Adriana Visonà

Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 × 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

Intimal medial thickening of common carotid artery as indicator of coronary artery disease

The authors investigated the relation between coronary atherosclerosis, angiographically detected, and intimal-medial (I-M) thickening of the common carotid artery (CCA), as measured by high-resolution B-mode ultrasound system. They studied 31 patients with coronary artery disease (CAD) and 23 healthy control subjects. I-M thickening of CCAs and atheromatous plaques at the carotid bifurcation were evaluated. A score system was defined (range 0-20) based on the absence or presence of atherosclerotic lesions at common and internal carotid arteries. A coronary angiography score was defined based on the presence of atherosclerotic lesions at nine coronary arterial segments (range 0-36) . The thickness of CCAs (M ±SD) in CAD patients was significantly higher (1.45 ±0.95 mm) than in controls (0.87 ±0.10 mm, P < 0.005), and an I-M thickening of 1.1 mm or more was specific and positively predictive of CAD. A significant positive correlation between coronary and carotid score was observed (P < 0.028, r=0.373). The study suggests that I-M thickening could be helpful for the identification of patients at risk for CAD.

Noninvasive study of arterial hypertension and carotid atherosclerosis.

We noninvasively evaluated the prevalence and severity of atherosclerotic lesions of the internal carotid artery in 146 nonobese, nondiabetic hypertensive patients who were free of cardiovascular symptoms. We found internal carotid artery disease in 63 patients (43%), 26 (18%) with unilateral disease and the other 37 (25%) with bilateral disease. Disease severity was correlated with age but not duration of hypertension, cholesterol level, or current smoking habit. We also followed disease progression and clinical outcome with respect to cardiovascular events for 3 years in a subgroup of 95 unselected patients. In 20 of the 93 survivors (21.5%) we noted progression of the atherosclerotic lesions that was predicted by neither risk factors nor initial status of the internal carotid artery. New neurologic symptoms developed in four survivors (4%) and symptoms of cardiac ischemia in six (6%). No survivor who developed new cerebrovascular symptoms showed progression of carotid disease. These data provide useful elements for a rational approach to prevention of the atherosclerotic complications of hypertension.

Sulodexide for the Prevention of Recurrent Venous Thromboembolism The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Background— Patients with a first episode of unprovoked venous thromboembolism have a high risk of recurrence after discontinuation of anticoagulant therapy. Extending anticoagulation reduces the risk of recurrence but is associated with increased bleeding. Sulodexide, a glycosaminoglycan, exerts antithrombotic and profibrinolytic actions with a low bleeding risk when administered orally, but its benefit for preventing recurrent venous thromboembolism is not well known. Methods and Results— In this multicenter, double-blind study, 615 patients with first-ever unprovoked venous thromboembolism who had completed 3 to 12 months of oral anticoagulant treatment were randomly assigned to sulodexide 500 lipasemic units twice daily or placebo for 2 years, in addition to elastic stockings. The primary efficacy outcome was recurrence of venous thromboembolism. Major or clinically relevant bleeding was the primary safety outcome. Venous thromboembolism recurred in 15 of the 307 patients who received sulodexide and in 30 of the 308 patients who received placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.27–0.92; P=0.02). The analysis in which lost to follow-up was assigned to failure yielded a risk ratio among treated versus control subjects of 0.54 (95% confidence interval, 0.35–0.85; P=0.009). No major bleeding episodes occurred; 2 patients in each treatment group had a clinically relevant bleeding episode. Adverse events were similar in the 2 groups. Conclusion— Sulodexide given after discontinuation of anticoagulant treatment reduced the risk of recurrence in patients with unprovoked venous thromboembolism, with no apparent increase of bleeding risk. Clinical Trial Registration— URL: https://www.clinicaltrialsregister.eu/. Identifier: EudraCT number 2009-016923-77.

Local photodynamic therapy with Zn(II)-phthalocyanine in an experimental model of intimal hyperplasia.

Photodynamic therapy (PDT) appears to be a novel promising modality to prevent intimal hyperplasia (IH) and restenosis after angioplasty. Local PDT, that consists of local delivery of photosensitizing agents followed by intraluminal local irradiation, represents a recent advancement. This methodology requires optimization in order to achieve the best prompt outcome especially in terms of pharmacokinetics of the photosensitizing agent. We studied the pharmacokinetic properties by using the photosensitizing agent Zn(II)-phthalocyanine (ZnPc), locally released by a channeled balloon. The efficacy of local PDT in reducing IH was evaluated in an experimental rabbit model of arterial injury. The maximum accumulation of ZnPc was found at 30 min: the injured portion of the artery gave a ZnPc recovery of 1.18 micromol/mg, as compared with undetectable amounts of ZnPc in the non injured arteries; within 90 min after the local delivery, clearance of the agent was almost complete. Local PDT produced an effective reduction of IH in our vascular injury model: at 7, 14, 21 and 28 days IH and intima/media ratio (IMR) was significantly reduced as compared with balloon injured arteries. The local delivery of ZnPc showed favourable pharmacokinetic properties, that allow the performance of PDT immediately after the vascular injury. Local PDT performed in these conditions represents a promising approach to prevent IH after balloon injury. Further studies are needed to better clarify the biological response of the injured arterial wall to local PDT.

Prevalence of atherosclerotic involvement of the internal carotid artery in hypertensive patients

The prevalence of atherosclerotic involvement of the internal carotid arteries, as diagnosed through an echo-Doppler imaging system with pulsed Doppler spectral analysis was evaluated in 49 hypertensives who had a negative history for neurological symptoms and 49 matched controls. The prevalence was 24.5% in the hypertensive group and 10.2% in the controls with a statistically significant difference (chi-square = 6.07, P less than 0.01). Two hypertensives had severe stenosis (above 50% diameter reduction) and 7 had potentially embolic lesions (irregular surface, inhomogeneous appearance). No one of the matched controls was as severely involved. We conclude that arterial hypertension can account for enhanced prevalence of carotid artery disease in asymptomatic patients.

Wall Thickening of Common Carotid Arteries in Patients Affected by Noninsulin-Dependent Diabetes Mellitus: Relationship to Microvascular Complications:

This study evaluates the wall thickness of common carotid arteries and the atherosclerotic involvement of the carotid bifurcations in patients with noninsulin-dependent diabetes mellitus (NIDDM), with and without microvascular complications. Seventy subjects affected by NIDDM, and 17 healthy controls were evaluated by means of high-resolu tion echo-Doppler scan. Twenty-six diabetics (Group A) had complications (overnight proteinuria > 500 mg, background retinopathy, sensory neuropathy), while 44 (Group B) had no complications. The two groups were comparable for age, sex, plasma lipid profile, and smoking habit. Arterial hypertension was present in 15 of 26 (58%) complicated patients (Group A) and in 18 of 44 (41%) uncomplicated patients (Group B). None of the patients had a history of cerebrovascular disease. The authors found that the wall thickness of the common carotid artery was greater and atherosclerotic lesions of the carotid bifurcation were more frequent in diabetic patients with microvascular complications than in uncomplicated diabetics (who had a similar distribution of other risk factors for atherosclerosis) and in nondiabetic controls. These data on the one hand confirm the role of diabetes as an independent risk factor for carotid atherosclerosis and, on the other hand, indicate a correlation between microvas cular lesions and early atherosclerosis in diabetes.

Immunoscintigraphic Detection of Venous Thrombosis of the Lower Extremities by Means of Human Antifibrin Monoclonal Antibodies Labeled with 111In

A new monoclonal antibody spe cific for the beta-chain of human fi brin (C22A) and labeled with 111In has been obtained and successfully used in rabbits and dogs for the in vivo de tection of venous thrombosis. Studies in humans are currently ongoing. In order to assess the diagnostic value of 111In-antifibrin for the detection of ve nous thrombosis of the lower extrem ities, the authors investigated 25 consecutive patients. Ten patients had clinical and instrumental (con trast phlebography and duplex scan ning) evidence of acute deep venous thrombosis (DVT), 3 had a long standing DVT with relapsing epi sodes of swelling and pain, 5 had superficial venous thrombosis, and the remaining 7 had no signs of thrombosis at all. Twenty patients were being treated with heparin. All patients received 111In-antifibrin at the dose of 74 MBq IV and were scanned with a large field of view gamma camera coupled with a high- energy, parallel-hole collimator at 30 minutes and three, six, and twenty- four hours postinjection. Only the persistence of an abnormal uptake at twenty-four hours confirmed by two observers at visual inspection was considered as positive. A positive result was obtained in 9 of 10 DVT patients (90% sensitivity) and in all SVT patients. The single DVT patient with a negative 111 In- antifibrin test had the longest inter val between scintigraphy and onset of symptoms (fifty-five days). Thus, the age of thrombi represented a sub stantial limitation for the test. A false-positive result was obtained in a single SVT patient, in whom also a deep involvement, unconfirmed by phlebography, was suspected (91.6% specificity). The authors conclude that 111In- antifibrin is a new diagnostic tool for studying deep venous thrombosis, which allows direct imaging of thrombi during their relatively early phase, with a high degree of sensitiv ity and specificity.

Transcutaneous Oxygen Tension (TcPO2) Measurement as a Diagnostic Tool in Patients with Peripheral Vascular Disease

Transcutaneous oxygen tension (TcPO2) was measured through Clarks elec trode at the dorsum of the foot in 52 healthy controls whose ages ranged from twenty to sixty-five years (mean 45.05 ±14.09) and 36 nondiabetic patients with peripheral vascular disease (PVD) (5 stage I, 16 stage II, 4 stage III, 11 stage IV), under standardized conditions at rest and during recovery from limb ische mia obtained with pneumatic cuff compression for 3 minutes. At rest the TcPO2 averaged 71.20±14.26 mm Hg (range 46-92) in the con trols and 51.56±26.38 in the PVD patients (p < .01). A wide overlap was ob served between the two groups and among the different stages of the disease, and consequently, the diagnostic value of TcPO2 at rest was limited (sensitivity equal to 32%). During the recovery from ischemia the time constant (recovery half-time, T½) averaged 38.01±7.23 sec in the controls and 55.84 ± 19.82 in the PVD patients (p < .01). The T½ added to the diagnostic value of the method, making it more sensitive (55%), especially for stage II patients. The TcPO2 at rest was lower with increasing severity of the disease; both the TcPO2 at rest and the T½ correlated with the ankle-arm pressure index in the diseased limbs (r = .48 and - .41 respectively, p < .001). The method showed a limited degree of reproducibility in the controls when the right and the left lower extremity were compared in each subject; in fact, the intrasubject variance of TcPO2 and T½ was of the same magnitude as the intersubject variance (F=1.73 and 1.26 respectively), and the standard devia tions of the difference between lower extremities was elevated (13.32 mm Hg for TcPO2 and 7.80 sec for T½). Moreover, the T½ decreased with increasing age in the controls (r = - .47, p < .001). The authors conclude that, although it is a good indicator of the severity of PVD, the TcPO2 has a limited diagnostic value in this kind of patients, owing to the wide range of normalcy, to the low degree of reproducibility in a single individual, and to the influence of the age factor.

Acromegalic cardiomyopathy. An echocardiography study

Eighteen acromegalic patients (A) and 18 controls without clinical evidence of cardiac involvement and/or endocrine disease (C), matched for sex, age, body surface area, and blood pressure (BP), were investigated by M-mode (2-D derived) echocardiography, to clarify the prevalence and the possible determinants of left ventricular hypertrophy (LVH). Seven patients in each group were hypertensive (BP > 160/95 mmHg). Left ventricular mass (LVM) was 183.1 ± 60.0 g/m2 in A and 130 ± 25.9 g/m2 in C. ALVM above 140 g/m2 (that is the upper normal range in our laboratory) was found in 15/18 A and 2/18 C. The LVH was concentric (h/r > 0.45) in 12/15 A and 1/2 C. Systolic function indexes (% FS, end-systolic stress/end-systolic volume), cardiac index and total peripheral resistance index (as determined by echo) were within the normal range and similar in both groups. No correlationwas found between LVM and BP, LVM and GH plasma levels, LVM and Sm-C levels. A significant correlation was found between LVM and duration of the disease (r 0.44; p<0.05). Our data confirm that LVH is an early and frequent finding in acromegaly. Its prevalence is not entirely accounted for by such factors as body size, BP or increased cardiac output. Metabolic factors may play a major role, and a long lasting exposition to increased GH levels seems the most relevant determinant of LVH.