Diabetic foot syndrome: Immune-inflammatory features as possible cardiovascular markers in diabetes

reported as vascular complications of diabetes mellitus associated with a high degree of morbidity and mortality. Diabetic foot syndrome (DFS), as defined by the World Health Organization, is an “ulceration of the foot (distally from the ankle and including the ankle) associated with neuropathy and different grades of ischemia and infection”. Pathogenic events able to cause diabetic foot ulcers are multifactorial. Among the commonest causes of this pathogenic pathway it’s possible to consider peripheral neuropathy, foot deformity, abnormal foot pressures, abnormal joint mobility, trauma, peripheral artery disease. Several studies reported how diabetic patients show a higher mortality rate compared to patients without diabetes and in particular these studies under filled how cardiovascular mortality and morbidity is 2-4 times higher among patients affected by type 2 diabetes mellitus. This higher degree of cardiovascular morbidity has been explained as due to the observed higher prevalence of major cardiovascular risk factor, of asymptomatic findings of cardiovascular diseases, and of prevalence and incidence of cardiovascular and cerebrovascular events in diabetic patients with foot complications. In diabetes a fundamental pathogenic pathway of most of vascular complications has been reported as linked to a complex interplay of inflammatory, metabolic and procoagulant variables. These pathogenetic aspects have a direct interplay with an insulin resistance, subsequent obesity, diabetes, hypertension, prothrombotic state and blood lipid disorder. Involvement of inflammatory markers such as IL-6 plasma levels and resistin in diabetic subjects as reported by Tuttolomondo et al confirmed the pathogenetic issue of the a “adipo-vascular” axis that may contribute to cardiovascular risk in patients with type 2 diabetes. This “adipo-vascular axis” in patients with type 2 diabetes has been reported as characterized by lower plasma levels of adiponectin and higher plasma levels of interleukin-6 thus linking foot ulcers pathogenesis to microvascular and inflammatory events. The purpose of this review is to highlight the immune inflammatory features of DFS and its possible role as a marker of cardiovascular risk in diabetes patients and to focus the management of major complications related to diabetes such as infections and peripheral arteriopathy

Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date

The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage or ischemia causes the release of active inflammatory substances such as cytokines that are the basis of second level damage . During brain ischemia and after brain trauma the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuro-inflammatory cascade has been reported as activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first source of this inflammatory cascade in the brain setting. Also in ischemic stroke setting an important mediator of this inflammatory reaction is TNF-, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and pro-thrombotic events. TNF- has been shown to have an important role within the CNS; its properties include microglia and astrocyte activation, an influence on blood brain barrier permeability, influences on glutamatergic transmission and synaptic plasticity. TNF- increases AMPA receptor density on the cell surface and simultaneously decreases expression of GABA-A receptor cells, and these effects are related to a direct neuro-toxic effect. Several endogenous mechanisms regulate TNF- activity during inflammatory responses. Among endogenous inhibitors of TNF, prostaglandins, cyclic AMP and glucocorticoids are included. Etanercept, a biologic TNF antagonist has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In the studies using animal models, authors reported a limitation of TBI-induced cerebral ischemia due to etanercept action, and amelioration of brain contusion signs, and of motor and cognitive dysfunction. On this basis it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings

Electrocardiographic Diagnosis of Atrial Tachycardia: Classification, P-Wave Morphology, and Differential Diagnosis with Other Supraventricular Tachycardias

Atrial tachycardia is defined as a regular atrial activation from atrial areas with centrifugal spread, caused by enhanced automaticity, triggered activity or microreentry. New ECG classification differentiates between focal andmacroreentrant atrial tachycardia. Macroreentrant atrial tachycardias include typical atrial flutter and other well characterized macroreentrant circuits in right and left atrium. Typical atrial flutter has been described as counterclockwise reentry within right atrial and it presents a characteristic ECG “sawtooth” pattern on the inferior leads. The foci responsible for focal atrial tachycardia do not occur randomly throughout the atria but tend to cluster at characteristic anatomical locations. The surface ECG is a very helpful tool in directing mapping to particular areas of interest. Atrial tachycardia should be differentiated from other supraventricular tachycardias. We propose a diagnostic algorithm in order to help the physician to discriminate among those. Holter analysis could offer further details to differentiate between atrial tachycardia and another supraventricular tachycardia. However, if the diagnosis is uncertain, it is possible to utilize vagal maneuvers or adenosine administration. In conclusion, in spite of well–known limits, a good interpretation of ECG is very importan

Cardiac involvement in patients with cirrhosis: a focus on clinical features and diagnosis

Cirrhotic heart has been traditionally considered protected from cardiovascular disease, even if a large amount of literature has recently shown that patients affected by chronic liver disease are exposed to cardiovascular events, as well. Since the first recognition of cardiac involvement in cirrhosis, all published studies explain that decompensated cirrhotic patients suffer from haemodynamic changes, currently known as hyperdynamic syndrome, which finally lead to cirrhotic cardiomyopathy. This is defined by the presence of a subclinical systolic dysfunction unmasked under stress conditions, impaired diastolic function and electrophysiological abnormalities, in the absence of any known cardiac disease. In this review, we will discuss the clinical and diagnostic features of this condition, the prevalence of associated comorbidities, echocardiographic, electrocardiographic and cardiac magnetic resonance hallmarks and the possible diagnostic role of serum biomarkers

Anderson-Fabry disease: a multiorgan disease.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A . FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (fig.2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis . These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males . Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestationsin Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood, but probably relates, in part, to abnormal functional control of the vessels, secondary to endothelial dysfunction as a consequence of α-galactosidase A deficiency. The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas (fig 19 A, B), irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. The resultant storage of undegraded glycolipids leads to the progressive development of potentially life-threatening manifestations affecting multiple organ systems in the body. The Mainz Severity Score Index (MSSI) (table 12), a scoring system for patients with Fabry disease has been proven to be representative in patients with 'classic' Fabry disease and may be useful for monitoring clinical improvement in patients receiving enzyme replacement therapy. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases

Effects of ACE-inhibitors and angiotensin receptor blockers on inflammation.

The role of inflammation in cardiovascular disease and in hypertensive disease above all, is complex. Several studies confirm that activation of renin-angiotensin-aldosterone system (RAAS), through increase in the production of angiotensin II (Ang II), is closely related to local vascular inflammation. Over the BP lowering effects of anti-hypertensive treatments, several ancillary effects for every class may be found, distinguishing the various drugs from one another. Given the pro-inflammatory effects of Ang II and aldosterone, agents that interfere with the components of RAAS, such as ACE inhibitors, Angiotensin Receptor Blockers (ARBs), and mineralocorticoid receptor antagonists (spironolactone or the more selective eplerenone), represent logical therapeutic tools to reduce vascular inflammation and cardiovascular risk, as suggested in large clinical trials in patients with hypertension and diabetes. Regarding ACE inhibitors, actually there is no convincing evidence indicating that ACEi's reduce plasma levels of major inflammatory markers in hypertension models. Lack of evidence concerns especially these inflammation markers, such as fibrinogen of CRP, which are less closely related to atherosclerotic disease and vascular damage and conversely are affected by several more aspecific factors. Results obtained by trials accomplished using ARBs seem to be more univocal to confirm, although to great extent, these is an anti-inflammatory effect of drugs blocking AT1 receptor. In order to strictly study the effects of blockage of RAAS on inflammation, future studies may explore different strategies by, for example, simultaneously acting on the ACE and the AT1 angiotensin receptors