial 2D-Echo showed that systematic tomographic imaging could provide quantitative data on regional and global LV geometry and function including the degree of RSD (depth, area, and volume). An early 2D-Echo not only provided diagnostic data on LV thrombi and complications of MI, but the extent of LV asynergy on the initial 2D-Echo predicted outcome at 3 months and 1 year. Importantly, the degree of RSD on the initial 2D-Echo predicted patients at high risk of adverse remodelling with infarct expansion, greater LV dysfunction, progressive LV dilatation, and poor outcome at 1 year. Survivors of MI with > 18% LV asynergy and significant RSD on a baseline 2D Echo were at increased risk of topographic deterioration on exercise programs. Anti-inflammatory therapy after MI resulted in more RSD and adverse remodelling. Short-term LV unloading with low-dose intravenous NTG therapy during the acute MI, as well as prolonged nitrate (eccentric dosing) and captopril therapy during healing over 6 weeks after MI, improved 2D-Echo indexes of LV geometry and function, decreased complications and improved outcome. Acute thrombolytic therapy also limited LV remodelling after MI. In all these studies, the degree of RSD and severity of LV dysfunction were greater with anterior than inferior MI, and with Q-wave than non-Q wave MI. In Conclusion, the overall results indicate that early RSD in the infarct zone leads to progressive global LV dilatation, LV dysfunction and poor outcome and the changes in LV geometry and function can be quantified by serial quantitative 2D-Echo imaging. Marked RSD is associated with early ECM disruption and aneurysm formation after transmural MI. During healing, infarct zones may be thinned and dilated before the collagen plateau, and collagen deposition into these zones result in further RSD and chronic aneurysms. Prolonged anti-remodelling therapy during healing, with agents that decrease wall stress without damaging the ECM, or decreasing infarct collagen, or causing infarct thinning, or impairing healing, might be more effective for reducing RSD, LV aneurysm, global dilatation and poor outcome. The 2D-Echo measurement of RSD early after MI might be potentially important for stratifying patients according to their topographic status and for the objective assessment of the effects of anti-remodelling strategies during healing after MI

Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy

EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI). The EphA2-receptor (EphA2-R) potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-κB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT) and EphA2-R-mutant (EphA2-R-M) mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2-R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-κB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF-κB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post-MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy

The Influence of Recovery and Training Phases on Body Composition, Peripheral Vascular Function and Immune System of Professional Soccer Players

Professional soccer players have a lengthy playing season, throughout which high levels of physical stress are maintained. The following recuperation period, before starting the next pre-season training phase, is generally considered short but sufficient to allow a decrease in these stress levels and therefore a reduction in the propensity for injury or musculoskeletal tissue damage. We hypothesised that these physical extremes influence the body composition, blood flow, and endothelial/immune function, but that the recuperation may be insufficient to allow a reduction of tissue stress damage. Ten professional football players were examined at the end of the playing season, at the end of the season intermission, and after the next pre-season endurance training. Peripheral blood flow and body composition were assessed using venous occlusion plethysmography and DEXA scanning respectively. In addition, selected inflammatory and immune parameters were analysed from blood samples. Following the recuperation period a significant decrease of lean body mass from 74.4±4.2 kg to 72.2±3.9 kg was observed, but an increase of fat mass from 10.3±5.6 kg to 11.1±5.4 kg, almost completely reversed the changes seen in the pre-season training phase. Remarkably, both resting and post-ischemic blood flow (7.3±3.4 and 26.0±6.3 ml/100 ml/min) respectively, were strongly reduced during the playing and training stress phases, but both parameters increased to normal levels (9.0±2.7 and 33.9±7.6 ml/100 ml/min) during the season intermission. Recovery was also characterized by rising levels of serum creatinine, granulocytes count, total IL-8, serum nitrate, ferritin, and bilirubin. These data suggest a compensated hypo-perfusion of muscle during the playing season, followed by an intramuscular ischemia/reperfusion syndrome during the recovery phase that is associated with muscle protein turnover and inflammatory endothelial reaction, as demonstrated by iNOS and HO-1 activation, as well as IL-8 release. The data provided from this study suggest that the immune system is not able to function fully during periods of high physical stress. The implications of this study are that recuperation should be carefully monitored in athletes who undergo intensive training over extended periods, but that these parameters may also prove useful for determining an individual's risk of tissue stress and possibly their susceptibility to progressive tissue damage or injury