The new “intermediate risk” group: A comparative analysis of the new 2013 ACC/AHA risk assessment guidelines versus prior guidelines in men

Background

The 2013 ACC/AHA Report on the Assessment of Cardiovascular (CVD) Risk redefined “intermediate risk”. We sought to critically compare the intermediate risk groups identified by prior guidelines and the new ACC/AHA guidelines.

Methods

We analyzed data from 30,005 adult men free of known CVD from a large, multi-ethnic study of middle-aged adults. The Framingham Risk Score was calculated using published equations, and CVD risk was calculated using the new ACC/AHA Pooled Cohort Equations Risk Estimator. We first compared the size and characteristics of the intermediate risk group identified by the old (ATP III, 10–20% 10-year CHD risk) and new guidelines (5–7.4% 10-year CVD risk). We then defined time-to-high-risk as the length of time an individual patient resides in the intermediate risk group before progressing to high risk status based on advancing age alone.

Results

The mean age of the study population was 53 ± 13 years, and 24% were African-American. Patients identified as intermediate risk by the new ACC/AHA Guidelines were younger and more likely to be African-American and have lower risk factor burden (all p < 0.05). The new intermediate risk group was just 37% the size of the traditional ATP III intermediate risk group, while the new high risk group was 103% larger. Under the new guidelines, men remain intermediate risk for an average of just 3 years, compared to 8 years under the prior guidelines (63% shorter time-to-high-risk, p < 0.05), before progressing to high risk based on advancing age alone.

Conclusion

The new 2013 ACC/AHA risk assessment guidelines produce a markedly smaller, lower absolute risk, and more temporary “intermediate risk” group. These findings reshape the modern understanding of “intermediate risk”, and have distinct implications for risk assessment, clinical decision making, and pharmacotherapy in primary prevention.     

Study of human leukocyte antigen class I phenotypes in Moroccan patients with nasopharyngeal carcinoma

Previous reports demonstrated an association between the human leukocyte antigen (HLA) and risk for nasopharyngeal carcinoma (NPC) among the Chinese in Singapore, a population with a high incidence of this malignancy. In our study, we assess the association between HLA and NPC in Morocco, a median-prevalence area for this cancer, where NPC presents the particularity of also affecting young individuals. Using the standard microlympho-cytotoxicity test, we typed a total of 154 Moroccan NPC patients and 257 unrelated healthy controls for their HLA-A and B antigens. The results of these analyses show that the frequencies of HLA-A10, HLA-B13 and HLA-B18 were found to be higher in the NPC group than in the control group, whereas HLA-A9 was associated with a decreased risk. After correction for the number of specificities tested, these differences were statistically significant only for HLA-B18 (corrected p value [pc] < 0.023, relative risk [RR] = 4.14) and HLA-A9 (pc < 0.023, RR = 0.45). The comparison of the distribution of the HLA antigens in younger and older cohorts of patients shows that the incidence of HLA-A10 and HLA- B18 was higher in the older group, whereas the frequencies of HLA-A19 and HLA-B13 were significantly higher in younger patients compared with controls. The presence of both HLA-A19 and HLA-B13 phenotypes correlated with an increased risk of developing NPC among overall patients compared with controls. According to the sex distribution, increased frequency of HLA-B18 was found in male and female NPC patients compared with controls, whereas the frequency of HLA-A10 was higher only in male NPC patients compared with controls.     

High frequency of latent membrane protein-1 30-bp deletion variant with specific single mutations in Epstein-Barr virus-associated nasopharyngeal carcinoma in Moroccan patients

Latent membrane protein 1 (LMP-1) is an Epstein-Barr virus-encoded oncoprotein expressed in approximately 50-70% of nasopharyngeal carcinoma (NPC). Previous studies have shown that NPC-derived LMP-1 variants carrying 30 bp deletion and specific mutations in the 3'C-terminal region confer high oncogenic potential and a weak immunogenicity. Although numerous polymorphism studies of LMP-1 have been carried out so far in the Asian population with NPC, very little is known in this regard on NPC patients from Northern Africa where there is a significantly high occurrence of this tumor. In our study, we examined the frequency of different LMP-1 sequence variants derived from Moroccan NPC patients. As compared to healthy donors, NPC patients showed a high prevalence of the 30bp deletion variant of LMP-1 (i.e. 84% vs. 36%; p<0.0005). Moreover, the del-LMP-1 variant derived from NPC tumors shared identical amino acid substitutions at positions 322, 334, 338, 352 and 366 with the Mediterranean (Med) variant, whereas those derived from peripheral blood mononuclear cells (PBMC) had similar mutation pattern as China1 variant. Additional mutations within the 342-352 regions (identified in LMP-1 variants without deletion derived from NPC tumors) were not found in healthy donors' PBMC. Our results support the assumption that the distribution of LMP-1 variants in NPC tumors co-segregate with geographic regions. Indeed, Med variant is found more frequently in tumors from NPC Moroccan patients, whereas China1 variant is more prevalent in tumors from NPC patients in endemic regions for NPC.     

Impact of natriuretic peptide clearance receptor (NPR3) gene variants on blood pressure in type 2 diabetes

OBJECTIVE

Hypertension in diabetes is characterized by abnormal sodium homeostasis, suggesting a particular role of natriuretic peptide pathway. Natriuretic peptides can affect blood pressure (BP) through their plasma concentrations, which are dependent on their receptor activities. We thus assessed the association between nine NPR3 gene polymorphisms and BP levels in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Nine single nucleotide polymorphisms (SNPs) tagging the haplotype structure of the NPR3 gene were genotyped in the 3,126 French Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial participants. We then used a second population (Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE]/Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) of 2,452 patients for the purpose of replication. Finally, we separately investigated subjects selected according to their rs 2270915SNP genotypes for their BP response to salt restriction.

RESULTS

In DIABHYCAR patients, three SNPs (rs6889608, rs1173773, and rs2270915) were significantly associated with systolic BP (SBP). The effect of the rs2270915 was replicated in the second step population: AA homozygotes had a lower SBP than G carriers (137.4 ± 19.1 vs. 140.0 ± 20.2 mmHg, P = 0.004). The rs2270915 influenced the response of SBP to salt reduction, with AA homozygous patients showing greater reductions after restriction of salt intake compared with G carriers: −20 mmHg (−43 to −8) vs. −3 (−20 to +7); P = 0.006.

CONCLUSIONS

We found a consistent and significant association between the rs2270915 polymorphism of the NPR3 gene and SBP in diabetic patients. This genetic variation may affect pressure response to changes in dietary sodium.Hypertension and type 2 diabetes are two chronic conditions associated epidemiologically and pathophysiologically. Hypertension is a well-known risk factor for diabetic vascular complications in type 1 diabetes and type 2 diabetes, and is a complex trait with an established heritability (1). Genome-wide association studies are complementary to a candidate gene approach and have helped to identify new genetic pathways involved in blood pressure (BP). However, only a few genetic associations have been clearly identified and replicated to date, leaving some impetus to search for new candidate genes.Diabetic patients differ from nondiabetic patients by having an increase in total body sodium (2,3), renal tubular sodium reabsorption, and an impaired ability to excrete a sodium load (4). These factors suggest that natriuretic peptides (NPs) may play a key role in the pathophysiology of hypertension in the diabetic population.The NP system regulates BP and fluid homeostasis by modifying glomerular filtration rate (GFR) and sodium urinary excretion. This system consists of a family of three peptidic hormones (A-type NP, B-type NP [BNP], and C-type NP) that interact with three receptors (NP receptor A, NP receptor B, and NP clearance receptor [NPRC]). The NPRC is encoded by the NPR3 gene and is a determinant of NP plasma concentration. Local expression of NPRC is linked to NP activity in the kidney (5,6). The intracellular domain of NPRC modulates the contraction/relaxation properties of smooth muscle cells (5). Genetic variation in the NPR3 may therefore affect the activity of NP through affecting plasma levels or NPRC-mediated vascular effects. The NPR3 is located on chromosome 5p14-p13. It spans ∼70 kb and contains eight exons and seven introns. Within the general population, allelic variants of the NPR3 gene have been reported to be associated with hypertension (6–8).This study aimed to assess the influence of genetic polymorphisms within NPR3 on BP in patients with type 2 diabetes. We first used a candidate gene approach in two independent large populations. We then completed our investigation with a sodium restriction functional study.     

Efficacy of two telemonitoring systems to improve glycaemic control during basal insulin initiation in patients with type 2 diabetes: The TeleDiab-2 randomized controlled trial

TeleDiab-2 was a 13-month randomized controlled trial evaluating the efficacy and safety of two telemonitoring systems to optimize basal insulin (BI) initiation in subjects with inadequately controlled type 2 diabetes (HbA1c, 7.5%-10%). A total of 191 participants (mean age 58.7 years, mean HbA1c 8.9%) were randomized into three groups: group 1(G1, standard care, n = 63), group 2 (G2, interactive voice response system, n = 64) and group 3 (G3, Diabeo-BI app software, n = 64). The two telemonitoring systems proposed daily adjustments of BI doses, in order to facilitate the achievement of fasting blood glucose (FBG) values targeted at ~100 mg/dL. At 4 months follow-up, HbA1c reduction was significantly higher in the telemonitoring groups (G2: −1.44% and G3: −1.48% vs. G1: −0.92%; P < 0.002). Moreover, target FBG was reached by twice as many patients in the telemonitoring groups as in the control group, and insulin doses were also titrated to higher levels. No severe hypoglycaemia was observed in the telemonitoring groups and mild hypoglycaemia frequency was similar in all groups. In conclusion, both telemonitoring systems improved glycaemic control to a similar extent, without increasing hypoglycaemic episodes.     

Rationale and design of the coronary artery calcium consortium: A multicenter cohort study

Background

Although coronary artery calcium (CAC) has been investigated for over two decades, there is very limited data on the association of CAC with cause of death. The CAC Consortium is a large ongoing multi-center observational cohort of individuals who underwent non-contrast cardiac-gated CAC testing and systematic, prospective, long-term follow-up for mortality with ascertainment of cause of death.

The evaluation of off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) randomized controlled trial: study design and rationale

Background

Off-loading is essential for diabetic foot management, but remains understudied. The evaluation of Off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) trial aims to evaluate the efficacy of a new removable device “Orthèse Diabète” in the healing of diabetic foot.

Methods/design

ORTHODIAB is a French multi-centre randomized, open label trial, with a blinded end points evaluation by an adjudication committee according to the Prospective Randomized Open Blinded End-point. Main endpoints are adjudicated based on the analysis of diabetic foot photographs. Orthèse Diabète is a new removable off-loading orthosis (PROTEOR, France) allowing innovative functions including real-time evaluation of off-loading and estimation of patients’ adherence. Diabetic patients with neuropathic plantar ulcer or amputation wounds (toes or transmetatarsal) are assigned to one of 2 parallel-groups: Orthèse Diabète or control group (any removable device) according to a central computer-based randomization. Study visits are scheduled for 6 months (days D7 and D14, and months M1, M2, M3, and M6). The primary endpoint is the proportion of patients whose principal ulcer is healed at M3. Secondary endpoints are: the proportion of patients whose principal ulcer is healed at M1, M2 and M6; the proportion of patients whose initial ulcers are all healed at M1, M2, M3, and M6; principal ulcer area reduction; time-related ulcer-free survival; development of new ulcers; new lower-extremity amputation; infectious complications; off-loading adherence; and patient satisfaction. The study protocol was approved by the French National Agency for Medicines and Health Products Safety, and by the ethics committee of Saint-Louis Hospital (Paris). Comprehensive study information including a Patient Information Sheet has been provided to each patient who must give written informed consent before enrolment. Monitoring, data management, and statistical analyses are providing by UMANIS Life Science (Paris), independently to the sponsor. Since 27/10/2013, 13 centres have agreed to participate in this study, 117 participants were included, and 70 have achieved the study schedules. The study completion is expected for the end of 2016, and the main results will be published in 2017.

Conclusion

ORTHODIAB trial evaluates an innovating removable off-loading device, seeking to improve diabetic foot healing (ClinicalTrials.gov identifier: NCT01956162).