Diabetes is accompanied by more extensive atherosclerosis and inadequate compensatory remodeling. Accelerated plaque progression, despite use of medical therapies, supports the need to develop new antiatherosclerotic strategies in diabetic patients.

Aldosterone is an important mediator in the pathogenesis of heart failure, and increased plasma aldosterone levels are associated with a poor prognosis. Aldosterone-receptor blocking drugs can slow the progression of left ventricular remodeling and reduce the occurrence of sudden cardiac death. Two widely publicized clinical trials provide data demonstrating survival benefits with spironolactone and eplerenone in chronic and postinfarction heart failure. The publication of these trials has generated widespread enthusiasm for spironolactone and eplerenone, leading to the more frequent and sometimes unbridled use of these drugs in the medical community. We herein describe the likely mechanisms of action of aldosterone-receptor antagonists, discuss the existing clinical evidence supporting their use, and provide practical advice on their use in the management of patients with heart failure.

Increasing attention has been focused on the appropriate role of surrogate markers in the development of novel anti-atherosclerotic therapies. Technological advances in imaging modalities allow for visualisation of the entire arterial wall. Intravascular ultrasound (IVUS) has been increasingly employed to precisely quantify the extent of coronary atherosclerosis. Use of IVUS has provided a number of important insights into the natural history of atherosclerosis and the remodelling changes of the arterial wall in response to plaque accumulation. More recently, clinical trials have employed serial evaluations of arterial segments by IVUS to assess the impact of medical therapies.

Increasing use of established medical therapies presents a major challenge for the assessment of experimental antiatherosclerotic agents. The requirement to perform clinical trials with increasing numbers of subjects, followed for longer periods of time, creates a scenario that is largely prohibitive for the development of most new agents. Technologic advances in arterial wall imaging provide the opportunity to evaluate the impact of therapies on the natural history of atherosclerosis. The design and implementation of clinical trials that employ serial imaging of the arterial wall has become increasingly used in the development of new therapies to target atherosclerotic cardiovascular disease.

Background : The development of cardiac allograft vasculopathy (CAV) portends an adverse clinical outcome in heart transplant recipients. Previous studies of clinical predictors of CAV have investigated small cohorts and have not evaluated the volumetric extent of disease. This study determined predictors of progression of the volumetric severity of vasculopathy in a large cohort of heart transplant recipients. Methods : Serial intravascular ultrasound examinations were performed in 119 heart transplant recipients at 1 month and 1 year following transplantation. Clinical predictors of serial changes in atheroma volume were determined. In particular, the impact of donor and recipient age stratified according to the median was investigated. Results : Patients ( donor age 33.3 ± 14.2 years, recipient age 54.5 ± 12.6 years, 71.9 % male) demonstrated an increase in atheroma volume (64.2 ± 41.7 mm 3 at 1 month vs. 78.1 ± 53.4 mm 3 at 1 year, p < 0.001) and a decrease in lumen volume (334.2 ± 197.3 mm 3 at 1 month vs. 321.6 ± 187.8 mm 3 at 1 year, p = 0.001). Greater increases in atheroma volume were observed in the setting of older donor age (r = 0.24, p = 0.008), older recipient age (r = 0.23, p = 0.01) and recipients not treated with an angiotensin-converting enzyme (ACE) inhibitor (without ACE inhibitor, 21.1 ± 33.3 mm 3 vs. with ACE inhibitor, 9.1 ± 27.6 mm 3 , p = 0.03). In multivariate analysis, donor age ( p = 0.01) and the lack of treatment with an ACE inhibitor ( p = 0.02) remained independent predictors of increases in atheroma volume. Increased disease progression with age was attenuated with the use of ACE inhibitors (table ). Conclusion : Donor age and ACE inhibitor treatment are major determinants of CAV progression. This analysis suggests that treatment with ACE inhibitors would attenuate age-related progression of CAV. Large randomized clinical trials are warranted to ascertain such a beneficial effect.

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Background: While the importance of coronary artery disease in females has become increasingly recognized, little is known regarding the impact of gender with regard to changes in arterial wall dimensions with progression and regression of atherosclerosis. This study investigated the remodeling response of the artery wall accompanying changes in atheroma burden in response to use of medical therapies, stratified according to gender. Methods: 1533 patients (27.5% female) underwent serial intravascular ultrasound evaluation of a single coronary artery in the context of clinical trials that assess the impact of medical therapies on plaque progression. The relationship between gender and remodeling of the arterial wall at baseline and its serial change in association with plaque progression and regression were studied. Results: Females were older (59 v 57 years, p<0.01), had a higher body mass index (31.5 v 29.5 kg/m 2 , p<0.01), were more likely to have hypertension (86 v 71.5%, p<0.01) and metabolic syndrome (57 v 49%, p<0.01) and less likely to have a history of smoking (57.5 v 73.5%, p=0.01) and myocardial infarction (27.5 v 35.5%, p<0.01). After adjusting for body surface area, females demonstrated a trend towards smaller external elastic membrane (EEM) (226.3 v 234.3 mm 3 , p=0.09) and larger lumen (143.7 v 137.7 mm 3 , p=0.01) volumes. The remodeling index at the most diseased site did not differ between genders (0.95 v 0.95, p=0.95). No differences were observed between genders with regard to changes in EEM (−5.6 v −6.2 mm 3 , p=0.29) and lumen (−4.9 v −4.5 mm 3 , p=0.82) volumes and remodeling index (−0.02 v −0.03, p=0.43) in response to use of medical therapies. Similarly, there were no differences between genders with regard to the percentage of patients undergoing expansion (34.7 v 35.5%, p=0.86) or contraction (20.4 v 21.8%, p=0.69) of lumen volume in association with regression of atherosclerotic plaque. Conclusion: A similar pattern of remodeling of the arterial wall was observed between genders in association with serial changes in atheroscle-rotic plaque. This further highlights our understanding of the pathological interactions between atherosclerosis and the arterial wall in females.

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy. Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C < 45 mg/dL for men and < 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C < 160mg/dL) Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p<0.001) and were more likely to fit the definition of the metabolic syndrome (93 v 30.3%, p<0.001). Accelerated progression of percent atheroma volume (PAV, +0.76 v +0.01%, p=0.001) and total atheroma volume (TAV, −4.75 v −7.18 mm3, p=0.022) was observed in patients with AD. Patients with AD were less likely to undergo substantial regression (reduction in PAV >5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV >5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045). Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.