Cardiovascular & Haematological Disorders - Drug Targets - Volume 7, Issue 1, 2007

Medial vascular calcification in an increasingly recognized problem in patients with diabetes and patients with chronic kidney disease. Calcification of the media is associated with significant morbidity and mortality. The phenotypic and the molecular fingerprints of medial calcification in patients with diabetes and patients with chronic kidney disease are strikingly similar. While disturbances in divalent ion homeostasis have been proposed to play a role in calcification of the media in patients with chronic kidney disease, patients with diabetes have an apparently intact bone and mineral metabolism. Chronic kidney disease as well as diabetes are now recognized as pro-inflammatory states. This review will explore the pathobiology of medial vascular calcification, review the evidence for diabetes and chronic kidney disease as pro-inflammatory states, and discuss the role of inflammation as a mechanistic link that explains the similarities in phenotypic and molecular characteristics of medial calcification in patients with chronic kidney disease and patients with diabetes mellitus.

HMG-CoA reductase inhibitors (statins) are among the most widely used hypolypemizing drugs with a pleiotropic activity. Numerous clinical trials have demonstrated that statins can have a significant effect in the prevention of cardiovascular diseases in the general population. In patients with renal failure, this drug preserves the hypolypemizing efficacy found in the general population without increasing their unwanted side-effects. The re-analysis of data from epidemiological studies conducted on the general population has confirmed that statins provide cardiovascular protection also in subjects with renal failure. These data have been partly confirmed by the findings made by 4D (Die Deutsche Diabetes Dialyse Studie) and Alert studies, conducted on diabetic patients on dialysis and patients with renal transplants, respectively. The results of other studies, such as AURORA, SHARP, REnal and Vascular End stage Disease, and ESPLANADE, clearly indicate that statins prevent cardiovascular disease in patients with renal insufficiency, just as they do in the general population.

A review of the existing evidence on the impact of percutaneous coronary intervention (PCI) in the setting of stable coronary artery disease (CAD) indicates that in patients with chronic coronary artery disease and good left ventricular function, PCI does not confer any clear benefit in terms of hard long-term clinical outcomes, such as mortality, myocardial infarction or the need for subsequent revascularization, as compared with medical conservative treatment. By comparing the benefits against cost considerations, it seems that many percutaneous interventions that are currently performed in patients with non-acute CAD are probably not justified. Determination of the functional significance of coronary artery disease can often be a challenge. Conventional coronary angiography and imaging tests, although suitable for risk stratification, may not be satisfactory as independent guides for specific decision-making regarding the optimum management of these patients. The development of more efficient methods for the identification of coronary lesions that should be the target of coronary intervention is certainly needed.

Cirrhotic cardiomyopathy is a recently identified pathological condition defined as “a chronic cardiac dysfunction in patients with cirrhosis characterized by blunted contractile responsiveness to stress and/or altered diastolic relaxation with electrophysiological abnormalities, in the absence of known cardiac disease”. Overall there seems to be a link between the progression of liver function impairment, the development of portal hypertension and the degree of hyperdynamic circulation, the hallmark of the deranged cardiovascular function in advanced liver diseases. Although mechanical factors contribute to much of the increased resistance within the liver in portal hypertension, there is clearly a vasculogenic component to the development, perpetuation and progression of this syndrome as well. The vascular component of portal hypertension includes an increase in splanchnic blood flow, as well as an increase in intrahepatic vascular resistance. Dysregulation of the nitric oxide system appears to play a key role in both these processes with a paradoxical reduction of intrahepatic availability despite increased disposal in the splanchnic and other vascular districts with adverse effects on cardiac function and structure. Nevertheless, other putative mediators of cardiac damage in cirrhosis have been proposed and their role in the pathogenesis of cirrhotic cardiomyopathy investigated. This review involves a discussion of data achieved on pathogenesis and clinical features of cirrhotic cardiomyopathy but mainly focuses on considerations on potential therapeutic targets, in the light of the evidence that this mainly subclinical condition merges to clinical relevance when challenged with those therapeutic interventions and procedures currently employed to treat the major complications of cirrhosis that might produce a negative impact on the cardiovascular system.

Pulmonary oedema (PO) can emerge from mechanical disorders in pulmonary circulation leading to elevated fluid filtration in the lung, or from increased vascular permeability due to inflammatory or toxic injury of the alveolarcapillary barrier. A number of these disorders causing PO is associated with increased catecholamine (CA) levels in plasma and lung tissue and/or increased sympathetic activation such as neurogenic PO, high-altitude PO or PO in patients with phaeochromocytoma. Experimental CA stimulation in animals induced PO after less than one hour of infusion. Both α- and β-adrenergic mechanisms are involved in the pathogenesis but also in the resolution of PO. CAs increase pulmonary capillary pressure and thus, enhance fluid filtration into the pulmonary interstitium. Additionally, by activation of proinflammatory cytokines, they induce pulmonary inflammation that may lead to capillary leak. Finally, they play an important role in the regulation of alveolar fluid clearance. The present paper considers the pathways by which CAs contribute to the development of PO of various origin.

Hypertension is a major risk factor leading to devastating cardiovascular events such as myocardial infarction, stroke, heart failure, and renal failure. Despite intensive research in this area, mechanisms underlying essential hypertension remain to be defined. Accumulating evidence indicates that neural components including both sympathetic and sensory nerves innervating the cardiovascular and renal tissues play a key role in regulating water and sodium homeostasis and blood pressure, and that abnormalities in these nervous systems contribute to increased salt sensitivity and development of hypertension. In contrast to relatively well-defined sympathetic nervous system, the role of sensory nerves in the control of cardiovascular homeostasis is largely unknown. Data from our laboratory show that degeneration of capsaicinsensitive sensory nerves renders a rat salt sensitive in terms of blood pressure regulation. Evidence is also available indicating that sensory nerves, in interacting with other neurohormonal systems including the sympathetic nervous system, the renin-angiotensin aldosterone system, the endothelin system, and superoxide, regulate cardiovascular and renal function in such that they play a counter-balancing role in preventing salt-induced increases in blood pressure under pathophysiological conditions. Altered activity of the sensory nervous system, a condition existed in both genetic and experimental models of hypertension, contributes to the development of hypertension. This article focuses on reviewing the current knowledge regarding the possible role of sensory nerves in regulating blood pressure homeostasis as well as the function and regulation of novel molecules expressed in sensory nerves.

In 1628, Harvey first correctly described the heart as a pump. It was another 350 years before the heart was established as an endocrine gland that synthesized a family of peptide hormones that regulate blood volume and blood pressure. There are now five peptide hormones made in the heart which have been demonstrated to have beneficial effects in persons with congestive heart failure. One of these peptide hormones i.e. brain natriuretic peptide (BNP) is commercially available and has been widely used in the United States for the treatment of acute congestive heart failure under the name Nesiritide/Natrecor®. Nesiritide has one serious side effect, i.e. it may worsen renal function in persons with acute decompensated cardiac failure. The best of these peptide hormones for the treatment of chronic heart failure is a cardiac hormone named vessel dilator which enhances sodium and water excretion 4- to 5-fold in persons with congestive heart failure but vessel dilator's biologic effects lasts six hours compared to less than 30 minutes for BNP, without the deleterious effects of BNP on renal function. This review will focus on six cardiac hormones' discovery, identification and comparison of their beneficial effects and side effects in humans with congestive heart failure.

Orthostatic hypotension (OH) may be dependent upon various neurogenic and non-neurogenic disorders and conditions. Neurogenic causes include the main autonomic failure syndromes, primary (multiple system atrophy, pure autonomic failure, and autonomic failure associated with Parkinson's disease) and secondary (central nervous system diseases, peripheral neuropathies and systemic diseases). Non-neurogenic causes of OH include cardiac impairment, fluid and electrolyte loss, vasodilatation, and old age. A number of drugs may also cause OH, through their vasoactive action or by interfering with the autonomic nervous system. Symptoms of OH are debilitating, often confining patients to bed, and longitudinal studies have shown that OH increases the risk of stroke, myocardial ischemia and mortality. The therapeutic goal is to decrease the incidence and severity of postural symptoms, rather than restore normotension. In non-neurogenic OH, treatment of the underlying cause may be curative. In neurogenic OH a combination of nonpharmacological and pharmacological measures is often needed. Patient education and non-pharmacological measures represent the first step; among these interventions, fluid repletion and physical countermanoeuvres have been proven very effective. Pharmacological treatment comprises a number of agents acting on blood vessels, on blood volume or with other pressor mechanisms. The drugs most currently used are fludrocortisone and midodrine. Fludrocortisone expands the extravascular body fluid volume and improves α-adrenergic sensitivity. Midodrine is a peripheral, selective α1-adrenergic agonist that causes arterial and venous vasoconstriction. Despite the wide use of these drugs, multicentre, randomised and controlled studies for the treatment of OH are still scarce and limited to few agents and groups of patients. Pharmacological management of OH substantially improves the quality of life of patients, although it may be problematic. The development of supine hypertension and subsequent congestive heart failure should be avoided, especially in those patients with a pre-existing cardiovascular risk, such as in diabetes or ischemic heart disease.

Platelet-collagen interaction plays an important role in hemostasis and pathological thrombosis. Upon an injury to the subendothelium of a blood vessel wall, platelets adhere to the denuded substrate, aggregate, and release biological substances. Many investigators have explored the use of blocking agents to interrupt the final step of binding fibrinogen on glycoprotein (GP) IIb/IIIa of activated platelets. A potent peptide is Arg-Gly-Asp-Ser (RGDS) and its derivatives in various forms. Results from many clinical trials show that the efficacy of these antagonists does not lie in blocking the adhesion of platelets to the distal site(s) of the injury as expected. Because type I and type III collagens are predominant components of blood vessel walls, other laboratories and ours have defined various active peptides from either collagen molecules or platelets as useful for blocking collagen-platelet interaction. An active hybrid peptide derived from both platelet types I and type III collagen receptors that abolishes type I and type III collagen-induced platelet aggregation has been obtained. The hybrid peptide inhibits the binding of type I and type III collagens to washed human platelets, platelet aggregation, and the adhesion of washed platelets to rabbit aortic segments. However, the usefulness of the defined hybrid peptide in preventing thrombi formation in vivo requires further investigation.