Cardiovascular therapy

The contribution of adult stem cells to cardiac repair is mostly ascribed to an indirect paracrine effect, rather than to their actual engraftment and differentiation into new contractile and vascular cells. This effect consists in a direct reduction of host cell death, promotion of neovascularization, and in a " bystander effect " on local inflammation. A number of cytokines secreted by adult stem/progenitor cells has been proposed to be responsible for the consistent beneficial effect reported in the early attempts to deliver different stem cell subsets to the injured myocardium. Aiming to maximize their beneficial activity on the diseased myocardium, the genetic modification of adult stem cells to enhance and/or control the secretion of specific cytokines would turn them into active drug delivery vectors. On the other hand, engineering biocompatible scaffolds as to release paracrine factors could result in multiple advantages: (1) achieve a local controlled release of the drug of interest, thus minimizing off-target effects, (2) enhance stem cell retention in the injured area and (3) boost the beneficial paracrine effects exerted by adult stem cells on the host tissue. In the present review, a critical overview of the state-of-the-art in the modification of stem cells and the functionalization of biocompatible scaffolds to deliver beneficial soluble factors to the injured myocardium is offered. Besides the number of concerns to be addressed before a clinical application can be foreseen for such concepts, this path could translate into the generation of active scaffolds as smart cell and drug delivery systems for cardiac repair. Current Medicinal Chemistry, 2013, Vol. 20, No. 1

Zofenopril is a lipophilic, sulfhydryl group-containing angiotensin-converting enzyme (ACE)-inhibitor, characterized by wide tissue distribution, long duration of action, and pleiotropic effects on endothelial dysfunction. Its clinical efficacy and safety have been described in the four randomized controlled trials of the SMILE program, which globally enrolled more than 3600 patients in post-acute myocardial infarction (AMI) setting. The SMILE-4 study specifically selected patients with left ventricular dysfunction at admission, and compared the effects of zofenopril or ramipril in combination with acetylsalicylic acid (ASA). Zofenopril demonstrated its superiority over ramipril in reducing the combined occurrence of death or hospitalization for cardiovascular causes both in the overall population included in the original study and in subgroups of patients at highest risk, namely hypertensive and diabetic subjects. The effects of the early treatment with zofenopril were sustained over time, and, after 5 years of follow-up, zofenopril increased the survival likelihood and reduced the hospitalization rate. Compared to ramipril, zofenopril was cost-effective with a number to treat of 13 and an incremental cost-effectiveness ratio (ICER) of 2125.45 euros for any additional event prevented. Furthermore, in real-world settings, zofenopril decreased the risk of death in patients with heart failure, particularly in men, and in subjects older than 76 years or with ejection fraction lower than 54%. These results support the early use of zofenopril immediately after AMI, even in the presence of comorbidities, and its maintenance over time to reduce the risk of heart failure.

Cardiovascular events in hypertensives are associated with elevated average blood pressure (BP) and higher short-term BP variability (V), but little is known on treatment effects on BPV and on how to assess changes in short-term BPV. Aim of our study was to address the methodology of short-term BPV assessment and its reduction by Lercanidipine (L) or Enalapril (E) and their combination, through analysis of 24-hour ambulatory BP recordings from two studies including subjects of different age. Study-1: 64 middle-age hypertensives (52.9 ± 9.5 yrs) received L and E s.i.d. at 10 mg (L10, E10) or 20 mg doses (L20, E20) for 8 weeks. Study-2: 66 elderly hypertensives (65.5 ± 4.7 yrs) received placebo, L10, E20 and L10 + E20 s.i.d. for 4 weeks. In middle-age subjects, both L and E decreased mean BP and, at the highest dose, also short-term BPV. In elderly subjects, L10 alone or in combination with E20 reduced BPV. Treatment-induced reductions in BP levels and BPV were uncorrelated. Different methods for short-term BPV assessment did not always provide superimposable results in the elderly. Our study supports a better reduction of BPV by L in the elderly and by E + L combination at any age, suggesting BPV reduction to be independent from reduction in average BP.

BACKGROUND:
Oxidative stress is increased in hyperuricemic patients with acute myocardial infarction (AMI). Use of sulfhydryl ACE-inhibitors (ACEIs), such as zofenopril or captopril, plus xanthine oxidase inhibitors (XOIs), may potentially result in enhanced antioxidant effects and improved survival.
OBJECTIVE:
We verified the benefit of such combination in a randomly stratified sample of 525 of the 3630 post-AMI patients of the four randomized prospective SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies.
METHODS:
One hundred sixty-five (31.4%) patients were treated with XOIs (79 under zofenopril, 86 placebo, lisinopril or ramipril), whereas 360 were not (192 zofenopril, 168 placebo or other ACEIs). In these four groups, we separately estimated the 1-year combined risk of major cardiovascular events (MACE, death or hospitalization for cardiovascular causes).

RESULTS:
MACE occurred in 10.1% of patients receiving zofenopril + XOIs, in 18.6% receiving placebo or other ACEIs + XOIs, in 13.5% receiving zofenopril without XOIs and in 22.0% receiving placebo or other ACEIs, but no XOIs (p = 0.034 across groups). Rate of survival free from MACE was significantly larger under treatment with zofenopril + XOIs than with other ACEIs with no XOIs [hazard ratio: 2.29 (1.06-4.91), p = 0.034]. A non-significant trend for superiority of zofenopril + XOIs combination was observed vs. zofenopril alone [1.19 (0.54-2.64), p = 0.669] or vs. placebo or other ACEIs + XOIs [1.82 (0.78-4.26), p = 0.169].
CONCLUSIONS:
Our retrospective analysis suggests an improved survival free from MACE in post-AMI patients treated with a combination of an urate lowering drug with antioxidant activity and an ACEI, with best effects observed with zofenopril.

Objective: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. Methods: This was a post-hoc analysis of pooled individual patient data from the four large random-ized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. Results: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR ¼ 0.66; and 95% confidence interval, CI ¼ 0.44–0.98; p ¼ .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR ¼ 0.78; 95% CI ¼ 0.63–0.97; p ¼ .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR ¼ 0.76; 95% CI ¼ 0.61–0.94); p ¼ .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. Conclusions: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year.