Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents.

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood.

The natural history of stenoses within lower limb arterial bypass grafts using a graft surveillance program.

Graft surveillance aims to identify those grafts that are at risk of failure as intervention in a patent but failing graft results in improved long-term patency and limb salvage rates compared to rescue of an occluded graft. Controversy exists as to which types of graft benefit the most from surveillance and whether patient factors such as diabetes and smoking status have an effect on graft survival. Our aims were (1) to clarify the natural history of midterm graft failure as a consequence of myointimal hyperplasia and (2) to identify which patients and grafts are at a higher risk of failure and at what time points this is most prevalent. Serial vascular laboratory and clinical data of 212 infrainguinal lower limb grafts in 197 patients were analyzed. Follow-up within the surveillance program was by focused examination with color flow duplex ultrasound at 0, 1, 3, 6, 12, and 18 months with respect to surgery. Outcomes were correlated with retrospectively collected data regarding patient demographics, smoking status, concurrent medication, comorbidity, and operative factors such as distal target vessel and conduit. During the program, 21.6% of grafts occluded. Overall, 16% of grafts underwent a salvage procedure, 40.5% of which were carried out at the 6-month time point. There were 56.6% of occlusions preceded by a stenotic lesion. Primary occlusions accounted for 95.9% in the prosthetic group and 66.5% in the femorocrural group. As a group, vein grafts were more likely to develop a progressive stenosis prior to occlusion, with 58.3% in this group predated by a stenotic lesion. Fewer than 75% of stenoses were common and had a variable natural history, with over 40% resolving or failing to progress. Throughout the study period, 56.2% of grafts remained stenosis-free. Stenoses were more common at the proximal anastomosis in the vein graft cohort. There were low rates of significant stenoses within the prosthetic group. These lesions were more likely to occur at the distal anastomosis but were poor predictors of occlusion. Statin use postoperatively was protective against the development of significant stenosis and occlusions, particularly in the above-knee grafts (p = 0.03). Surprisingly, preoperative smoking status was predictive of neither occlusion nor development of significant stenosis. The presence of diabetes was not predictive of poor outcome. Our findings suggest that graft surveillance is a valid method for detecting the presence of significant stenoses in vein grafts at high risk of failure without intervention. Despite the intensive follow-up, the program failed to detect lesions prior to occlusion in a large percentage of prosthetic and femorocrural grafts, so perhaps this group is poorly served by graft surveillance.

Intimal neovascularisation is a prominent feature of atherosclerotic plaques in diabetic patients with critical limb ischaemia.

INTRODUCTION: Neovascularisation of atherosclerotic plaques correlates with increased plaque instability and subsequent risk of vascular complications. Diabetics have widespread atherosclerotic involvement of the arterial tree and a more aggressive form of the disease culminating in increased plaque instability. This results in a greater incidence of ischaemic sequelae than in non-diabetics. Previous studies have examined neovascularisation as a marker of plaque instability in both the carotid and coronary territories and revealed a greater degree in both symptomatic and diabetic patients. This is the first study to examine intimal neovascularisation in lower limb peripheral arterial disease. METHODS: Arterial specimens were taken from 20 patients, ten of whom were type 2 diabetics, undergoing major lower limb amputation for unreconstructable critical ischaemia. Sections were stained with H&E for morphological assessment and inflammatory cell characterisation. Additional sections underwent immunohistochemical staining for CD31 and von-Willebrand Factor (vWF) and the number of intimal vessels per four 40x magnification fields assessed. RESULTS: There was a more prominent inflammatory infiltrate in diabetic subjects compared to non-diabetic controls. Diabetic patients had a greater degree of intimal neovascularisation compared to controls with a median of 11.5 and 2.0 vessels per field respectively (P<0.05). Sub-group analysis revealed that diabetic patients medicating with HMG-CoA Reductase inhibitors (Statins) had a greater degree of neovascularisation compared to those not taking this class of medication. CONCLUSION: Diabetic patients with critical limb ischaemia requiring amputation demonstrate a greater degree of plaque intimal neovascularisation and inflammatory infiltrate compared to their non-diabetic counterparts. This may explain the greater plaque instability and subsequent cardiovascular complications seen in these patients.

Expression of growth factors and growth factor receptor in non-healing and healing ischaemic ulceration.

OBJECTIVES: To characterise the histological and cytokinetic characteristics of purely ischaemic ulcers and the processes that underpin healing following successful revascularisation. DESIGN: Prospective observational study. MATERIALS AND METHODS: Biopsies were taken immediately pre- and 6 weeks following successful revascularisation of solely ischaemic ulceration. They were evaluated for morphological differences using H&E staining for the platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), TGFbeta receptorIII (TGFbetaRIII), transforming growth factor beta 1 and 3 (TGFbeta1 and TGFbeta3) and von Willebrand factor (vWF) expression using immunohistochemistry. Localisation and quantification of these growth factors and receptors was assessed systematically by three independent investigators who were blinded to the timing of biopsy. RESULTS: Pre-operatively, small vessel vasculitis, necrosis and infection with a profuse neutrophil and macrophage infiltrate was observed in all samples. Post-operative biopsies revealed a proliferation of new capillaries in and around the ulcer edge and base. vWF staining confirmed an endothelial layer within these new vessels. Following successful revascularisation there was less infection and inflammation with minimal vasculitis. These newly formed capillaries had increased staining for TGFbeta3, PDGFR and TGFbetaRIII with staining for PDGFR also localised to dermal fibroblasts which were larger and more numerous. Accelerated epithelial cell proliferation was observed with detachment from the underlying dermis. CONCLUSIONS: Healing of purely ischaemic ulcers is characterised by vasculogenesis associated with increased presence of the proangiogenic cytokines PDGF and TGFbeta3. These findings show promise for the use of growth factor manipulation to aid healing in ischaemic ulcers.

Colonic epithelial apoptosis during conventional and endoluminal aortic surgery.

BACKGROUND: This study characterized the initial modes of colonic mucosal injury during aneurysm surgery and correlated these with proinflammatory cytokine release into the colonic and systemic circulations. METHODS: Twenty-four patients undergoing conventional open aortic aneurysm repair and ten who had endovascular aneurysm repair (EVAR) were recruited. Mucosal biopsies were taken from the sigmoid colon immediately before and after surgery, for histological examination. Inferior mesenteric vein (IMV) and peripheral blood from patients who had conventional surgery was assayed for interleukin (IL) 1 beta, IL-6 and tumour necrosis factor (TNF) alpha. Only peripheral blood from patients who had EVAR was assayed. RESULTS: Conventional aneurysm repair resulted in a threefold increase in columnar epithelial apoptosis. There was a 26-fold increase in IL-6 in IMV blood within 5 min of reperfusion, with an equivalent rise in peripheral blood after 30 min. A 20-fold rise in peripheral blood TNF-alpha was observed after surgery. Splanchnic IL-6 correlated positively with cross-clamp time and increased apoptosis. No histological changes were seen after EVAR. There were no intraoperative cytokine changes during EVAR, although a postoperative increase in IL-6 and TNF-alpha was observed. CONCLUSION: The lack of columnar epithelial apoptosis following EVAR reflects the relatively minor ischaemic injury incurred during this procedure.

The influence of asymptomatic significant carotid disease on mortality and morbidity in patients undergoing coronary artery bypass surgery.

OBJECTIVES: Controversy exists regarding the optimal management of patients with coexisting coronary and extracranial carotid artery disease. This study investigates the incidence of death, cerebrovascular events and myocardial infarction (MI) in patients with asymptomatic significant carotid artery disease undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Prospective cohort. METHODS: Fifty patients with asymptomatic carotid stenoses > or =70% associated with cervical bruits undergoing CABG without prophylactic carotid endarterectomy (CEA) were followed up over a median period of 68 months following surgery cerebrovascular events, MI and mortality were recorded. All patients received optimal secondary prevention for cardiovascular disease unless contraindicated. RESULTS: No cerebrovascular events occurred within 30 days of surgery. One patient suffered an ipsilateral transient ischaemic attack (TIA) 14 months after CABG. Two patients died within 30 days; one from an MI, the other from pancreatitis. Three deaths occurred after 30 days; one from MI, one from primary lung cancer and one following rupture of an abdominal aortic aneurysm. No non-fatal MIs occurred. CONCLUSIONS: In this patient group the overall risk of death, cerebrovascular events and MI was 4% during the first 30 days postoperatively and 8% thereafter. This compares favourably with published series for staged or combined CEA-CABG procedures. For asymptomatic significant carotid disease, prophylactic CEA prior to CABG does not appear to confer any advantage over CABG alone.

Transient neonatal pustular melanosis.

A black male infant had congenital lesions that consisted of pigmented macules, many of which had a peripheral collarette of scale, and vesicopustules. The appearance of this patient fit the clinical syndrome of transient neonatal pustular melanosis, a newly described vesicopustular disease of the newborn. Differential diagnosis in this patient included the following conditions: erythema toxicum neonatorum, staphylococcal pyoderma, and herpes simplex.