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Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Rose JJ, Voora D, Cyr DD, Lucas JE, Zaas AK, Woods CW, Newby LK, Kraus WE, Ginsburg GS - PLoS ONE (2015)

Bottom Line: A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17).A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation.Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.

Methods: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status.

Results: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04).

Conclusions: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

No MeSH data available.


Related in: MedlinePlus

Design of viral exposure of infection cohort patients.Four cohorts of healthy volunteers were exposed to different viruses (H1N1—Influenza A (A/Brisbane/59/2007); H3N2—Influenza A A/Wisconsin/67/2005 (H3N2); HRV—Human rhinovirus; RSV—Respiratory Syncytial Virus). Blood RNA data were collected at baseline and at additional timepoints following viral exposure to assess for changes in the platelet gene expression signature (platelet GES) (S1 Table) Median time post exposure for peak symptom of each respective virus is shown (in hours). The point of treatment with Tamiflu (H1N1 and H3N2) or release from quarantine is shown as end of arrow (in hours). The final numbers of symptomatic (symp) or a symptomatic (asymp) status of each cohort is also shown.
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pone.0132259.g001: Design of viral exposure of infection cohort patients.Four cohorts of healthy volunteers were exposed to different viruses (H1N1—Influenza A (A/Brisbane/59/2007); H3N2—Influenza A A/Wisconsin/67/2005 (H3N2); HRV—Human rhinovirus; RSV—Respiratory Syncytial Virus). Blood RNA data were collected at baseline and at additional timepoints following viral exposure to assess for changes in the platelet gene expression signature (platelet GES) (S1 Table) Median time post exposure for peak symptom of each respective virus is shown (in hours). The point of treatment with Tamiflu (H1N1 and H3N2) or release from quarantine is shown as end of arrow (in hours). The final numbers of symptomatic (symp) or a symptomatic (asymp) status of each cohort is also shown.

Mentions: Four separate healthy volunteer cohorts were each exposed to a different viral strain, and then monitored for symptoms, and RNA was ascertained at different time points as previously described [9][11] (Fig 1). In general, “healthy” was defined as absence of any significant acute or chronic, uncontrolled medical or psychiatric illness, that in was associated with increased risk of complications of respiratory viral illness (subjects with uncomplicated chronic diagnoses stable and treated for three [3] months, e.g., mild hypertension well-controlled with medication, were enrolled—provided the condition and its therapy are not known to be associated with an immunocompromised state or increased risk of complications of respiratory viral illness). Although certain concomitant medications were allowed, none were on aspirin at the time of viral challenge. Subjects were classified as symptomatic vs. asymptomatic based on the Modified Jackson Score [15][16][17].


Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction.

Rose JJ, Voora D, Cyr DD, Lucas JE, Zaas AK, Woods CW, Newby LK, Kraus WE, Ginsburg GS - PLoS ONE (2015)

Design of viral exposure of infection cohort patients.Four cohorts of healthy volunteers were exposed to different viruses (H1N1—Influenza A (A/Brisbane/59/2007); H3N2—Influenza A A/Wisconsin/67/2005 (H3N2); HRV—Human rhinovirus; RSV—Respiratory Syncytial Virus). Blood RNA data were collected at baseline and at additional timepoints following viral exposure to assess for changes in the platelet gene expression signature (platelet GES) (S1 Table) Median time post exposure for peak symptom of each respective virus is shown (in hours). The point of treatment with Tamiflu (H1N1 and H3N2) or release from quarantine is shown as end of arrow (in hours). The final numbers of symptomatic (symp) or a symptomatic (asymp) status of each cohort is also shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507878&req=5

pone.0132259.g001: Design of viral exposure of infection cohort patients.Four cohorts of healthy volunteers were exposed to different viruses (H1N1—Influenza A (A/Brisbane/59/2007); H3N2—Influenza A A/Wisconsin/67/2005 (H3N2); HRV—Human rhinovirus; RSV—Respiratory Syncytial Virus). Blood RNA data were collected at baseline and at additional timepoints following viral exposure to assess for changes in the platelet gene expression signature (platelet GES) (S1 Table) Median time post exposure for peak symptom of each respective virus is shown (in hours). The point of treatment with Tamiflu (H1N1 and H3N2) or release from quarantine is shown as end of arrow (in hours). The final numbers of symptomatic (symp) or a symptomatic (asymp) status of each cohort is also shown.
Mentions: Four separate healthy volunteer cohorts were each exposed to a different viral strain, and then monitored for symptoms, and RNA was ascertained at different time points as previously described [9][11] (Fig 1). In general, “healthy” was defined as absence of any significant acute or chronic, uncontrolled medical or psychiatric illness, that in was associated with increased risk of complications of respiratory viral illness (subjects with uncomplicated chronic diagnoses stable and treated for three [3] months, e.g., mild hypertension well-controlled with medication, were enrolled—provided the condition and its therapy are not known to be associated with an immunocompromised state or increased risk of complications of respiratory viral illness). Although certain concomitant medications were allowed, none were on aspirin at the time of viral challenge. Subjects were classified as symptomatic vs. asymptomatic based on the Modified Jackson Score [15][16][17].

Bottom Line: A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17).A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation.Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI.

View Article: PubMed Central - PubMed

Affiliation: Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT

Background: Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.

Methods: A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status.

Results: In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04).

Conclusions: A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.

No MeSH data available.


Related in: MedlinePlus