Molecular Mechanisms of Myocardial Infarction
Section snippets
The Inflamed Artery and Vulnerable Plaque
MI is the result of a series of complex events determined by the interaction between a person’s inherent genetic makeup and the interplay with various environmental factors. With atherosclerotic plaque nearly endemic in the population, the genesis of a MI involves factors that allow the maturing plaque to fissure and expose the lipid-laden core of the plaque to the circulating blood components. The process culminates in acute thrombus formation over the plaque with abrupt vessel closure.
The Leukocyte
An elevated white blood cell count is a nonspecific marker of inflammation and leukocytosis was recognized to be an early marker of adverse prognosis associated with MI.11, 12, 13 These initial observations have been confirmed in multiple large studies and expanded into patients undergoing both surgical and percutaneous revascularization.14, 15 These findings are not surprising since the white blood cell is the core cellular mediator of the inflammatory cascade.
Poor outcomes in patients with an
Components of the Inflammatory Cascade
Neutrophils and leukocytes contain and release many important mediators of the inflammatory cascade such as interleukins, myeloperoxidase, and C-reactive protein (CRP). These protein mediators have all been associated with the increasing risk for transformation of a stable plaque to a vulnerable one and their serum levels are correlated with increased risk for adverse events.18, 19, 20 Validation of these proteins as risk markers for poor outcomes has contributed to an era of cardiovascular
CRP—The Role Model for the Biomarker Era
CRP is prototypic of the biomarker era of cardiovascular medicine, an informative era based on new insight of the underlying pathobiology and activity of the disease state. The role of CRP in identifying those with increased risk is now well established. The recent CDC-AHA guidelines have incorporated CRP testing into their guidelines for identifying and treating patients at risk.22 There is now little debate as to the importance of CRP in the process of risk stratification for patients with
The New Era of Sequenced-Based Medicine
Identification of protein biomarkers associated with MI has led to a more detailed understanding of the underlying pathogenesis leading to plaque rupture. Similarly, the description of several genetic markers associated with MI has continued to elucidate on many new underlying molecular mechanisms. Discovery of these novel markers of genetic risk also presents new opportunities to eventually determine an individual’s risk of MI based on their inherited predisposition. Just as we will soon be
High-Throughput SNP Association Studies
Newer techniques allow high-throughput genotyping and enable assay of large numbers (hundreds to thousands) of polymorphisms. To date, several large SNP association studies have been conducted. The results of these studies have highlighted many new gene targets, some of which were previously unknown to participate in the genesis of coronary disease and MI. Not surprisingly, many of these new genes have an important role in the inflammatory process and in endothelial cell biology.
The GENEQUEST
Genome-Wide Scanning
In addition to high-throughput SNP studies, genome-wide scanning has illuminated other specific genes and markers for CAD and MI. In SNP association studies, specific gene candidates are identified and evaluated for association with a particular phenotype. In traditional genome-wide scans, approximately 400 microsatellites (short-tandem repeat markers), evenly spaced every 10 cM across the genome, are evaluated to search for a linkage peak of shared alleles across patients with a phenotype of
Genome-Wide Scans With Successful Fine Mapping and Positional Cloning
One genome-wide scan in 298 Icelandic families with MI has been successful in identifying the linkage peak to be 5-lipoxygenase activating peptide (FLAP). Using genome-wide scanning and SNP analysis, Helgadottir and coworkers implicated the leukotriene biosynthetic pathway in the pathogenesis of atherosclerosis and MI. The Helgadottir group identified a four-marker haplotype in FLAP that is associated with a twofold increased risk of MI and cerebral vascular accident in Iceland.52 This study
Lymphotoxin-α and Galectin-2: More Evidence for the Role of Inflammation in MI
Lymphotoxin-α, also known as TNF-β, is a cytokine and has multiple functions in the regulation of the immune system and in inflammatory reactions.66 Variants of the enzyme have been reported in inflammatory conditions such as asthma and rheumatoid arthritis.67, 68 Using genome-wide screening with SNP markers spanning the genome and subsequent functional fine mapping, Ozaki and coworkers found variants of lymphotoxin-α and an associated protein galectin-2 to be associated with the underlying
Enriched Pedigree Analysis and MEF2A
In addition to genome-wide scanning and high-throughput SNP analysis, Wang and coworkers recently reported a large pedigree analysis from an extended family enriched for CAD defined by a history of MI or surgical or percutaneous revascularization.72 Thirteen affected subjects from this kindred were identified and the phenotype displayed an autosomal-dominant form of inheritance. Nine of the 13 subjects developed MI (Fig 26). Using a genome-wide scan linkage analysis of 382 microsatellite
“Are We There Yet?”
The utilization of new molecular technologies has created the opportunity to understand and describe the mechanisms involved in the development of atherogenesis and MI. The knowledge of the molecular pathogenesis of CAD and MI continues to rapidly advance and provide clues beyond simple clinical risk factors, which are omnipresent in our society. Clinical application of this knowledge has facilitated identification of novel risk factors for adverse events. MI is a complex disease based on the
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Dr. Jefferson and Dr. Topol have no conflict of interest to disclose.