Sangiorgi, Giuseppe

Transcatheter aortic valve replacement is now indicated across all risk categories of patients with symptomatic severe aortic stenosis and has been proposed as first line option for the majority of patients >74 years old. However, median age of patients enrolled in the transcatheter aortic valve replacement low-risk trials is 74 years and transcatheter aortic valve replacement has never been systematically investigated in young low risk patients. Although the long-term data in surgical aortic valve replacement in young patients (age <75) are well known, such data remain lacking in transcatheter aortic valve replacement. In the absence of clear guideline recommendations in patients with challenging anatomies (eg, hostile calcium, bicuspid), it is important to know the potential advantages and disadvantages of each treatment and to consider how they might integrate with each other in the lifetime management of such patients. In this review, we discuss current outstanding issues on the management of severe aortic stenosis from a lifetime management perspective, particularly in terms of initial intervention and future reinterventions.

Experimental studies suggest that DNA content is increased in the smooth muscle cells of the arteries of hypertensive animals. It is unclear whether an increase in DNA content occurring in the smooth muscle cells of hypertensive rats represents a pressure-dependent effect. To evaluate the antihypertensive effect of long-term treatment with propionyl- l -carnitine and the possible morphological changes in thoracic smooth muscle cells correlated with this effect, we studied 4-month-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) randomly divided into five groups. One group of SHR was treated with propionyl- l -carnitine for 12 months; the other four groups of SHR and WKY received no treatment and were controls. We used static and flow cytometry to evaluate the polyploid cell content in thoracic aorta smooth muscle cells. Systolic pressure in untreated SHR progressively increased during the experiment. Treatment did not significantly influence pressure values in SHR. In WKY, blood pressure was significantly lower than that in treated and untreated age-matched SHR (2 P <.02). The number of polyploid smooth muscle cells was significantly lower in the propionyl- l -carnitine–treated SHR than in the untreated rats (2 P <.04) and similar to values for WKY. The reduction of polyploid cells in treated SHR was paralleled by a significant decrease of the aortic total DNA content, whereas no modifications occurred in smooth muscle cell mass. Long-term treatment with propionyl- l -carnitine may interfere with cellular mechanisms regulating the secondary responses involved in DNA synthesis.

Background —Despite the increasing use of stents, few reports have described human coronary artery morphology early and late after stenting. Methods and Results —Histology was performed on 55 stents in 35 coronary vessels (32 native arteries and 3 vein grafts) from 32 patients. The mean duration of stent placement was 39±82 days. Fibrin, platelets, and neutrophils were associated with stent struts ≤11 days after deployment. In stents implanted for ≤3 days, only 3% of struts in contact with fibrous plaque had >20 associated inflammatory cells compared with 44% of struts embedded in a lipid core and 36% of struts in contact with damaged media ( P <0.001). Neointimal growth determined late histological success, and increased neointimal growth correlated with increased stent size relative to the proximal reference lumen area. Neointimal thickness was greater for struts associated with medial damage than struts in contact with plaque ( P <0.0001) or intact media ( P <0.0001). When matched for time since treatment, neointimal cell density in stented arteries was similar to that in unstented arteries that had undergone balloon angioplasty and showed similar proteoglycan deposition. Conclusions —Morphology after coronary stenting demonstrates early thrombus formation and acute inflammation followed by neointimal growth. Medial injury and lipid core penetration by struts result in increased inflammation. Neointima increases as the ratio of stent area to reference lumen area increases. Deployment strategies that reduce medial damage and avoid stent oversizing may lower the frequency of in-stent restenosis.

Background —Epidemiological studies have demonstrated that hyperfibrinogenemia is an independent risk factor for cerebrovascular atherosclerosis. However, the underlying mechanisms are poorly understood. We studied whether hyperfibrinogenemia could modify the histological composition of atherosclerotic plaque and precipitate carotid thrombosis resulting from rupture of the plaque. Methods and Results —We studied the histological composition of 71 carotid atherosclerotic plaques from patients who had undergone surgical endarterectomy after a first episode of transient ischemic attack. Patients were divided into 3 groups corresponding to the tertiles of plasma fibrinogen values. Hypercholesterolemia, hypertriglyceridemia, hypertension, diabetes, and smoking habit were also assessed. At the histological analysis, plaques of patients in the highest tertile of fibrinogen (>407 mg/dL) were characterized by a high incidence of thrombosis (66.7% of cases) compared with plaques of subjects in the lower (21.7%) ( P =0.002) and middle (29.2%) ( P =0.009) tertiles. Plaque rupture was significantly associated with high fibrinogen levels (54.2%, P =0.003). Multivariate logistic regression indicated that hyperfibrinogenemia was an independent risk factor for a decrease in cap thickness ( P =0.0005), macrophage foam cell infiltration of the cap ( P =0.003), and thrombosis ( P =0.003). When the presence of other risk factors was accounted for, hyperfibrinogenemia remained an independent predictor of carotid thrombosis with an odds ratio of 5.83, compared with other risk factors. Conclusions —The results of the present study add to the evidence that hyperfibrinogenemia, independently of other risk factors, is associated with a specific histological composition of carotid atherosclerotic plaques that predisposes them to rupture and thrombosis.

Abstract —Apoptosis is an active form of cell death that is intricately regulated and distinct from necrosis. Data suggest that apoptosis may play a role in the pathophysiology of coronary atherosclerotic disease. Anatomic evidence of apoptosis has been observed in coronary atherosclerosis, restenosis, and transplant arteriopathy, accompanied by an increase in biochemical and genetic markers of apoptosis. Vasoactive substances such as nitric oxide and angiotensin II also regulate vascular smooth muscle cell apoptosis; vasodilating factors may induce apoptosis, whereas vasoconstricting factors may inhibit apoptosis. The aim of this article is to review key points regarding the detection of apoptosis, its regulation, and its possible role in the pathogenesis of coronary artery disease.

Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases (matrix metalloproteinases, adamalysins, or pappalysins), serine proteases (elastase, coagulation factors, plasmin, tissue plasminogen activator, urokinase plasminogen activator), and the cysteine proteases (such cathepsins). In addition to their matrix degradation capabilities, they have other less well known biologic functions that include angiogenesis, growth factor bioavailability, cytokine modulation, receptor shedding, enhancing cell migration, proliferation, invasion, and apoptosis. This review discusses extracellular proteases relevant to the vasculature, their classification and function, and how protease disorders contribute to arterial plaque growth, including chronic atherosclerosis, acute coronary syndromes, restenosis, and vascular remodeling. These broad extracellular protease functions make them potentially interesting therapeutic targets.