Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 8, Issue 1, 2010

The renin-angiotensin-aldosterone system plays a key role in the development of hypertension-related target organ damage. Nonetheless, compensatory increases in plasma renin levels that lead to adjustments in angiotensin production and conversion limit the potential benefits of both angiotensin converting enzyme inhibitors and angiotensin receptor blockers. On the other hand, the ONTARGET trial reported that the combination of two renin-angiotensin system inhibitors was associated with more adverse events without an increase in benefit. Aliskiren is a novel direct renin inhibitor with promising results. In this manuscript the current evidence about aliskiren, alone or in combination, is analyzed.

The development of the so-called “targeted therapies”, particularly those drugs that inhibit the activity of tyrosine kinases, has become a remarkable progress in the treatment of neoplastic diseases. The small molecule tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia, and trastuzumab, the humanized monoclonal antibody against the ERBB2 receptor tyrosine kinase, has proved to have a high efficacy in 25% of breast cancers. On the basis of treatment success it is expected that targeted therapies will spread its use in the future. Recent data has shown that some of these therapies are associated with certain cardiotoxicity ranging from asymptomatic mild left ventricular dysfunction to congestive heart failure through different mechanisms. However, rates of cardiotoxicity associated with TKI are not well known mainly because clinical trials usually do not include predefined cardiac endpoints or the assessment of left ventricular function before and during treatment. In addition, it is especially difficult to diagnose heart failure in patients with some kinds of cancer who have many reasons to develop dyspnoea. Here we summarize what is known up to date about the cardiotoxicity of drugs targeting the tyrosine kinases. Being aware of the risk of using these drugs is particularly important to early detect and institute the appropriate treatment to prevent irreversible myocardial injury, especially when some neoplastic diseases, as hematological or breast cancers, can affect young people with an estimated long-term survival.

Serial IVUS has demonstrated significant differences in intimal hyperplasia (IH) volume between drug-eluting stent (DES) and bare metal stents (BMS) in recent clinical trials. It has also been reported that IVUS is a useful tool in determining optimal DES implantation, especially for diabetes mellitus (DM) patients. Recent data have also suggested a critical role for, IVUS guidance in reduction of risk for DES thrombosis. IVUS has been invaluable in the elucidation of DES effects on the arterial wall, offering insight into the potential mechanisms of DES failure. Therefore, in this current manuscript, we review the potential benefits of intravascular ultrasound (IVUS) during drug eluting stent (DES) implantation.

Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERα, ERβ and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERα such as PPT, ERβ such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.

Many human diseases are characterized by vasculature disorders. Out of the many players in the angiogenic network, the vascular endothelial growth genes are by far the best characterized. The vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of coronary artery disease (CAD) and in its complication, the acute myocardial infarction (AMI). Several common polymorphisms in the promoter region of the VEGF gene have been reported, but only few single nucleotide polymorphisms (SNPs) have been demonstrated to be associated with variations in VEGF serum concentrations and with a susceptibility to CAD and its complications - acute coronary syndromes. Moreover, the -634 C/G VEGF SNP (rs2010963) has been demonstrated to be associated with AMI and the development of heart failure after AMI. Gene-based therapy for patients with refractory CAD has been the subject of extensive investigation. Preclinical studies have shown promise for the delivery of VEGF gene for treating CAD, whereas the results of randomized placebocontrolled trials have not demonstrated unequivocal evidence of efficacy. To conclude, at present the role of VEGF and VEGF SNPs in pathogenesis of AMI and the development of heart failure after AMI is still uncertain and remains to be determined. Obviously, larger studies as well as functional studies are needed to confirm the role of VEGF SNPs in AMI and its complications after AMI.

Cardiovascular diseases and cancer represent respectively the first and second cause of death in industrialized countries. These two conditions may become synergistic when cardiovascular complications of anti-cancer therapy are considered. More than 70% of childhood and 50% of adult cancer patients can be cured, however this important success obtained by the biological and medical research is obfuscated by emerging findings of early and late morbidity due to cardiovascular events. Although anthracyclines are effective drugs against cancer a dose-dependent cardiotoxic effects whose mechanism has not been elucidated resulting in failure of therapeutic interventions limit their use. Unexpectedly, tyrosine/ kinase inhibitors (TKIs) aimed at molecularly interfering with oncogenic pathways, have been implicated in cardiac side effects. Possible explanations of this phenomenon have been ambiguous, further strengthening the need to deepen our understanding on the mechanism of cardiotoxicity. In addition to a detailed description of anthracyclines and TKIs-related cardiovascular effects, the present review highlights recent observations supporting the hypothesis that the cellular target of anthracyclines and TKIs may include myocardial compartments other than parenchymal cells. The demonstration that the adult mammalian heart possesses a cell turnover regulated by primitive cells suggests that this cell population may be implicated in the onset and development of cardiovascular effects of anti-cancer strategies. The possibility of preventing cardiotoxicity by preservation and/or expansion of the resident stem cell pool responsible for cardiac repair may open new therapeutic options to unravel an unsolved clinical issue.

An impressive amount of experimental evidence accumulated over the last two decades has clearly demonstrated that Ca2+ influx through plasma membrane Ca2+-permeable channels plays a critical role in endothelial cell physiology and pathophysiology. Research efforts aimed at understanding the role of Ca2+ influx within the signaling events underlying endothelial dysfunction have grown at a fast pace over more recent years. Transient Receptor Potential Canonical (TRPC) proteins, which belong to the larger TRP superfamily of channel forming proteins, form Ca2+-permeable cation channels in vascular endothelium and there is currently no question about their involvement in Ca2+ influx associated with endothelial cell's physiology. It is also becoming evident that TRPCs are important players in the pathogenesis of cardiovascular disease. Therefore, it is imperative to elucidate the mechanism/s underlying regulation of endothelial TRPC channels as well as to identify signaling events downstream TRPC activation in order to better comprehend their role in cardiovascular physiology and disease. This review focuses on members of the TRPC3/6/7 group of TRPC proteins, revises current knowledge on their expression and regulation in endothelium, and discusses their role in cardiovascular disease as it relates to endothelial dysfunction.