Current Pharmaceutical Biotechnology - Volume 13, Issue 13, 2012

Although atherosclerosis was previously thought to be mainly a degenerative disease, it is now well ascertained that its pathogenesis is inflammatory. There was a pivotal role of apoE-knockout mice in understanding the inflammatory background of atherosclerosis. Currently, atherosclerosis is known as a chronic inflammatory disease, in most cases initiated by hypercholesterolemia. Recently, the mouse has become the best model for experimental atherosclerosis. It was in 1992 that the first line of gene targeted mice, namely apolipoprotein E-knockout mice was developed. The apoE-deficient model develops extensive atherosclerotic lesions on a chow diet. The LDL receptor - deficient model has elevated LDL levels, but no lesions, or only very small lesions, form on the chow diet. However, robust lesions do form on the westerntype diet. The creation of apoE- knockout mice has changed the face of atherosclerosis research. Gene-targeted mouse models has changed the face of atherosclerotic research and helped in creation of the new theory of atherosclerosis: as an inflammatory disease. Recently, the mouse has become the best model for experimental atherosclerosis. It was in 1992 that the first line of gene targeted mice, namely apolipoprotein E-knockout mice was developed. The apoE-deficient model develops extensive atherosclerotic lesions on a chow diet. It is also the model in which the lesions have been characterized most thoroughly. The lesions develop into fibrous plaques; however, there is no evidence that plaque rupture occurs in this model. The LDL receptor - deficient model has elevated LDL levels, but no lesions, or only very small lesions, form on the chow diet. However, robust lesions do form on the western-type diet. The creation of apoE-knockout mice has changed the face of atherosclerosis research. Gene-targeted mouse models has changed the face of atherosclerotic research and helped in creation of the new theory of atherosclerosis: as an inflammatory disease. Nowadays, apoE- knockout mice model is therefore used in developing new drugs against atherosclerosis. This review describes how new groups of agents are searched.

The novel vascular solution, the bioresorbable scaffold, has already been called Vascular Regeneration Therapy (VRT), providing a new quality in interventional cardiology. This new generation of stents gives a potential advantage over the permanent metal prosthesis, mainly restoration of vasomotion after full biodegradation. In the article we summarize the latest achievements in stent technologies allowing complete regeneration of arterial wall functions after implantation of biodegradable scaffold.

Although the differences between central and peripheral blood pressure (BP) have been known for decades, the consequences of decision-making based on peripheral rather than central BP have only recently been recognized. Central PP is closer to the heart, coronary and carotid arteries, which are the most important sites of cardiovascular events. The influence of cyclic stretch (owing to cyclic changes in BP) on the arterial wall has been documented at every stage of atherosclerosis development. Apart from mediating atherosclerosis progression and plaque instability, the pulsatile component of BP is the main mechanism leading to plaque rupture and, consequently, to acute coronary syndromes and other vascular complications. Latest evidence suggests that the effect of some antihypertensive drugs on central BP (especially on central pulse pressure) is greater when compared with the effect on peripheral pressure, especially if systolic or pulse pressure are measured. Recently, a new group of drugs (advanced glycation end products cross-link breakers) were developed which have ability to decrease pulsatile component of blood pressure. The principal goal of the present review is to update the latest advances in this field.

Cardiomyopathies are categorized as extrinsic, being caused by external factors, such as hypertension, ischemia, inflammation, valvular dysfunction, or as intrinsic, which correspond to myocardial diseases without identifiable external causes. These so called primary cardiomyopathies can be categorized in four main forms: hypertrophic, dilated, restrictive, and arrhythmogenic right ventricular cardiomyopathy. Cardiomyopathies are diagnosed by clinical expression, echocardiography, electrocardiography, non-invasive imaging, and sometimes by cardiac catheterization to rule out external causes as ischemia. The two main forms of primary cardiomyopathies are the hypertrophic and dilated cardiomyopathies. Most of hypertrophic cardiomyopathy and 20-50% of dilated cardiomyopathy are familial showing a wide genetic and phenotypic heterogeneity. This review presents the current knowledge on the causative genes, molecular mechanisms and the genotype-phenotype relations of hypertrophic and dilated cardiomyopathies.

Fabry disease is an X chromosome linked disorder caused by the inherited deficiency of lysosomal enzyme α- galactosidase A. The deficiency results in abnormal degradation of certain glycosphingolipids. Although the disease is known for more than hundred years and the underlying molecular basis is getting to be well defined, there are still a lot of unanswered questions regarding the different clinical presentations, available diagnostic procedures and therapeutic interventions. The scope of the article is to review the molecular basis of Fabry disease and summarize the available data about Fabry disease cardiomyopathy, highlight the controversies of current knowledge and evaluate future research directions.

Morbidity from degenerative aortic valve disease (AVS) is increasing worldwide, concomitant with the ageing of the population and the growing consumption of high caloric and cholesterol diets of the western countries. Despite the increasing prevalence of AVS, with its high mortality and morbidity, studies on the molecular and cellular mechanisms underlying the onset of aortic valve degeneration have only advanced in the last 15 years. The result of this effort is now beginning to reveal several mechanisms with great therapeutic targeting potential that may alter the natural history of this progressive pathology. Indeed, the view of this disease has changed from being an unmodifiable degenerative disease to an active biological process regulated by highly conserved cellular pathways. The progression of AVS includes inflammation, angiogenesis and remodelling of the extracellular matrix leading to osteogenesis in the aortic valve and revealing many mechanisms and risk factors similar to atherosclerosis. Therefore statins and angiotensin II antagonists seemed promising treatment options; however, experimental results are still controversial. Nonetheless, valvular degeneration results in dramatic myocardial changes induced by chronic pressure overload such as left ventricular hypertrophy as well as other paramount myocardial extracellular changes. Currently, a strong impulse for future research to investigate the pathophysiological mechanisms and their modulation in order to prevent/delay the onset or progression of valve degeneration is needed. In the present review, we focused on the molecular and cellular mechanisms underlying degenerative AVS and its myocardial impact.

Aortic stenosis (AS) is a degenerative valvular disease that has, until recently, been considered to be a progressive and the most importantly unmodifiable process. However, recent histopathologic studies have clearly reported that the both development and progression of AS is based on an biochemically active process which is mediated by a chronic inflammation (featured by many similarities with atherosclerosis) and includes inflammatory-cell infiltrates, lipoproteins, lipids and factors responsible for calcification (extracellular-bone-matrix proteins and bone mineral). Targeted drug therapy to prevent the progression of calcific AS disease should ideally be based on the knowledge of risk factors and the molecular pathogenesis of the disease. Treatment trials using various drugs have been undertaken to test whether medical therapy (statins, renin-angiotensin inhibition and anti-osteoporosis drugs) can prevent or beneficially modify the disease course. Although retrospective and non-randomized studies suggested a positive effect of statins, benefit has not been seen in perspective randomized controlled trials. Inhibition of renin-angiotensin has shown discordant results in retrospective studies with no randomized controlled data published. In the future, we need to consider other medical therapies (antiosteoporosis drugs are attractive candidates) that might target different pathways in this disease process. Additionally, we need to detect the optimal moment to start statin therapy for this chronic slowly progressive disease; treatments aimed at the early disease process (pre-obstructive form of aortic sclerosis) may be ineffective with end-stage tissue changes.

Aortic stenosis is the most common type of valvular heart disease and its recent increase is related to aging. The decreased aortic valve area imposes a chronic systolic pressure overload to the left ventricle. In response, the ventricle hypertrophies in an attempt to normalize the increased wall stress, but this response is not uniform in patients with similar degrees of stenosis and its regression after surgical correction is variable, suggesting that several factors, other than load, can explain these differences. These findings are particularly important since the presence of left ventricular hypertrophy after aortic valve replacement is an independent predictor of worse outcome, probably because it indicates irreversible remodeling. Age, gender, hypertension, patient-prosthesis mismatch and interstitial remodeling also play an important role in this setting, raising the possibility of intervention beyond valve replacement. The possibility of combining estrogen treatment, antihypertensive agents, antioxidants and modulators of the renin-angiotensin-aldosterone system with surgical treatment to promote reverse remodeling is very appealing. On the other hand, a preventive strategy to intervene earlier in patients with significant left ventricular mass and avoid patient-prosthesis mismatch, especially in the younger and those with systolic dysfunction, can have a significant impact on prognosis. Further evidence, with well designed clinical trials, is needed but the spotlight must be in the ventricle, not the valve.

Naturally occurring decline in cardiovascular reserve with age associates with a combination of the reduction in cardiomyocyte number and altered cardiomyocyte function. Recent investigations suggested that about half of the cardiomyocytes is the same as at birth, while the other half of the cardiomyocytes is the result of cardiomyocyte renewal in the senescent heart. In addition, the total number of cardiomyocytes is estimated to be less by one third in the old heart than the number of cardiomyocytes at birth. Thus, the reduction in cardiomyocyte number of the aging heart cannot be fully compensated by cardiomyocyte renewal. Aging of long-lived differentiated myocardial cells, as well as of cardiac progenitor stem cells may contribute to an increased rate of apoptosis, and decreased capacity of cell duplication and/or differentiation. In addition, differentiated cardiomyocytes are prone for accumulating biological by-products of cellular metabolism and of incompletely processed oxidative insults. In this context, interactions between lysosomes and mitochondria may provide a mechanistic background for the age-dependent alterations in cardiac macromolecules. This reasoning postulates a direct relationship between the number of pro-oxidative, ill-functioning mitochondria and the amount of ballast- overloaded lysosomes in long-lived cardiomyocytes. Accumulation of biological garbage and telomere shortening might be considered as hallmarks of cardiomyocyte aging with implications for depressed cardiac function and cardiomyocyte renewal. Changes in protein expression together with posttranslational modifications of myocardial proteins affect excitation-contraction coupling and explain the declining mechanical function of the cardiomyocytes. Altogether, these changes represent a significant part of the reduced cardiovascular reserve in aged individuals.

Heart failure is characterized by elevated circulating catecholamine levels and extensive abnormalities in β-adrenergic receptor signaling. Under physiological conditions, sympathetic modulation via catecholamines induces positive inotropic, chronotropic and lusitropic responses. Well established in heart failure patients is a pronounced activation of the sympathetic system, accompanied by downregulation and desensitization of β-adrenergic receptors, leading to a markedly diminished β-adrenergic contractile response. In this review, we will discuss the normal β-adrenergic receptor signaling pathway in the heart and focus on the pathphysiological alterations of β-adrenergic receptor signaling and contractile proteins in heart failure.

Left ventricular (LV) diastolic dysfunction is an important contributor to many different cardiovascular diseases. LV diastolic dysfunction can manifest itself as slow LV relaxation, slow LV filling or high diastolic LV stiffness. Diastolic abnormalities have been described in the senescent heart, in heart failure with preserved ejection fraction (HFPEF), in diabetic cardiomyopathy, in aortic valve stenosis (AVS), in hypertrophic cardiomyopathy (HCM), as well as in Fabry disease (FD), however, exact cellular and molecular alterations behind the diastolic deterioration in these diseases are not yet completely characterized. Several studies thoroughly investigated altered cardiomyocyte function, changes of contractile myofilaments, extracellular collagen deposition and advanced glycation end products (AGEs) cross-linking in the background of diastolic dysfunction. These clinical and experimental data suggest that underlying mechanisms of LV diastolic dysfunction are divergent in different cardiac pathologies, therefore the present review aims to summarize mechanisms at the cellular level of diastolic abnormalities in various cardiovascular diseases.

Our knowledge of diastolic heart failure (DHF) is still limited with regard to pathophysiology, diagnosis and clinical treatment. Amongst others, LV dyssynchrony was suggested to be an additional factor involved in the pathogenesis of subgroup of patients with DHF. In 20-30% of patients with DHF a systolic LV dyssynchrony could be detected and about 20% DHF patients evidenced a diastolic dyssyncrony. Both systolic and diastolic dyssynchrony may contribute to the impairment of cardiac function and clinical manifestation in DHF. Opposite to the systolic heart failure, wide QRS complex is uncommon which incriminates that dyssynchrony in DHF is rather related to regional disperse in contractility than to electromechanical coupling delay. Asynchronous LV relaxation and impairment of ventricular restoring forces may also impair the LV filing and lead to a diastolic dyssynchrony. Particularly in patients with preserved LV contractility mechanical LV dyssynchrony induces energy wastage and consequently reduces cardiac reserves. However, up to date it is not clear to what degree LV dyssynchrony is involved in the pathomechanisms of this subpopulation of DHF.