The apoprotein pattern in normolipemic peripheral vascular disease

The relationship between peripheral vascular disease (PVD) and plasma apoproteins has still not been well defined. The lipid and apoprotein pattern of a group of 20 normolipemic patients affected by peripheral vascular disease has been compared with 20 healthy normolipemic subjects. Mean triglyceride plasma levels were higher in normolipemic patients than in the healthy controls (107.8 +/- 31.5 mg% vs 73.3 +/- 28.6 mg%; p less than 0.03) while mean HDL-cholesterol values were significantly lower (36.5 +/- 5.4 mg% vs 44.4 +/- 7.1 mg%; p less than 0.003). No significant difference was observed between the two groups in the mean values of the apoproteins AI (112.1 +/- 41.2 mg% in PVD vs 117.2 +/- 17.7 mg% in controls), AII (45.1 +/- 12.2 mg% vs 50.1 +/- 11.1 mg%), B (93.7 +/- 23.5 mg% vs 91.3 +/- 21.6 mg%), CII (3.9 +/- 2.6 mg% vs 2.6 +/- 1.7 mg%), CIII (6.7 +/- 1.5 vs 5.9 +/- 1.4 mg%) and E (3.09 +/- 1.4 mg% vs 3.3 +/- 0.9 mg%). On the contrary the mean triglyceride/Apo-E ratio was higher in PVD patients than in the controls (52.3 +/- 42 vs 23.3 +/- +/- 10; p less than 0.03).     

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies

Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.     

β3‐Adrenoceptors modulate left ventricular relaxation in the rat heart via the NO‐cGMP‐PKG pathway

Aims: Using a model of isolated and Langendorff‐perfused rat heart we analysed whether activation of β₃‐adrenergic receptors (β₃‐ARs) influences ventricular lusitropic performance. We also focused on the NOS/NO/cGMP/PKG cascade as the signal transduction mechanism. Methods: Hearts were treated with increasing concentrations (from 10^?12 to 10^?6 m ) of BRL₃₇₃₄₄, a selective β₃‐AR agonist, and cardiac performance was evaluated by analysing both lusitropic parameters and coronary motility. Cardiac preparations were also perfused with BRL₃₇₃₄₄ in the presence of either isoproterenol (ISO) or nadolol, or pertussis toxin (PTx), or selective inhibitors of the NOS/NO/cGMP/PKG pathway. Results: BRL₃₇₃₄₄ caused a significant concentration‐dependent reduction in (LVdP/dt)_min, a decrease in half time relaxation significant starting from 10^?12 m , and an increase in (LVdP/dt)_max/(LVdP/dt)_min ratio (T/?t). BRL₃₇₃₄₄ abolished the ISO‐mediated positive lusitropism. β₃‐AR‐dependent effects on relaxation were insensitive to β₁/β₂‐AR inhibition by nadolol (100 nm ), and were abolished by G_i/o protein inhibition by PTx (0.01 nm ). NO scavenging by haemoglobin (10 μm ), and nitric oxide synthase (NOS) inhibition by NG‐monomethyl‐l ‐arginine (10 μm ) revealed the involvement of NO signalling in BRL₃₇₃₄₄ response. Pre‐treatment with inhibitors of either soluble guanylate cyclase (ODQ; 10 μm ) or PKG (KT₅₈₂₃; 100 nm ) abolished β₃‐AR‐dependent negative lusitropism. In contrast, anantin (10 nm ), an inhibitor of particulate guanylate cyclase, did not modify the effect of BRL₃₇₃₄₄ on relaxation. Conclusion: Taken together, our findings provide functional evidence for β₃‐AR modulation of ventricular relaxation in the rat heart which involves PTx‐sensitive inhibitory Gi protein and occurs via an NO‐cGMP‐PKG cascade. Whether the effects of β₃‐AR stimulation on lusitropism are beneficial or detrimental remains to be established.     

Effect of body weight changes on 24-hour blood pressure and left ventricular mass in hypertension: a 4-year follow-up

BACKGROUND: Few data are available on the long-term effects of weight loss on 24-h blood pressure (BP) and left ventricular mass in overweight hypertensive patients. METHODS: A total of 181 never-treated overweight hypertensive subjects (body mass index, 25 to 39 kg/m(2), office BP 145/94 +/- 12/7 mm Hg) had 24-h BP monitoring and echocardiography twice, at baseline and after 3.8 +/- 2 years (minimum 1 year). None of the subjects received antihypertensive drugs during the follow-up. Main outcome measures were changes in 24-h BP and in left ventricular mass. RESULTS: Percent change in body weight had a direct relationship with 24-h BP changes (r = 0.35 and 0.31 for systolic and diastolic BP, respectively; both P <.001). The associations with office BP changes (r = 0.13, P =.10 for systolic BP; r = 0.15, P =.06 for diastolic BP) were significantly weaker (both P <.01, z test). The patients who lost weight during follow-up (n = 106) had a significantly lower increase in 24-h BP (+0.6 +/- 9/ +0.2 +/- 6 v +4.9 +/- 9/ +2.7 +/- 7 mm Hg for systolic/diastolic BP, both P <.01) and in left ventricular mass (-3 +/- 30 g v +9 +/- 32 g, P <.02) than the remaining subjects. In a multiple linear regression, a 10% weight loss independently predicted a 4.3/3.8 mm Hg decrease in 24-h systolic/diastolic BP. CONCLUSIONS: Long-term weight loss determines a sustained BP reduction during the 24 h and a decrease in left ventricular mass in overweight hypertensive subjects. The relation of weight loss with ambulatory BP changes is closer than that with office BP.     

Prognostic value of low and high ankle-brachial index in hospitalized medical patients

BackgroundPeripheral arterial disease (PAD) is frequently underdiagnosed in the clinical practice, leading to a lack of opportunity to detect subjects at a high risk for cardiovascular (CV) death. The ankle-brachial pressure index (ABI) represents a noninvasive, objective tool to diagnose PAD and to predict adverse outcome.MethodsABI was determined by means of Doppler velocimetry, in 707 patients, aged 50 years or older, consecutively hospitalized in an internal medicine ward, who were followed-up for at least 12 months in order to assess all-cause and CV mortality.ResultsSymptomatic PAD affected 8% of the population while the prevalence of PAD, defined as ABI < 0.90, was 29%; high ABI (> 1.40) was found in 8% of the patients. After a mean follow-up period of 1.6 years, both low and high ABI were independently associated with CV mortality with a hazard ratio of 1.99 (p = 0.016) for low and 2.13 (p = 0.04) for high ABI, compared with normal ABI (0.90–1.40). High ABI also independently predicted all-cause mortality with a hazard ratio of 1.77 (p = 0.04).DiscussionABI measurement reveals a large number of individuals with asymptomatic PAD among those hospitalized in an internal medicine department. An increased mortality was observed in patients with both low and high ABI. Hospital admission for any reason may serve as an opportunity to detect PAD and start appropriate preventive actions.