Cardiotoxicity of molecularly targeted agents

Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics.     

Statins and hypertension

Hypertension and dyslipidemia are frequently associated as risk factors for cardiovascular diseases. Statins are among the most potent drugs to correct hypercholesterolemia, and their use across a wide range of cardiovascular risk levels significantly reduced morbidity and mortality in large intervention trials. Aside from (or in addition to) reducing plasma cholesterol, statins also reduce blood pressure, another effect associated with cardiovascular risk reduction by other antihypertensive drugs. This review examines the proposition that a part of the statins' beneficial effect in cardiovascular diseases may result from direct effects on blood pressure regulation, perhaps independent of lipid lowering. Potential molecular mechanisms are considered (e.g., "pleiotropic" effects on endothelial vasoactive mediators, oxidant stress, or inflammation), all of which may affect the central or peripheral control of blood pressure homeostasis, as well as modulate target organ damage. In particular, potential effects of statins on blood pressure and heart rate variability open new perspectives for a better tailoring of drug treatment in high-cardiovascular risk patients.     

Modifiable lifestyle and environmental risk factors affecting the retinal microcirculation

Structural changes within the human retinal vasculature may reflect systemic vascular changes associated with various cardiovascular and metabolic disorders. Recent data suggest that systemic exposure from a range of modifiable lifestyle and environmental risk factors (e.g., diet, physical activity, and smoking) may affect the morphology of the retinal vasculature. Being easily accessible and non-invasively visualized, the retinal microvasculature therefore can be a clinically useful biomarker of reversible sub-clinical physiologic deviation of the systemic circulation as results of such unfavorable exposures. Importantly, quantitative analysis of the retinal microvasculature may be utilized as a prognostic tool, allowing for targeted vascular therapies before the onset of overt cardiovascular and metabolic disorders. This review summarizes the modifiable lifestyle and environmental risk factors that affect retinal microvascular structure and the possible clinical implications of such relationships.     

Microvascular changes in the retina as a risk marker for cardiovascular disease

The retinal vasculature can be viewed directly and noninvasively, offering an easily accessible window through which to study the human microcirculation in vivo and, therefore, early processes and pathways in cardiovascular disease (CVD) development. Recent advances in digital retinal photography and image analysis have allowed reliable and objective evaluation of retinal vascular pathologies (eg, retinopathy signs) as well as quantitative assessment of other topographic retinal vascular parameters, including retinal vascular caliber. An expanding series of clinical and epidemiologic studies now show that retinal vascular changes are associated with cardiovascular and metabolic diseases, including hypertension, diabetes, obesity, stroke, coronary heart disease, and heart failure. These data indicate that structural alterations in the retinal vasculature may mirror pathologic processes occurring in the systemic circulation and may represent novel biomarkers for CVD risk. This review summarizes the systemic cardiovascular associations of retinal vascular changes and discusses their clinical and research implications.     

Air pollution and cardiovascular injury epidemiology, toxicology, and mechanisms

Recent epidemiologic studies show that increased levels of air pollutants are positively associated with cardiovascular morbidity and mortality. Inhalation of air pollutants affects heart rate, heart rate variability, blood pressure, vascular tone, blood coagulability, and the progression of atherosclerosis. Several categories within the general population (i.e., people with pre-existing cardiovascular disease and diabetic and elderly individuals) are considered to be more susceptible to air pollution-mediated cardiovascular effects. Major mechanisms of inhalation-mediated cardiovascular toxicity include activation of pro-inflammatory pathways and generation of reactive oxygen species. Although most studies focus on the influence of systemic effects, recent studies indicate that ultrafine particles may be translocated into the circulation and directly transported to the vasculature and heart where they can induce cardiac arrhythmias and decrease cardiac contractility and coronary flow.     

Vascular disease and diabetes: is hypoglycaemia an aggravating factor?

Acute hypoglycaemia provokes profound physiological changes affecting the cardiovascular system and several haematological parameters, principally as a consequence of sympatho-adrenal activation and counter-regulatory hormonal secretion. Many of these responses have an important role in protecting the brain from neuroglycopenia, through altering regional blood flow and promoting metabolic changes that will restore blood glucose to normal. In healthy young adults the cardiovascular effects are transient and have no obvious detrimental consequences. However, some of the effected changes are potentially pathophysiological and in people with diabetes who have developed endothelial dysfunction, they may have an adverse impact on a vasculature that is already damaged. The acute haemodynamic and haematological changes may increase the risk of localized tissue ischaemia, and major vascular events can certainly be precipitated by acute hypoglycaemia. These include myocardial and cerebral ischaemia and occasionally infarction. Established diabetic retinopathy often deteriorates after strict glycaemic control is instituted, the latter being associated with a threefold increase in frequency of severe hypoglycaemia, and enhanced exposure to mild hypoglycaemia. The possible mechanisms underlying these hypoglycaemia-induced effects include haemorrheological changes, white cell activation, vasoconstriction, and the release of inflammatory mediators and cytokines. The concept that acute hypoglycaemia could aggravate vascular complications associated with diabetes is discussed in relation to evolving comprehension of the pathogenesis of atherosclerosis and blood vessel disease.     

The clinical assessment of retinal microvascular structure and therapeutic implications

Opinion statement Examination of the retinal microvasculature is widely used to assess diabetic eye disease and as an indicator of target organ damage in hypertension. The diagnostic value of grading of hypertensive retinopathy is dubious; however, many recent studies have demonstrated that hypertensive retinopathy is associated with a range of risk factors for cardiovascular disease and may predict cardiovascular events independently of blood pressure. Developments in digital imaging and computer-assisted analysis have facilitated the quantitative assessment of microvascular changes in cardiovascular disease. These approaches may be useful for assessing cardiovascular risk and targeting therapeutic intervention.     

Basic evaluation of older persons with hypertension

To achieve the objectives of the baseline evaluation of older persons with hypertension, age-related changes that affect blood pressure measurement, assessment of target-organ effects, cardiovascular disease risk, and comorbidities need to be recognized. Careful attention to recommended procedures for blood pressure measurement, conducting a history, performing a physical examination, and using laboratory tests will allow the physician to confirm the presence of hypertension; to assess its effects on target organs; to determine cardiovascular risk status relating to other factors; and to identify other diseases, laboratory abnormalities, or psychosocial factors that may affect subsequent management.     

Cysteine Protease Cathepsins in Atherosclerosis and Abdominal Aortic Aneurysm

Extracellular matrix remodeling is an important mechanism in the initiation and progression of cardiovascular diseases. Cysteine protease cathepsins are among the important proteases that affect major events in the pathogenesis of atherosclerosis and abdominal aortic aneurysm, including smooth muscle cell transmigration through elastic lamina, macrophage foam cell formation, vascular cell and macrophage apoptosis, and plaque rupture. These events have been studied in cathepsin deficiencies and cathepsin inhibitor deficiencies in mice and have provided invaluable insights regarding the roles of cathepsins in cardiovascular diseases. Pharmacological inhibitions for cathepsins are under evaluation for other human diseases and may be used as clinical treatments for cardiovascular diseases in the near future. This article reviews different mechanisms for cathepsins in atherosclerosis and abdominal aortic aneurysm that could be targeted by selective cathepsin inhibitors.     

Cardiovascular alteration and treatment of hypertension: do men and women differ?

Cardiovascular disease is one of the most common causes of mortality affecting both men and women in industrialized nations. Sex-related differences have been well established with regard to heart and vascular function as well as cardiovascular disease processes. Nevertheless, the precise mechanisms of action behind these gender-related differences are poorly understood. Premenopausal women have a relatively lower arterial blood pressure compared to age-matched men and post-menopausal women, suggesting a role of ovarian hormones in blood pressure regulation. Sex-related differences in vasculature and neuroendocrine systems are also present that can affect hemostasis, vascular reactivity, and vascular tone. Treatment for cardiovascular disease and hypertension has been challenging and unsatisfactory. Men and women may require different antihypertensive regimens due to differences in the progression and presentation of hypertension. Additionally, hormone replacement therapy in postmenopausal women has been controversial, producing both beneficial and detrimental effects. Therefore, this review will focus on sex-related differences in the heart and vasculature, and treatments for cardiovascular disease, such as hypertension.     

Angiotensin II type I receptor blocker and endothelial function in humans: role of nitric oxide and oxidative stress

Recent large clinical trials have shown that angiotensin II type I receptor blockers (ARBs) reduce cardiovascular morbidity and mortality in patients with heart failure, acute myocardial infarction, and hypertension. However, the mechanism underlying antiatherogenic effects of ARBs remains unclear. The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation. Several investigators have reported impairment in endothelium-dependent vasodilation in the forearm, coronary, and renal vasculature in cardiovascular diseases, including hypertensive patients. Cardiovascular diseases are associated with alteration in endothelial function. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis. Anti-renin-angiotensin system agents, angiotensin-converting enzyme (ACE) inhibitors improve endothelial function in patients with hypertension, diabetes mellitus, and coronary artery disease. It is well known that ACE inhibitors augment endothelium-dependent vasodilation through an increase in NO bioavailability, by an increase in NO production and a decrease in NO inactivation. ARBs are also thought to prevent cardiovascular complications through an augmentation of endothelial function. In this review, we focus on recent findings and putative mechanisms of the beneficial effects of ARBs on endothelial function.     

Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases

In humans and most animal models, the development of obesity leads not only to increased fat depots in classical adipose tissue locations but also to significant lipid deposits within and around other tissues and organs, a phenomenon known as ectopic fat storage. The purpose of this review is to explore the possible locations of ectopic fat in key target-organs of cardiovascular control (heart, blood vessels and kidneys) and to propose how ectopic fat storage can play a role in the pathogenesis of cardiovascular diseases associated with obesity. In animals fed a high-fat diet, cardiac fat depots within and around the heart impair both systolic and diastolic functions, and may in the long-term promote heart failure. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete vascular relaxing factors, proatherogenic cytokines and smooth muscle cell growth factors. Furthermore, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Taken together, ectopic fat storage in key target-organs of cardiovascular control may impair their functions, contributing to the increased prevalence of cardiovascular diseases in obese subjects.     

微小RNAs与新生血管形成

新生血管形成是一种复杂的动态过程，其是在原有血管基础上通过促血管生成途径以及抗血管生成途径之间严密的协同作用而形成的。促血管生成途径与抗血管生成途径之间的平衡一旦被打破，则可导致病理性的新生血管形成，参与到肿瘤、炎症、心血管疾病等多种疾病的发生发展过程中。微小RNAs(miRNAs)可在mRNA和蛋白质水平调节基因表达，是细胞生命活动中重要的小分子调节物质。不同的miRNAs通过对特定靶基因的调节，在新生血管形成中发挥着重要作用。本文将就调控新生血管形成的重要miRNAs及其潜在的临床应用价值做一综述。     

Endothelial dysfunction and subclinical hypothyroidism: a brief review

Subclinical hypothyroidism (SH) is characterized by normal serum free T4 and free T3 levels and increased serum TSH levels. The relationship between SH and cardiovascular diseases has been one of the most popular topics recently. There is still some controversy concerning the cardiovascular impact of SH and management protocols. The vast majority of the studies published so far, suggests that SH accelerates endothelial dysfunction through traditional effects on risk factors that promote atherosclerosis and nontraditional effects on vasculature. In particular, SH is associated with increased of LDL-cholesterol, diastolic blood pressure, and markers of chronic inflammation (C reactive protein) and simultaneously reduces the bioavailability of nitric oxide to blood vessels and increases the expression of angiotensin receptor. Furthermore, replacement therapy seems to improve all these aspects.     

Impaired angiogenesis in aminopeptidase N-null mice

Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APN-null mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases.     

GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier

Every organ in the body requires blood vessels for efficient delivery of oxygen and nutrients, but independent vascular beds are highly specialized to meet the individual needs of specific organs. The vasculature of the brain is tightly sealed, with blood-brain barrier (BBB) properties developing coincident with neural vascularization. G protein-coupled receptor 124 (GPR124) (tumor endothelial marker 5, TEM5), an orphan member of the adhesion family of G protein-coupled receptors, was previously identified on the basis of its overexpression in tumor vasculature. Here, we show that global deletion or endothelial-specific deletion of GPR124 in mice results in embryonic lethality associated with abnormal angiogenesis of the forebrain and spinal cord. Expression of GPR124 was found to be required for invasion and migration of blood vessels into neuroepithelium, establishment of BBB properties, and expansion of the cerebral cortex. Thus, GPR124 is an important regulator of neurovasculature development and a potential drug target for cerebrovascular diseases.     

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高血压与血脂异常是两大可控制的心血管疾病的重要危险因素,其相互影响明显增加心血管疾病的风险,而同时控制血压与血脂异常对防治心血管疾病将产生更多的获益。治疗时强调在血压达标基础上选择优化治疗方案,建议在降压同时对多种危险因素进行治疗,包括结合血脂水平来综合评估心血管疾病的发病危险性,确定治疗的目标值。     

Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy

In the past two decades advances in the development of targeted nanoparticles have facilitated their application as molecular imaging agents and targeted drug delivery vehicles. Nanoparticle-enhanced molecular imaging of the angiogenic tumor vasculature has been of particular interest. Not only because angiogenesis plays an important role in various pathologies, but also since endothelial cell surface receptors are directly accessible for relatively large circulating nanoparticles. Typically, nanoparticle targeting towards these receptors is studied by analyzing the contrast distribution on tumor images acquired before and at set time points after administration. Although several exciting proof-of-concept studies demonstrated qualitative assessment of relative target concentration and distribution, these studies did not provide quantitative information on the nanoparticle targeting kinetics. These kinetics will not only depend on nanoparticle characteristics, but also on receptor binding and recycling. In this study, we monitored the in vivo targeting kinetics of α_vβ₃-integrin specific nanoparticles with intravital microscopy and dynamic contrast enhanced magnetic resonance imaging, and using compartment modeling we were able to quantify nanoparticle targeting rates. As such, this approach can facilitate optimization of targeted nanoparticle design and it holds promise for providing more quantitative information on in vivo receptor levels. Interestingly, we also observed a periodicity in the accumulation kinetics of α_vβ₃-integrin targeted nanoparticles and hypothesize that this periodicity is caused by receptor binding, internalization and recycling dynamics. Taken together, this demonstrates that our experimental approach provides new insights in in vivo nanoparticle targeting, which may proof useful for vascular targeting in general.     

Expression and activation of the farnesoid X receptor in the vasculature

The farnesoid X receptor/bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.     

Obesity and target organ damage: the heart

In most patients, coronary atherosclerosis or congestive heart failure develop as an integrated response to multiple cardiovascular risk factors. Obesity increases the prevalence of most cardiovascular risk factors and is the predominant cause of diabetes mellitus and arterial hypertension. Moreover, obesity shifts the manifestation of these risk factors to younger age groups, such that subsequent damage results prematurely in clinically overt cardiac diseases. In addition, due to clustering of obesity-related risk factors, obesity may amplify the risk by synergistic mechanisms acting in parallel. Finally, an elevated body mass index (BMI) results in an increase in heart rate and blood volume, as well as increased systolic and diastolic blood pressure. These changes affect cardiac geometry and mass in addition to the alterations of the coronary vasculature. At the population level, the role of obesity in promoting multiple risk factors and, subsequently, the development of heart diseases cannot be underestimated. In individual patients, however, the clinical presentation may be dominated by obesity-related hypertension, diabetes, metabolic and inflammatory derangements or clinical symptoms of heart failure or coronary artery disease. Weight reduction remains a crucial component of the therapeutic strategy to ameliorate insulin resistance, hypertension and left ventricular hypertrophy, among other risk factors, with profound implications for the individual's prognosis.