Publications

BACKGROUND

Distal coronary artery disease (CAD) is less amenable to surgery or stenting compared with proximal disease. However, little is known about the epidemiology of distal versus proximal CAD.

METHODS

We determined the prevalence and factors associated with proximal, mid, and distally located plaque in the left anterior descending, left circumflex, and right coronary arteries in 418 subjects without prior CAD history who underwent coronary computed tomographic angiography for symptoms or stress test results. Clinical characteristics and coronary artery calcium (CAC) scores were also determined.

RESULTS

Most subjects (88%) had plaque, but only 18% of plaques were associated with stenosis >50%. In subjects with single-vessel plaque, only 7% had distal plaque, whereas 75% had proximal plaque. With 3-vessel plaque, 70% had distal and 100% had proximal plaques. Of subjects with a single location of plaque along a vessel, most had proximal plaque (69%); isolated distal-vessel plaque was rare (2%). Distal plaque was dominantly found in association with both proximal and mid plaque (88%). After multivariable adjustment for demographics, traditional, and nontraditional risk factors, both increasing number of vessels with plaque and clinically significant CAC scores were independently associated with higher odds of distal plaque, whereas associations of traditional risk factors were weaker. Distal plaque was independently associated with stenosis > 50%.

CONCLUSION

These data support the concept that early lesions are most often proximal and that CAC scoring may be a poor screening tool for detecting proximal disease. Furthermore, distal lesions are more associated with advanced disease than with traditional cardiovascular risk factors.

Cyclin D1 belongs to the core cell cycle machinery, and it is frequently overexpressed in human cancers. The full repertoire of cyclin D1 functions in normal development and oncogenesis is unclear at present. Here we developed Flag- and haemagglutinin-tagged cyclin D1 knock-in mouse strains that allowed a high-throughput mass spectrometry approach to search for cyclin D1-binding proteins in different mouse organs. In addition to cell cycle partners, we observed several proteins involved in transcription. Genome-wide location analyses (chromatin immunoprecipitation coupled to DNA microarray; ChIP-chip) showed that during mouse development cyclin D1 occupies promoters of abundantly expressed genes. In particular, we found that in developing mouse retinas-an organ that critically requires cyclin D1 function-cyclin D1 binds the upstream regulatory region of the Notch1 gene, where it serves to recruit CREB binding protein (CBP) histone acetyltransferase. Genetic ablation of cyclin D1 resulted in decreased CBP recruitment, decreased histone acetylation of the Notch1 promoter region, and led to decreased levels of the Notch1 transcript and protein in cyclin D1-null (Ccnd1(-/-)) retinas. Transduction of an activated allele of Notch1 into Ccnd1(-/-) retinas increased proliferation of retinal progenitor cells, indicating that upregulation of Notch1 signalling alleviates the phenotype of cyclin D1-deficiency. These studies show that in addition to its well-established cell cycle roles, cyclin D1 has an in vivo transcriptional function in mouse development. Our approach, which we term 'genetic-proteomic', can be used to study the in vivo function of essentially any protein.

The 1000 Genomes Project, an international collaboration, is sequencing the whole genome of approximately 2,000 individuals from different worldwide populations. The central goal of this project is to describe most of the genetic variation that occurs at a population frequency greater than 1%. The results of this project will allow scientists to identify genetic variation at an unprecedented degree of resolution and will also help improve the imputation methods for determining unobserved genetic variants that are not represented on current genotyping arrays. By identifying novel or rare functional genetic variants, researchers will be able to pinpoint disease-causing genes in genomic regions initially identified by association studies. This level of detailed sequence information will also improve our knowledge of the evolutionary processes and the genomic patterns that have shaped the human species as we know it today. The new data will also lay the foundation for future clinical applications, such as prediction of disease susceptibility and drug response. However, the forthcoming availability of whole genome sequences at affordable prices will raise ethical concerns and pose potential threats to individual privacy. Nevertheless, we believe that these potential risks are outweighed by the benefits in terms of diagnosis and research, so long as rigorous safeguards are kept in place through legislation that prevents discrimination on the basis of the results of genetic testing.

CONTEXT

Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood.

OBJECTIVE

To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age.

DESIGN, SETTING, AND PARTICIPANTS

Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years).

MAIN OUTCOME MEASURES

We measured leukocyte telomere length at baseline and again after 5 years of follow-up. Multivariable linear and logistic regression models were used to investigate the association of baseline levels of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) with subsequent change in telomere length.

RESULTS

Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). Levels of DHA+EPA were associated with less telomere shortening before (unadjusted beta coefficient x 10(-3) = 0.06; 95% CI, 0.02-0.10) and after (adjusted beta coefficient x 10(-3) = 0.05; 95% CI, 0.01-0.08) sequential adjustment for established risk factors and potential confounders. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98).

CONCLUSION

Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.