Current Pharmaceutical Design - Volume 19, Issue 9, 2013

Stable angina (SA) pectoris is a common and disabling disorder in patients with coronary artery disease (CAD), with increasing epidemiology and is associated with myocardial infarction and increased mortality. However, within the population of SA patients, an individual's prognosis can vary considerably. Except from conventional risk factors a variety of biomarkers have been evaluated for their prognostic significance in the settings of SA. Novel biomarkers associated with inflammatory status, such as C reactive protein and tumor necrosis factor alpha, with myocardial performance, such as B-type natriuretic peptide, with extracellular matrix remodeling, with vascular calcification such as osteoprotogerin and osteopontin, with myocardial ischemia, such as ischemia modified albumin have been associated with the progression of CAD and with the prognosis of SA patients. Despite the multiplicity of novel biomarkers there is lack of a clinical useful, highly specific for CAD biomarker with the ability to guide treatment decisions. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors with SA physical history, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.

Heart rate is a major determinant of cardiac output and myocardial oxygen utilization and is increasingly being nominated as a modifiable risk factor for cardiovascular disease. Despite this evidence, screening strategies for preventing cardiovascular diseases do not include routine assessment of resting heart rate. Reasonably, heart rate reduction has been suggested as a useful approach against angina pectoris in subjects with acute or chronic coronary syndromes. Accordingly, reduction of heart rate in patients with stable angina could be an additional goal of therapy. Important data have shown retrospectively the beneficial effect of heart rate-lowering drugs, such as betaadrenoceptor antagonists, non-dihydropyridine calcium channel antagonists, as well as other agents, on several parameters in patients with coronary artery disease and stable angina. However, additional data are now being sought to assess the impact of this approach on clinical practice.

Stable angina represents the main symptom of established coronary artery disease. In addition atherosclerosis is the common pathological substrate of chronic stable angina as well as acute coronary syndromes. The aim of stable angina management is the symptomatic relief and the secondary prevention. Lifestyle modification and pharmacological therapy are the cornerstones of chronic coronary artery disease management irrespectively of possible surgical or percutaneous revascularization. Optimal medical therapy is a combination of antianginal/antiischemic drugs and disease modifying agents, including nitrates, beta-blockers, calcium channel blockers, antiplatelets, statins and angiotensin converting enzyme inhibitors. Novel classes of treatment with different mechanisms of action have been developed in the last years, including nicorandil, ivabradine, trimetazidine and ranolazine. These drugs, which are currently approved as second-line treatments, have dynamically entered the clinical practice and their long-term effects are still under investigation.

Antiplatelet treatment is an important element in the medical treatment of patients with stable angina. Single antiplatelet therapy with low-dose aspirin is recommended in the absence of contraindications in all patients with diagnosed chronic stable angina and ischemic heart disease. Dual antiplatelet therapy is recommended initially for all patients with stable angina undergoing elective angioplasty with the duration of P2Y12 antagonist administration depending on the type of coronary stent. Despite the demonstrated clinical benefit in a wide range of patients, residual risk of ischemic events with aspirin and a P2Y12 inhibitor has also been attributed to the fact that these agents do not inhibit all pathways involved in platelet activation and aggregation. Other platelet activation pathways, including the PAR-1 pathway activated by thrombin (the most potent platelet activator), remain active in the presence of current antiplatelet agents. A combination of current therapies with novel agents could provide more comprehensive platelet inhibition leading to incremental decrease of cardiovascular events at the expense of increased bleeding risk. The current review presents traditional and novel antiplatelet treatment options and discusses the indications for aggressive antiplatelet management in patients with stable angina pectoris.

The goals of pharmacological treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms and also the long-term prognosis. Patients with coronary artery disease have viable but dysfunctional myocardium. The metabolism of the ischemic myocardium is characterized by a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Targeting myocardial metabolism as a pharmacologic approach for chronic angina is based on the concept that metabolic adaptive mechanisms during ischemia resemble fetal energy metabolism by shifting substrate use towards glucose metabolism. Potential pharmacologic approaches should target i) the suppression of lipolysis and the plasma fatty acid levels and subsequent uptake and oxidation by the heart, ii) direct inhibition of the enzymes of fatty acid beta-oxidation, iii) inhibition of carnitine palmitoyl transferase- I (CPT-1). Currently, there are no approved medications directly targeting myocardial metabolism. However, in the last two years a number of medications indirectly targeting cardiac metabolism have been tested in small clinical trials, and some of them appear to be promising potential therapies for stable angina. This review summarizes the main aspects of myocardial metabolism and focuses on the therapeutic approaches that could offer clinical benefit in patients with stable angina.

Atherosclerosis is a chronic disease which mainly represents an inflammatory response in the vessels. Myocardial ischemia manifested by angina pectoris can be either acute or chronic and usually is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. Chronic stable angina is chest discomfort attributed to myocardial ischemia without the presence of necrosis and is the most common symptom encountered by emergency room physicians. A growing amount of data has shown that endothelial dysfunction, is now considered an important early event in the development of atherosclerosis, while in the absence of angiographically obstructive coronary artery disease, anginal chest pain is often attributed to microvascular coronary dysfunction. Moreover, atheroma formation and in turn, atherosclerotic plaques seem to affect coronary flow, given that multivessel flow-limiting obstructions are observed in patients with chronic coronary syndrome. Morphological changes of diseased arteries related to significant atherosclerosis, such as vascular remodeling may also result in stable angina or claudication. However, several issues with respect to the comprehension of the pathophysiology of the chronic coronary syndrome have not been fully elucidated.

Medical treatment plays an important role in the therapy of coronary artery disease and stable angina. Whereas nitrates are used to improve symptoms, beta-blockers, statins, and ACE-inhibitors/angiotensin receptor blockers are given also to target prognosis in part by slowing the progression of disease. Major cardiovascular risk factors including tobacco smoking, physical inactivity, obesity, arterial hypertension, hyperlipidemia, and diabetes mellitus were associated with overproduction of reactive oxygen species (ROS). In animal models, increased ROS production was associated with the initial steps of atherosclerosis including vascular cell dysfunction, intimal hypertrophy, the formation and destabilization of plaque. As a consequence, ROS were believed to be major contributors to the development of cardiovascular diseases and antioxidant treatments were proposed as promising therapeutic strategies. Nevertheless, intervention studies with antioxidant vitamins have failed to positively affect cardiovascular outcome in prospective trials. Specific inhibitors of prooxidant enzymes are being developed but their efficacy to improve cardiovascular endpoints has not been tested so far. Newer evidence suggests that phytonutrients including flavanols may posses vascular protective effects that are independent of their antioxidant properties observed in vitro. Taken together, there is currently not enough evidence that treatment with antioxidants per se will play a role in cardiovascular medicine.

Atherosclerosis is characterized by chronic inflammation of the vascular wall. Macrophages, which differentiate from circulating monocytes, give rise to foam cells by excessive accumulation of modified lipoproteins. Atherogenesis subsequently progresses through necrotic core expansion associated with apoptosis and the suppressed clearance of apoptotic macrophage (i.e. efferocytosis), followed by the transition to vulnerable plaques. The vulnerable plaque is characterized by thinning of the fibrous cap and necrotic core expansion. Here, the impact of monocytes/macrophages in both early atherogenesis and advanced plaque progression is discussed with a focus on the potential targeting of inflammatory processes in atherosclerosis.

Conventional therapeutic options to treat chronic angina pectoris are pharmacological interventions, coronary bypass surgery (CABG) and percutaneous coronary intervention (PCI). In animal models, it was shown that gene delivery strategies harbour an exciting potential to support and maybe even replace conventional anti-angina treatments, but the translation of the basic science to clinical practise appears problematic. Gene therapy targeting key elements of neointima formation (e.g. cell cycle regulators, metalloproteinases, inflammation and oxidative stress) reduces vein graft and stent failure in experimental models. Additionally, systemic gene delivery of genes targeting NO production, oxidative stress, inflammation and foam cell formation has been shown to prevent atherosclerosis in different animal models. During CABG the vein graft can be transfected ex vivo and during PCI, a stent carrying transfection vectors can be deployed. Both strategies result in the induction of local transgene expression at the site of interest. This limits unwarranted transgene expression and the toxicity seen with systemic gene delivery. However, with the development of new transfection vectors, able to induce local transgene expression without detrimental side effects, systemic anti-inflammatory and anti-oxidative, gene delivery could be a powerful tool in secondary prevention.

Infections are the most common inflammatory triggers and acute and chronic infections have been associated with the development and progression of atherosclerotic disease raising interest in the infectious hypothesis of atherosclerosis. Pathogens have been identified in atherosclerotic plaques and large epidemiological studies have documented conflicting associations between serological evidence of infection and cardiovascular events. Influenza A was mostly studied as a trigger for cardiovascular events during winter months, whilst cytomegalovirus, Chlamydia pneumoniae, helicobacter pylori and porphyromonas ginigivalis were the most studied chronic pathogens which had been associated with the development and progression of cardiovascular disease. Infectious agents can contribute to atherosclerosis by having a direct effect on the vascular wall or via indirect effects including inflammatory responses and molecular mimicry. Efforts to prevent infection with vaccination or treat specific infectious agents with antibiotics have provided mostly negative results, thereby challenging the validity of the infectious hypothesis of atherosclerosis.

Atherosclerosis is a chronic process related to several underlying mechanisms leading to the formation and evolution of atherosclerotic plaque. Of great interest are during the last years short, non-coding RNAs, called microRNAs and responsible for several aspects of homeostasis and disease. According to the available data microRNAs are expressed in the cardiovascular system and have key roles in normal states, as well as in disease development and progression. Moreover, it has been shown that they contribute to atherogenesis, coronary artery disease and myocardial infarction. Importantly, microRNAs circulate in the bloodstream, while they exist in tissues, affect plaque initiation and progression and seem to be essential biomarkers of atherosclerosis. Therefore, understanding the role of these molecules may be of great importance in the understanding of the pathogenesis of atheromatous plaque providing new evidence for diagnosis and treatment of atherosclerosis and its' clinical presentation.

Refractory angina pectoris constitutes a manifestation of severe ischemic heart disease that cannot be treated adequately either with conventional medication or with interventional techniques including percutaneous coronary angioplasty (PTCA). As a result, new therapeutic strategies, aiming on angiogenesis, were evolved in order to improve functional class and health related quality of life (HRQOL) indices. Among them, gene therapy constitutes a very promising alternative treatment for these patients. In this review, we will describe i) the definition of refractory angina ii) pathophysiology of angiogenesis, iii) routine as well as novel imaging techniques of neovascularization and iv) current treatment options for refractory angina. Secondly we will review the main angiogenic clinical trials, which will also be commented regarding their effectiveness to reduce the recurrency of angina symptoms and improve health-related quality-of-life, as well as the functional class of patients with chronic ischemic disease.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm- aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act.

The decline of the immune system appears to be an intractable consequence of aging, leading to increased susceptibility to infections, reduced effectiveness of vaccination and higher incidences of many diseases including osteoporosis and cancer in the elderly. These outcomes can be attributed, at least in part, to a phenomenon known as T cell replicative senescence, a terminal state characterized by dysregulated immune function, loss of the CD28 costimulatory molecule, shortened telomeres and elevated production of proinflammatory cytokines. Senescent CD8 T cells, which accumulate in the elderly, have been shown to frequently bear antigen specificity against cytomegalovirus (CMV), suggesting that this common and persistent infection may drive immune senescence and result in functional and phenotypic changes to the T cell repertoire. Senescent T cells have also been identified in patients with certain cancers, autoimmune diseases and chronic infections, such as HIV. This review discusses the in vivo and in vitro evidence for the contribution of CD8 T cell replicative senescence to a plethora of age-related pathologies and a few possible therapeutic avenues to delay or prevent this differentiative end-state in T cells. The age-associated remodeling of the immune system, through accumulation of senescent T cells has farreaching consequences on the individual and society alike, for the current healthcare system needs to meet the urgent demands of the increasing proportions of the elderly in the US and abroad.

Cellular senescence is a response to nonlethal intrinsic or extrinsic stress that results in persistent growth arrest with a distinct morphological and biochemical phenotype. The engagement of senescence may represent a key component for therapeutic intervention in the eradication of cancer. Nevertheless, for many years, the role of senescence in opposing tumour growth in vivo had previously been underestimated. The potential role of cellular senescence in anti-cancer therapy may be particularly attractive in advanced age, because of the age-related changes occurring at the level of both tumor suppressor genes and immune functions. This review, which is focused on the impact of cellular senescence in aging and cancer, summarises the intrinsic pathways and the molecular and epigenetic changes involved in the induction of cellular senescence, and analyzes the changes occurring at the level of these pathways during aging and cancer.

The aging process is associated with a loss of complexity in the dynamics of physiological systems that reduce the ability to adapt to stress, causing frailty and/or age-related diseases. At the cellular level, proliferative and/or oxidative-stress induced cell senescence associated with a pro-inflammatory state may greatly contribute to age-associated impaired tissue and organ functions. Senescence of endothelial and cardiac cells observed over normal aging, appear to be accelerated in age-related diseases and in particular, in cardiovascular disease (CVD). Although the molecular mechanisms of cellular senescence have been extensively studied, a complete understanding of their role in CVD is still limited. Cardiac, endothelial (EC), vascular smooth muscle (VSMC), leukocytic and stem cells (endothelial progenitor cells (EPC), embryonic stem cells (ESC) and haematopoietic stem cells (HSC)) may play a pivotal role on the maintenance and regeneration of cardiovascular tissue. Age-associated changes of such cells may enhance the risk of developing CVD. The purpose of this review is to illustrate how cellular senescence may affect tissue repair and maintenance toward CVD, focusing on the role played by telomere length and microRNA expression. Finally, interventions aimed at improving the age-related decline in vascular cells during aging and disease, as well as strategies to harness the regenerative capacity of stem cells in CVD will be discussed.

Recent observations have pointed out that microglia, astrocytes and cerebrovascular endothelial cells senescence might contribute to the onset or progression of sporadic AD. The accumulation of senescent dysfunctional microglia or senescence related changes of other cells within CNS could be causally implicated in AD and age-related dysfunction and their efficient removal could represent a pivotal mechanism to prevent or delay neurodegeneration. The question how senescent cells are cleared from CNS has been poorly investigated, even though it is reasonable to believe that resident microglia is involved in this task. However, accumulating evidence now support the idea that assistance by peripheral mononuclear phagocytes (MP) in AD could be essential to control local brain inflammation and remove Abeta depots. Based on the current knowledge it is reasonable to hypothesize that senescence surveillance might be among the tasks that blood derived MP are called to envelop in the CNS during particular conditions, especially in the case senescent microglia is not able to achieve this task properly. However, age-related dysfunctions of these players of innate immunity could lead to depict a series of events that synergically with microglia and other CNS cells senescence could lead to a rapid progression of the disease. Hence, the design of intervention aimed at targeting accumulating senescent cells by rejuvenation of peripheral MP function seems an attractive tool that perhaps would also help to clarify the processes involved in senescence surveillance in normal and AD brain.

Alzheimer's disease (AD) is a complex degenerative disorder of the brain, associated with a progressive cognitive decline. Age is the main risk factor with almost half of the population above 90 years affected by this pathology. AD and brain aging share common molecular changes, so it has been hypothesized that AD could be a form of accelerated brain aging. In this context, senescenceassociated mechanisms could be a valuable target of investigation both to analyze the causes of this disease and to define therapeutic strategies. Senescent phenotypes of glia and neurons, as well as of peripheral cells, have been described in AD. Much evidence indicate that vascular impairment is a fundamental contributor to AD pathology and platelets are generally considered a key element because they represent the link between amyloid-ß (Aß) deposition, peripheral inflammation and endothelial senescence. Both activated and senescent platelets are a source of Aß, in addition activated platelets secrete many proinflammatory mediators that could contribute to increased peripheral inflammation and endothelial senescence. Treatments aimed to target peripheral endothelial senescence include antioxidants and some substances, such as aspirin, that modulate platelet aggregation and inflammatory response. Heparin has been proposed as a treatment for senile dementia and exhibits anti-inflammatory action as well as inhibitory effects on Aß assembly. Identifying peripheral targets for AD treatments could also result advantageous as it would be possible to monitor directly their efficacy. Nevertheless more research is needed to clarify all the different aspects and interactions of blood cells, vascular cells and their secretory products.