Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 7, Issue 2, 2009

The aim of cardiac cell therapy is to restore at least in part the functionality of the diseased or injured myocardium by the use of stem/progenitor cells. Recent clinical trials have shown the safety of cardiac cell therapy and encouraging efficacy results. A surprisingly wide range of non-myogenic cell types improves ventricular function, suggesting that benefits may result in part from mechanisms that are distinct from true myocardial regeneration. While clinical trials explore cells derived from skeletal muscle and bone marrow, basic researchers are investigating sources of new cardiomyogenic cells, such as resident myocardial progenitors and embryonic stem cells. In this commentary we briefly review the evolution of cell-based cardiac repair, some progress that has been made toward this goal, and future perspectives in the regeneration of cardiac tissue.

Hypoxia-ischemia constitutes a risk in infants by altering cerebral blood flow regulatory mechanisms and causing loss of cerebral vascular auto-regulation. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents of calcium mediated effects could be responsible for reperfusion injury, which, in turns, leads to cerebral hemorrhage and damage. These dramatic phenomena represent a common repertoire in infants complicated by perinatal acute or chronic hypoxia or cardiovascular disorders treated by risky procedures such as open heart surgery and cardiopulmonary by-pass (CPB). To date, despite accurate perinatal and intra-operative monitoring, the post-insult period is crucial, since clinical symptoms and monitoring parameters may be of no avail and therapeutic window for pharmacological intervention (6-12 hours) may be limited, at a time when brain damage is already occurring. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk infants. The present review is aimed at investigating the role as circulating biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein; neuronal specific enolase (NSE), a dimeric isoenzyme; glial fibrillary acid protein (GFAP), a astroglial protein, in the cascade of events leading to ischemia reperfusion injury in infants complicated by perinatal asphyxia or cardiovascular disorders requiring risky therapeutic strategies such as CPB and/or extracorporeal membrane oxygenation.

Reperfusion therapy has significantly improved survival and prognosis of patients with acute myocardial infarction. However, the development of heart failure, particularly in patients after a large myocardial damage, remains a major challenge. Cell therapy may provide a novel therapeutic option to modify left ventricular remodeling processes and prevent postinfarction heart failure. Experimental studies have suggested that the infusion of different subsets of bone marrow-derived progenitor cells, circulating endothelial progenitor cells, or tissue-residing stem cells improved neovascularization and cardiac function. Clinical studies at present predominantly used bone marrow mononuclear cells (BMNC) isolated from bone marrow aspirates by density gradient centrifugation. Intracoronary infusion of BMNC significantly increased global or regional ejection fraction and/or reduced infarct size and endsystolic volumes in patients with acute myocardial infarction as demonstrated in initial pilot trials and in randomized studies. We aim to review the existing evidence of the beneficial effect of BMNC infusion as well the controversial issues regarding this promising novel therapeutic approach.

Atrial fibrillation is a frequent complication after CABG. It occurs in 20-50% of patients, most often between the 2nd and 3rd postoperative day. About 40 % of patients experience more than 1 episode. Postoperative AF (POAF) is associated with an increase in adverse events and hospital stay and, therefore, costs of care. The incidence of POAF is not influenced by the technique of CABG with or without cardiopulmonary by-pass Neurohormonal activation, electrolyte imbalance, fluid overload, surgical practices and finally an exaggerated inflammatory response has been proposed to be etiological factor. Advanced age, history of AF or heart failure, COPD, postoperative withdrawal of β -blockers are independent risk factors of postoperative AF. Conversely, postoperative administration of β-blockers, ACE inhibitors, potassium supplementation and NSAID were associated with a reduced risk of POAF. Pharmacological strategies for prevention of POAF may be divided in two main groups : the first one encompasses the use of antiarrhythmic drugs (amiodarone, metoprolol, sotalol) before and /or after surgery and has been extensively investigated in the last two decades. Recently an Italian study has shown that PUFA administration during hospitalization in patients undergoing CABG significantly decreased the incidence of POAF and was associated with a shorter hospital stay. Since an exaggerated inflammatory reaction may play a significant role in POAF, treatments directed to antagonize inflammation are presently under investigation. Despite different action mechanisms both hydrocortisone and statins have been shown to decrease postoperative AF risk. These two prophylactic regimens are not mutually exclusive and some data suggest that their association may be useful to further decrease the risk of POAF.

Direct inhibition of blood coagulation factors such as thrombin, factor VIIa, and factor Xa has shown great promise for treating thrombosis disorders. Inhibitors of these serine proteases have been designed, synthesized, and evaluated. Small molecule thrombin inhibitors typically contain P1-P2-P3 components targeting the active binding site. Structure optimizations on the P1 position and the P3 position have been done extensively, but the P2 position has not been as thoroughly studied as the other positions. Thrombin inhibitors with a rigid bicyclic P2 unit are interesting compounds with a more defined conformation. Aeruginosins are a family of naturally occurring small molecules that exhibit serine protease inhibition activities; their structures are typically tetrapeptides with an unusual bicyclic amino acid core structure occupying the P2 position. About 21 compounds sharing the same core structure have been isolated and identified so far, and their analogs have also been synthesized. In this review, the Structure Activity Relationship (SAR) of these compounds against thrombin and other serine proteases and their potential as antithrombotic agents will be discussed. The binding modes to thrombin and other factors of the coagulation cascade and the preparation of the aeruginosin core structure will be summarized. Besides the aeruginosin family, the SAR of other small molecule serine protease inhibitors with a rigid bicyclic P2 unit will also be covered.

Diagnostic and interventional cardiac imaging modalities employing contrast media (CMs) have become increasingly widespread in the recent years, especially multi-slice coronary computed tomography (MSCCT) and percutaneous coronary intervention (PCI). Contrast medium induced nephropathy (CIN), defined as impairment of renal function within 48-72 hours after administering CM, is one of the most common causes of hospital acquired renal insufficiency. The overall incidence of CIN in the general population is low (0.6-2.3%), but it may become remarkably elevated in patients with pre-existing renal failure, diabetes mellitus and in the elderly, all of whom represent a large cohort of patients undergoing cardiac studies. Calculating a simple risk score that is based on readily available information can assess the overall risk of CIN in each individual patient. Volume supplementation in moderate-high risk patients remains the cornerstone for preventing CIN. The combination of oral volume overload and intravenous (i.v.) hydration with normal saline (NS) or bicarbonate significantly reduces the risk. Since no ideal CM exists, preventing CIN involves reducing the given volume, avoiding the use of high osmolality or high viscosity CM, and limiting repeated exposure. Several vasodilators have been tested and controversial results have been observed. Recently, considerable interest has arisen due to the initial positive data on the effectiveness of antioxidant agents in reducing CIN incidence. In this review, we focus on the current strategies in the risk management of CIN and on the effectiveness of new preventive pharmacological therapies.