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AMPD1 Genotype Predicts Survival in Patients with Heart Failure
Evan Loh, M.D.
Cardiovascular Division
University of Pennsylvania Health System
Philadelphia, PA, USA
  • Background
  • Molecular epidemiology in heart failure
  • AMPD1 locus
  • AMPD1 study
  • Adenosine as a modulator of survival
  • Clinical implications

  • Loh reviewed studies in their laboratory using a molecular epidemiology approach to determine whether the inheritance of the adenosine monophosphate deaminase-1 mutant (AMPD1) was a predictor of survival in patients with heart failure. A functional hypothesis for the roles of adenosine and AMPD1 in heart failure and its therapeutic implications were presented.




    Understanding the natural history of heart failure remains a challenge. Loh's view, yet to be proven, is that symptomatic heart failure, with its inevitable steep progression ending in death, is preceded by a very long asymptomatic phase in patients with left ventricular (LV) systolic dysfunction. Supporting evidence from the Framingham Heart Study was cited: after hospitalization with symptomatic heart failure the median survival for men is 1.7 years and for women 3.4 years. Comparing the survival of patients with heart failure and women with pre-menopausal breast carcinoma, a group perceived to have a very high morbidity and mortality rate, the 10-year survival of symptomatic heart failure patients is about 25-30% and for breast cancer patients about 50-55%.

    Limitations of univariate predictors

    Clinical, hemodynamic, neurohormonal, and functional parameters have limited usefulness in predicting survival in patients with heart failure, because they are 1) univariate, 2) cross-sectional and not followed serially, 3) the response to therapy is not incorporated, and 4) there is little understanding about how quickly longitudinal changes occur.

    Several parameters that are known to reflect worsening heart failure are not used in clinical practice and provide little information that is relevant in an individual patient. Increasing levels of norepinephrine in patients with more advanced disease is associated with worsening survival. Large population-based studies show outcomes are worse with lower left ventricular ejection fractions (LVEF). But, LVEF is not an important predictor of exercise capacity or long-term natural history. Data from the post-infarction study by Moss clearly show that one-year mortality increases as LVEF falls. However, resting LVEF and exercise capacity have little correlation. Data from the Ve-HeFT studies of nearly 1300 patients who underwent metabolic stress testing showed virtually no correlation between LVEF and VO2 maximum, with r values less than 0.2.

    Data from Mancini of patients referred for heart transplantation evaluation showed that patients with significantly reduced VO2 maximum had a 50-60% one year mortality. The data further show that exercise performance was the only predictor of long-term survival. LVEF and norepinephrine levels are not used carefully as predictors of survival, and exercise capacity has been relied on heavily.

    Thus, Loh thinks the development of symptomatic heart failure dramatically changes the slope of the natural history deterioration curve. The SAVE trial showed that in post-infarct patients randomized to either captopril or placebo, the captopril-treated patients had an overall 19% reduction in overall cardiovascular (CV) mortality (p=0.019). These asymptomatic patients had a 4-year mortality rate of 20-25%. Mortality following first hospitalization for heart failure more than doubled in the captopril-treated group to 50-55% at 4 years. In the placebo group the mortality was nearly 70%.



    Molecular epidemiology in heart failure

    A molecular epidemiology approach was used to determine predictors of survival in patients with heart failure. The genetic background of a person likely plays a role in determining the response to the complex pathophysiology of heart failure. To date, genetic determinants of prognosis and survival in patients with heart failure have not been established.

    Molecular epidemiology seeks to determine whether a biologically-plausible candidate gene with an association to a well-defined disease affects 1) etiology, 2) risk stratification, 3) prognosis, and 4) design of novel therapeutic interventions. In contrast to identifying genes that cause a disease, this approach seeks to identify genes that modify the natural history.

    Establishing a causal relationship

    To establish a causal relation between a mutant allele and a clinical phenotype, an increased frequency of the mutant allele in persons with phenotypic characteristics of the disease is needed. This causal relation will likely be useful to identify genes that produce or modify symptoms later in life, and hopefully to provide a rationale for investigating the biochemical and/or physiologic basis of disease progression.

    This approach has proven useful in identifying "disease-modifying" loci in a variety of disease states: 1) apolipoprotein E e2 allele and longevity, 2) apolipoprotein E e4 allele and Alzheimer's disease, 3) CCR-5 chemokine receptor gene mutation and resistance to HIV-1 infection, 4) NRAMP1 polymorphism and susceptibility to tuberculosis in West Africans, and 5) CETP polymorphism and the progression of coronary atherosclerosis.



    AMPD1 locus

    The AMPD1 locus identifies and transcribes the enzyme adenosine monophosphate deaminase (AMPD) located on the human chromosome in the p13 region. AMPD1 is putatively the most common single point mutation in the Caucasian and African American populations, with a heterozygous frequency of about 20%, and a homozygote recessive frequency of about 3-4%. It identifies a single non-lethal point mutation in the second exon, resulting in a nonsense mutation. Affected persons develop a skeletal muscle myopathy characterized by impaired exercise capacity and the potential to produce increased circulating levels of adenosine_relating to the theme of exercise capacity as a good predictor of survival in patients with heart failure.

    AMPD is driven by AMP levels in ATP catabolism during times of exercise or stress. AMP is catabolized to IMP in patients with two normal copies of the gene, therefore providing fumarate for the purine nucleotide cycle to allow regeneration of ATP. In persons with a defective enzyme, AMP is shuttled via 5'nucleotidase and de-phosphorylates with adenosine.

    This increased potential capacity to produce increased circulating levels of adenosine with exercise is important because adenosine is 1) a putative modulator of the ischemic preconditioning response, 2) a potent coronary and arteriolar vasodilator, 3) anti-adrenergic, 4) anti-inflammatory, and 5) has anti-arrhythmic properties. These factors provide an opportunity to intervene in the progression cascade of heart failure at an early stage, perhaps in the asymptomatic phase.

    Plasma concentrations of hypoxanthine and ammonia decrease and plasma concentrations of adenosine increase in proportion to the severity of heart failure. Their hypothesis is that the ability to understand modulation of AMP levels in relation to production of circulating adenosine may lead to a permissive effect that improves the prognosis of patients with symptomatic heart failure.



    AMPD1 study


    To determine if the inheritance of the mutant AMPD1 allele was associated with increased survival duration in patients with symptomatic heart failure, a series of 132 patients referred for heart failure transplantation evaluation were studied. The mean age was 52.8 +/- 11.2 years, mean LVEF 19.7 +/- 6.7%, and VO2 max 13.9 +/- 4.9 ml/kg/min. Etiology of heart failure was coronary artery disease in 69 patients, idiopathic cardiomyopathy in 48, and other in 15. The baseline characteristics are shown in Table 1.

    A simple AMPD1 allele-specific oligonucleotide detection assay was used. For each patient, clinical phenotypic data was collected and AMPD1 genotyping performed.

    Figure 1. Probability of survival without cardiac transplantation in heart failure patients stratified across AMPD1genotype by Kaplan-Meier analysis. The two curves are statistically different (P=0.002). (Circulation 1999;99:1422-1425.)
    Click to enlarge
    Reprinted with permission from Lippincott Williams and Wilkins (www.lww.com).
    Twenty-one of the 132 patients were either heterozygous or homozygous recessive for the mutation. These 21 patients had a significantly longer duration of heart failure symptoms before presentation, compared to those without the mutation (7.6 +/-6.5 yrs vs 3.2 +/- 3.6 yrs, respectively). There was virtually no difference between these groups in terms of age, VO2 max, LVEF, cardiac index, pulmonary capillary wedge pressure, and pulmonary vascular resistance.
    Figure 1 shows the probability of survival without heart transplant based on AMPD1 gentotype.

    Study results

    The patients with either one or two copies of the mutation had a significantly better survival at 15 years of nearly 70-72%, compared to patients without either one or two copies of the mutation. This was based on a retrospective review from the time of presentation of symptomatic heart failure to time of presentation for evaluation and/or death. The single most important multivariate predictor was inheritance of the AMPD1 allele, with a hazard ratio of 4.65 (95% CI 1.48-14.68; p=0.009). As shown in Table 2, independent multivariate predictors of survival were identified to be: use of diuretics (HR 0.31, 95% CI 0.11-0.83, p=0.02), ischemic cardiomyopathy (HR 2.93, 95% CI 1.39-6.19, p=0.005), a lower VO2 max (HR 0.80, 95% CI 0.72-0.89, p=0.001), and greater age (HR 0.92, 95% CI 0.89-0.95, p=0.001).

    In patients with advanced heart failure, the inheritance of the mutant AMPD1 allele is associated with a 1) milder clinical natural history, and 2) prolonged survival after the onset of symptomatic heart failure symptoms.

    Study limitations

    The limitations in this retrospective association study include: 1) a selective patient population of inference, 2) other potentially beneficial effects of reduced AMPD activity can not be excluded, and 3) another polymorphism in another gene on chromosome 1 may be in linkage disequilibrium with AMPD1, and it alone or in conjunction with AMPD1 may be responsible for the observed clinical benefit.



    Adenosine as a modulator of survival

    In collaboration with Hisatomi, using human tissue taken during heart transplantation, they showed that the AMPD1 isoform was found only in the right atrium.

    Therefore, they believe that AMPD1 is important at either an autocrine or paracrine level for cardiac myocyte production, directing attention to the skeletal muscle to understand how the modulation of circulating adenosine levels may be based on changes in skeletal muscle physiology.

    Preliminary data showed that patients with more preserved exercise capacity had higher levels of circulating adenosine. Patients with asymptomatic heart failure were exercised. Baseline and peak exercise levels of norepinephrine and adenosine were measured. Group A was comprised of 26 patients with relatively impaired VO2 max (cut-off of 16 ml/kl/min) and Group B was comprised of 27 patients with better preserved exercise capacity. Both groups had a significant increase in serum levels of circulating norepinephrine. But, the patients with better preserved exercise capacity (greater mean level of VO2 max) had a much greater increase in circulating levels of adenosine, (150 pg/ml at baseline vs 180 at peak VO2 in Group A, 110 pg/ml at baseline vs 170 at peak VO2 in Group B, p<0.0001.

    Functional hypothesis

    A link between skeletal muscle and cardiac physiology is provided by the belief that the skeletal muscle is the potential source of adenosine. Persons with the AMPD1 mutation produce higher circulating levels of adenosine, which can go to the heart and modulate ventricular function, coronary vasodilator function, and also potentially vascular function by modulating and counteracting the deleterious effects of increased levels of norepinephrine that are well characterized in patients with heart failure. Therefore, adenosine can work as a compensatory mechanism to stabilize patients with heart failure, and decrease the deterioration seen in patients with symptomatic heart failure. This hypothesis remains to be proven.



    Clinical implications

    Inhibition of AMP deaminase and/or regulation of adenosine production may present novel therapeutic targets to change the natural history of heart failure. Molecular epidemiology techniques offer promise for identification of disease modifying loci in common complex disorders such as heart failure. A genetic and biochemical plausibility to the hypothesis is required; at least one plausible hypothesis based on their data has been developed. The clinical importance of the observation is dependent upon an understanding of the genetic makeup of the population of inference. The gene of interest must cause relevant and important changes in structure or function at the level of the gene product; this remains the principle experiment they must prove using genotyping.

    Future work includes: 1) amplifying the genotype-phenotype association based on whether or not this is an inherited mutation, 2) to risk stratify future populations based on these studies in a prospective manner (a large prospective study is ongoing), and 3) develop translational interventions based on the combined understanding of the molecular and biochemical bases of the disease process.



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