Cardiovascular proteomics: past, present, and future

With cardiovascular (CV)-related disorders accounting for the highest mortality rates in the world, affecting the quantity and quality of life of patients and creating an economic burden of prolonged therapeutic intervention, there is great significance in understanding the cellular and molecular alterations that influence the progression of these pathologies. The cellular genotype is regulated by the DNA component, whilst the cellular phenotype is influenced by the protein complement. By improving the understanding of the molecular mechanisms that influence the protein profile, the pathologies that influence the intrinsic functions of the CV system may be detected earlier or managed more efficiently. This is achievable with technologies encompassed by 'proteomics.' Proteomic investigations of CV diseases, including dilated cardiomyopathy (DCM), atherosclerosis, and ischemia/reperfusion (I/R) injury, have identified candidate proteins altered with the pathologic states, complementing past biochemical and physiologic observations. Whilst proteomics is still a relatively new discipline to be applied to the basic scientific investigation of CV diseases, it is emerging as a technique to screen for potential biomarkers in both tissues/cells and biologic fluids (biofluids), as well as to identify the targets of existing therapeutics. By enabling the separation of complex mixtures over numerous dimensions, exploiting the intrinsic properties of proteins, including charge state, molecular mass, and hydrophobicity, in addition to cellular location, the discrete alterations within the cell may be resolved. Proteomics has shown alterations to myofilament proteins including troponin I and myosin light chain, correlating with the reduction in contractility in the myocardium from DCM and I/R. The diverse cell types that coalesce to induce atherosclerotic plaque formation have been investigated both collectively and individually to elucidate the influence of the modifications to single cell types on the developing plaque as a whole. Proteomics has also been used to observe changes to biofluids occurring with these pathologies, a new potential link between basic science and clinical applications. The development of CV proteomics has helped to identify a number of possible protein candidates, and offers the potential to treat and diagnose CV disease more effectively in the future.     

Cardiovascular genomics: recent progress, current challenges, future promise

A report from the second Annual Cardiovascular Genomics Meeting, Sponsored by Cambridge Healthtech, Inc., Miami, January 31-February 1, 2000.     

Cardiovascular autophagy

Despite recent scientific and technological advances, cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Autophagy, an evolutionarily ancient response to cellular stress, has been implicated in the pathogenesis of a wide range of heart pathologies. However, the precise role of autophagy in these contexts remains obscure owing to its multifarious actions. Here, we review recently derived insights regarding the role of autophagy in multiple manifestations of cardiac plasticity and disease.     

Inflammation, Coagulation and Cardiovascular Disease in HIV-Infected Individuals

Background

The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.

Methods

A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1^st quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.

Results

There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).

Conclusions

In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.     

Cardiovascular risk factors, erection disorders and endothelium dysfunction

Upon sexual stimulation, penile erection, occurring in response to the activation of pro-erectile autonomic pathways, is greatly dependent on adequate inflow of blood to the erectile tissue and requires coordinated arterial endothelium-dependent vasodilatation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. Nitric oxide (NO) is the principal peripheral pro-erectile neurotransmitter which is released by both non-adrenergic, non-cholinergic neurons and the sinusoidal endothelium to relax corporal smooth muscle through the cGMP pathway. Any factors modifying the basal corporal tone, the arterial inflow of blood to the corpora, the synthesis/release of neurogenic or endothelial NO are prime suspects for being involved in the pathophysiology of erectile dysfunction (ED). In fact, conditions associated with altered endothelial function, such as ageing, hypertension, hypercholesterolemia and diabetes, may, by changing the balance between contractant and relaxant factors, cause circulatory and structural changes in penile tissues, resulting in arterial insufficiency and defect in smooth muscle relaxation and thus, ED. There is increasing evidence to suggest that ED is predominantly a vascular disease and may even be a marker for occult cardiovascular disease. Recent results illustrating the importance of endothelial dysfunction in the pathophysiology of different forms of experimental ED are discussed. These pathways may represent new potential treatment targets.