Platelet GP IIIA polymorphism HPA-1 (PLA1/2) is associated with hypertension as the primary cause for end-stage renal disease in hemodialysis patients from Greece.

Human platelets carry membrane glycoproteins that control platelet aggregation and activation. A number of clinical studies have suggested that certain polymorphisms of genes encoding these proteins increase the risk for cardiovascular disease. The frequency of gene polymorphisms for the four most common platelet glycoproteins (HPA 1, 2, 3 and 5) was examined and correlated with the primary cause of end-stage renal disease (ESRD) in Greek patients on HD. Fifty-five (55) patients on chronic maintenance haemodialysis (HD) (22 female, 33 male), aged from 23- to 87-years-old, (mean age 66 years), being on dialysis for 53 +/- 34 months, were included in the study. HPA-1, -2, -3, and -5 genotyping was performed using polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP). Calculated relative frequencies of the alleles were as follows: HPA-1a/b 0.81/0.19, HPA-2a/b 0.92/0.08, HPA-3a/b 0.62/0.38 and HPA-5a/b 0.93/0.07. There was a statistically significant association between the HPA-1b allele and hypertension as the primary cause of ESRD (65% of patients with hypertension vs 23% of all other patients carried the HPA-1b allele, p=0.02, Fisher's exact test). The results suggest that Greek carriers of the HPA-1b allele with hypertension may be at increased risk for developing end-stage renal disease.

Incidence and risk factors of coronary heart disease in elderly patients on chronic hemodialysis.

AIM: To determine the incidence of coronary heart disease (CHD) in patients (pts) over 65 years (y) and its relation to common risk factors. METHODS: We retrospectively studied 128 hemodialysis (HD) pts (80 M and 48 F), mean age 73+/-6.5 years, mean time on HD 44.4+/-26.4 months and BMI 25.4+/-3 kg/m2. They were evaluated for: age, sex, smoking, diabetes, hypertension, left ventricular hypertrophy, secondary hyperparathyroidism (SHP), inflammation, as evidence by elevated level of hsCRP, hyperhomocysteinemia (HOC), time on HD, fluid overload and adequacy of HD. Forty-eight pts (37%) had CAD diagnosed by coronary angiography in 22 (46%) and (201)TL-chloride dipyridamole stress test in 26 (54%). RESULTS: There was a statistically significant correlation between CAD and increasing age (p<0.0001). The relative risk was significantly increased concerning: (1) male over female pts (RR: 1.95, p<0.01), (2) diabetic vs. non diabetic pts (RR: 2.09, p<0.001), (3) patients with SHP over pts with iPTH values<250 pg/ml (RR: 2.16, p<0.001), (4) hypertensive vs. non hypertensive pts (RR: 2.26, p=0.002), (5) smokers vs. non smokers (RR: 1.69, p<0.05), (6) pts with HOC over pts with normal homocysteine values (RR: 2.09, p<0.05), (7) pts with increased CRP levels over pts with normal CRP levels (RR: 1.8, p<0.01), (8) pts undergoing HD for 36 vs. 12 months (RR: 1.71, p=0.03), (9) between pts with inadequate or adequate HD (RR: 1.73, p=0.02). No significant correlation existed between CAD incidence and the other risk factors. CONCLUSIONS: Coronary heart disease incidence in elderly HD patients increases with age, male sex, diabetes, SHP, hypertension, increased CRP levels, HOC, smoking, time on HD and inadequacy of HD.

Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors.

BACKGROUND: Gene therapy offers an unprecedented opportunity to treat diverse pathologies. Adeno-associated virus (AAV) is a promising gene delivery vector for cardiovascular disease. However, AAV transduces the liver after systemic administration, reducing its usefulness for therapies targeted at other sites. Because vascular endothelial cells (ECs) are in contact with the bloodstream and are heterogeneous between organs, they represent an ideal target for site-specific delivery of biological agents. METHODS AND RESULTS: We isolated human venous EC-targeting peptides by phage display and genetically incorporated them into AAV capsids after amino acid 587. Peptide-modified AAVs transduced venous (but not arterial) ECs in vitro, whereas hepatocyte transduction was significantly lower than with native AAV. Intravenous infusion of engineered AAVs into mice produced reduced vector accumulation in liver measured 1 hour and 28 days after injection and delayed blood clearance rates compared with native AAV. Peptide-modified AAVs produced enhanced uptake of virions in the vena cava with selective transgene expression. Retargeting was dose dependent, and coinfusion of either heparin or free competing peptides indicated that uptake was principally independent of native AAV tropism and mediated via the peptide. CONCLUSIONS: AAV tropism can be genetically engineered by use of phage display-derived peptides to generate vectors that are selective for the vasculature.