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Jul 18, 2014

Molecular Diagnostics in Cardiovascular Disease

Novel gene expression tests could help clinicians make treatment decisions for heart disease patients.

Molecular Diagnostics in Cardiovascular Disease

Determination of an individual’s risk for severe arrhythmias before a life-threatening event occurs remains a significant medical challenge. [© kmiragaya - Fotolia.com]

  • Advances in molecular diagnostics, physicians say, have the potential to improve identification of cardiac diseases and further understanding of mechanisms responsible for their pathogenesis and phenotypic expression. These tests may also predict the need for specific treatment, or help avoid unnecessary therapies and invasive diagnostic procedures.

    And, scientists add, while genomic research in cardiovascular disease (CVD) has progressed rapidly over the last few years, “groundbreaking observations” have not yet been accompanied by clinically applicable tools for risk prediction, diagnosis, or therapeutic interventions.

    Schnabel and colleagues, writing in the Journal of Clinical Chemistry in 2012, anticipated that advances in key areas will be critical for the advancement of CVD genomics, including exome-centered and whole-genome next-generation sequencing that will identify rare and novel genetic variants associated with CVD and its risk factors.

    They further noted that static DNA sequence variation explains only a fraction of the inherited phenotype and expect that multiple epigenetic and gene expression signatures will be related to CVD in experimental and clinical settings.

    However, a few institutions and companies are developing gene expression tests that may, says the Schnabel team, help clinicians make treatment decisions for several types of heart disease.

    The University of Washington in St. Louis announced last year that it now offers clinicians genetic testing through the school’s Genomics and Pathology Services (GPS) to aid in diagnosing and treating heart disorders that could lead to sudden death. The test, called the Washington University CardioGene Set, analyzes genes linked to arrhythmias and cardiomyopathies, yielding a report based on patient blood samples submitted by their physicians. The cardiac testing panel includes genes linked to eight cardiac disorders that are characterized by arrhythmias or cardiomyopathies. Testing is traditionally offered one gene at a time, but the new test can report on as many as 69 genes.

    The testing panel analyzes, for example, the sequences of genes linked to long-QT syndrome, a rare inherited arrhythmia that lengthens the time between heartbeats, potentially causing heart palpitations or cardiac arrest. These genes can identify particular subtypes of long QT, distinguishing among forms of it that respond to different therapies to help guide treatment decisions.

    Patients with hypertrophic cardiomyopathy (HCM), a thickening of the heart muscle that can lead to sudden cardiac arrest and other problems, also can benefit, according to the GPS, from the CardioGene Set. HCM can cause sudden fatal cardiac arrest in young athletes who have not shown any prior symptoms of heart problems. Genetic diagnosis of this condition could lead physicians to advise a patient against physical overexertion, for example.

  • Common Clinical Challenge

    The determination of the underlying etiology of symptoms suggestive of coronary artery disease (CAD), which is defined as greater than or equal to ≥50% stenosis in a major coronary artery, presents a common clinical challenge in both primary care and cardiology clinics, according to physicians. Usual care, they say, in low to medium risk patients involves a family history, risk factor assessment, and then stress testing with or without noninvasive imaging. If positive, this is often followed by invasive coronary angiography. Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD.

    CardioDx, a Palo Alto-based molecular diagnostics company specializing in cardiovascular genomics, has developed the Corus® CAD blood-based gene expression test that it says can help physicians assess whether a patient's chest discomfort or other symptoms are due to obstructive CAD.

    Corus CAD uses real-time PCR to gauge mRNA expression in 23 genes to help physicians exclude obstructive coronary artery disease as the cause of cardiac symptoms in stable nondiabetic patients. The test yields a score from one to 40. For patients who receive a score below 15, CardioDx recommends doctors not refer them to cardiologists for additional costly and more invasive procedures.

    The company claims its test provides the first and only commercially available blood-based gene expression test that can assess current-state obstructive CAD in nondiabetic patients presenting with typical or atypical symptoms. With a 96% negative predictive value and 89% sensitivity, Corus CAD can help clinicians accurately rule out obstructive CAD as the source of their patients’ symptoms, so that they may investigate other noncardiac causes, according to the company.

    Severe cardiac arrhythmias, disturbances in normal heart electrical activity causing the heart to beat too fast, too slow, or irregularly, cause up to half a million deaths annually in the U.S. and about half of all mortality in patients with heart failure. Determination of an individual’s risk for severe arrhythmias before a life-threatening event occurs remains a significant medical challenge. A genomic test, the company says, may provide cardiologists a decision-making tool that will identify patients who would benefit most from an implantable cardioverter defibrillator.

    CardioDx is conducting a prospective, multicenter clinical study (DISCERN: Diagnostic Investigation of Sudden Cardiac Event Risk) aimed at developing and validating a genetics-based noninvasive test that will help identify ejection-fraction compromised patients at risk for sudden cardiac arrest.

    Last month, the company announced results of its The REGISTRY I study, which measured the impact of Corus CAD testing on primary care referral decisions among 342 patients in seven community-based primary care practices, based on each patient’s individualized gene expression score. Approximately 49% of patients had a low Corus CAD score, allowing their primary care providers to focus on other causes for their symptoms. Each 10-point decrease in a patient’s Corus CAD score was associated with 14-fold decreased odds of referral for further cardiac evaluation or testing. Additionally, the company said, patients with a low Corus CAD score had 94% reduced odds of referral relative to patients with an elevated Corus CAD score.

    In its initial try at an S-1 filing last October, the company said, “As healthcare reform is implemented, we expect that there will be even more emphasis placed on avoiding procedures that have a low probability of changing a clinical decision, especially in large patient populations with high treatment costs such as the [coronary artery disease] market. We believe the gatekeeper nature of the Corus CAD test is well suited for this evolving healthcare landscape.”

    As Enrique Lara-Pezzi, Ana Dopazo, and Miguel Manzanares noted in their 2012 paper, “Understanding cardiovascular disease: a journey through the genome (and what we found there),” while a genetic contribution to CVD has long been recognized, it has proved more challenging than anticipated to identify the precise genomic components responsible for the development of CVD.

    The authors pointed out that genome-wide association studies have provided information about specific genetic variations associated with CVD but are only beginning to reveal the underlying molecular mechanisms.

    Understanding the biological implications of these associations, they said, will require that they be related to “the exquisite, multilayered regulation of protein expression, which includes chromatin remodeling, regulatory elements, microRNAs, and alternative splicing.”

    Until that goal is achieved, practical approaches such as tests that can reduce the odds of making the wrong clinical call in terms of the need for invasive testing and choosing appropriate therapeutic interventions will likely prove more useful for multifactorial diseases.


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